Genitourinary Cancer

Combining magnetic resonance imaging (MRI)–targeted biopsy and systematic biopsy improved detection of prostate cancer among men with MRI-visible lesions in a single-center study.

Compared with either method alone, a combination of the two biopsy methods resulted in 9.9% more prostate cancer diagnoses, explained study author Michael Ahdoot, MD, of the National Institutes of Health and colleagues. Their report was published in the New England Journal of Medicine.

“With the addition of MRI-targeted biopsy to systematic biopsy, we may have entered an era of increased diagnostic certainty in prostate cancer,” the researchers wrote.

Their single-center, comparative diagnostic study included 2,103 patients with MRI-visible prostate lesions who underwent both systematic and MRI-targeted biopsy. In cases of multiple biopsies, only the results of the initial biopsies were included.

Each individual specimen was assigned a Gleason score by a genitourinary pathologist and was subsequently categorized into a grade group on a scale of 1-5, with higher scores reflecting greater cancer risk. Grade group 1 was defined as clinically insignificant disease. Grade group 2 was defined as favorable intermediate-risk disease. Grade group 3 or higher was defined as unfavorable intermediate-risk disease or worse.

The primary endpoints were cancer detection rates for each biopsy method, based on grade group. “Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens [was also assessed],” the researchers explained.

Among patients who underwent combined biopsy, prostate cancer was identified in 62.4% of patients, and 19.2% underwent radical prostatectomy.

For grade groups 3-5, rates of cancer detection were significantly higher with MRI-targeted biopsy than with systematic biopsy (P less than .01 for all). For grade group 1, detection rates were significantly lower with MRI-targeted biopsy (P less than .01).

“Although many of [the] benefits resulted from MRI-targeted biopsy alone, omission of systematic biopsy would have led to missing the diagnosis of 8.8% of clinically significant cancers,” the researchers reported.

In addition, among patients who underwent radical prostatectomy, the rates of upgrading (grade group 3 or higher) on histopathological analysis were lower for combined biopsy (3.5%) than for MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%).

The researchers acknowledged that a key limitation of this study was the single-center design. As a result, the findings may not be generalizable to other institutions.

However, the researchers concluded that “these findings suggest that combined biopsy provides improved diagnostic accuracy over either systematic or MRI-targeted biopsy alone and better predicts the results of final histopathological analysis.”

The study was funded by the National Institutes of Health, Philips, and the Dr. Mildred Scheel Foundation for Cancer Research. The authors disclosed financial affiliations with Philips, Biocompatibles UK, Boston Scientific, Celsion, and other companies.

SOURCE: Ahdoot M et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1910038.

Combining magnetic resonance imaging (MRI)–targeted biopsy and systematic biopsy improved detection of prostate cancer among men with MRI-visible lesions in a single-center study.

Compared with either method alone, a combination of the two biopsy methods resulted in 9.9% more prostate cancer diagnoses, explained study author Michael Ahdoot, MD, of the National Institutes of Health and colleagues. Their report was published in the New England Journal of Medicine.

“With the addition of MRI-targeted biopsy to systematic biopsy, we may have entered an era of increased diagnostic certainty in prostate cancer,” the researchers wrote.

Their single-center, comparative diagnostic study included 2,103 patients with MRI-visible prostate lesions who underwent both systematic and MRI-targeted biopsy. In cases of multiple biopsies, only the results of the initial biopsies were included.

Each individual specimen was assigned a Gleason score by a genitourinary pathologist and was subsequently categorized into a grade group on a scale of 1-5, with higher scores reflecting greater cancer risk. Grade group 1 was defined as clinically insignificant disease. Grade group 2 was defined as favorable intermediate-risk disease. Grade group 3 or higher was defined as unfavorable intermediate-risk disease or worse.

The primary endpoints were cancer detection rates for each biopsy method, based on grade group. “Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens [was also assessed],” the researchers explained.

Among patients who underwent combined biopsy, prostate cancer was identified in 62.4% of patients, and 19.2% underwent radical prostatectomy.

For grade groups 3-5, rates of cancer detection were significantly higher with MRI-targeted biopsy than with systematic biopsy (P less than .01 for all). For grade group 1, detection rates were significantly lower with MRI-targeted biopsy (P less than .01).

“Although many of [the] benefits resulted from MRI-targeted biopsy alone, omission of systematic biopsy would have led to missing the diagnosis of 8.8% of clinically significant cancers,” the researchers reported.

In addition, among patients who underwent radical prostatectomy, the rates of upgrading (grade group 3 or higher) on histopathological analysis were lower for combined biopsy (3.5%) than for MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%).

The researchers acknowledged that a key limitation of this study was the single-center design. As a result, the findings may not be generalizable to other institutions.

However, the researchers concluded that “these findings suggest that combined biopsy provides improved diagnostic accuracy over either systematic or MRI-targeted biopsy alone and better predicts the results of final histopathological analysis.”

The study was funded by the National Institutes of Health, Philips, and the Dr. Mildred Scheel Foundation for Cancer Research. The authors disclosed financial affiliations with Philips, Biocompatibles UK, Boston Scientific, Celsion, and other companies.

SOURCE: Ahdoot M et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1910038.

Combining magnetic resonance imaging (MRI)–targeted biopsy and systematic biopsy improved detection of prostate cancer among men with MRI-visible lesions in a single-center study.

Compared with either method alone, a combination of the two biopsy methods resulted in 9.9% more prostate cancer diagnoses, explained study author Michael Ahdoot, MD, of the National Institutes of Health and colleagues. Their report was published in the New England Journal of Medicine.

“With the addition of MRI-targeted biopsy to systematic biopsy, we may have entered an era of increased diagnostic certainty in prostate cancer,” the researchers wrote.

Their single-center, comparative diagnostic study included 2,103 patients with MRI-visible prostate lesions who underwent both systematic and MRI-targeted biopsy. In cases of multiple biopsies, only the results of the initial biopsies were included.

Each individual specimen was assigned a Gleason score by a genitourinary pathologist and was subsequently categorized into a grade group on a scale of 1-5, with higher scores reflecting greater cancer risk. Grade group 1 was defined as clinically insignificant disease. Grade group 2 was defined as favorable intermediate-risk disease. Grade group 3 or higher was defined as unfavorable intermediate-risk disease or worse.

The primary endpoints were cancer detection rates for each biopsy method, based on grade group. “Among the men who underwent subsequent radical prostatectomy, upgrading and downgrading of grade group from biopsy to whole-mount histopathological analysis of surgical specimens [was also assessed],” the researchers explained.

Among patients who underwent combined biopsy, prostate cancer was identified in 62.4% of patients, and 19.2% underwent radical prostatectomy.

For grade groups 3-5, rates of cancer detection were significantly higher with MRI-targeted biopsy than with systematic biopsy (P less than .01 for all). For grade group 1, detection rates were significantly lower with MRI-targeted biopsy (P less than .01).

“Although many of [the] benefits resulted from MRI-targeted biopsy alone, omission of systematic biopsy would have led to missing the diagnosis of 8.8% of clinically significant cancers,” the researchers reported.

In addition, among patients who underwent radical prostatectomy, the rates of upgrading (grade group 3 or higher) on histopathological analysis were lower for combined biopsy (3.5%) than for MRI-targeted biopsy (8.7%) and systematic biopsy (16.8%).

The researchers acknowledged that a key limitation of this study was the single-center design. As a result, the findings may not be generalizable to other institutions.

However, the researchers concluded that “these findings suggest that combined biopsy provides improved diagnostic accuracy over either systematic or MRI-targeted biopsy alone and better predicts the results of final histopathological analysis.”

The study was funded by the National Institutes of Health, Philips, and the Dr. Mildred Scheel Foundation for Cancer Research. The authors disclosed financial affiliations with Philips, Biocompatibles UK, Boston Scientific, Celsion, and other companies.

SOURCE: Ahdoot M et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1910038.

SAN FRANCISCO – A large share of men with testicular cancer undergoing postchemotherapy retroperitoneal lymph node dissection (RPLND) may be having organs unnecessarily removed at the time, a retrospective analysis suggests.

However, determining which of these patients do not require adjunct resection remains challenging, according to Tim Nestler, MD, of the University Hospital of Cologne in Germany.

Dr. Nestler presented the retrospective analysis at the the 2020 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Nestler and his colleagues analyzed the frequency and pathologic findings of adjunctive organ resection (encompassing organs, blood vessels, and bones) among 1,181 men undergoing postchemotherapy RPLND during 2008-2018.

Adjunctive organ resection was performed in 20% of patients. Pathologic evaluation of the resection specimens showed viable germ cell tumors in 21.7% of these patients, teratomas in 38.7%, and necrosis or fibrosis in 39.6%. The prevalence of necrosis/fibrosis was generally similar across various organs, blood vessels, and bones.

At a median follow-up of 22 months, 27% of the study cohort experienced a relapse. The 5-year rate of relapse-free survival was 18% for patients with viable germ cell tumors in adjunctively resected organs, 54% for those with teratomas, and 81% for those with necrosis/fibrosis.

“Within this cohort, about 40% of all resections finally showed necrosis/fibrosis, and these are patients that were kind of unnecessarily treated from the oncological standpoint,” Dr. Nestler said, although he noted that such resections should continue until there is a reliable way to identify this subset of patients.

“We are thinking of increasing the rate of frozen sections within surgery, especially to avoid nephrectomies, hepatectomies, and vascular resections,” he said. “Or, if we are thinking about bone metastasis, then we also might think about presurgical biopsies.”

Stepping back even further, clinicians could do “a more accurate presurgical work-up to identify those patients that are really in need of postchemotherapy RPLND, compared to those who will have a high chance of showing necrosis/fibrosis,” Dr. Nestler said. “Here, we are currently working on means like radiomics and molecular markers.”
 

Implications for patient counseling

“The problem is, and this is the central crux of the issue, that we cannot accurately identify ‘cancer or teratoma’ from ‘not cancer or teratoma’ prior to surgery,” said session cochair Brant A. Inman, MD, of the Duke Prostate and Urologic Cancer Center in Durham, N.C.

Preoperative biopsies are not helpful in differentiating these groups because of their technical difficulty and very high false-negative rate, Dr. Inman said. And intraoperative biopsies with frozen sections have the same sampling problem, plus problems of diagnostic accuracy and differentiation of live from dead tumor.

“This research is mainly helpful for preoperative patient counseling,” Dr. Inman said. “You have to tell your patient prior to RPLND, especially if they have a large postchemotherapy mass, several things.”

Specifically, patients should be informed about the probability of needing adjunctive resection and what that entails, he said. If this additional surgery is needed, patients should be informed of the probability that the tissues removed will not contain any cancer or teratoma. Moreover, “if this is the case, the blood vessel or organ will likely have been removed without benefit to you,” he added.

Finally, patients should be told that “there is no accurate way presently to distinguish cancer/teratoma from necrosis/fibrosis preoperatively or intraoperatively, including imaging and biopsies,” Dr. Inman said. “New technologies, like microRNA tests, are being developed to help sort this out.”

There was no funding for this research. Dr. Nestler disclosed no relevant conflicts of interest. Dr. Inman disclosed relationships with several pharmaceutical companies as well as patents or royalties for soluble B7-H1.

SOURCE: Nestler T et al. GUCS 2020, Abstract 388.

SAN FRANCISCO – A large share of men with testicular cancer undergoing postchemotherapy retroperitoneal lymph node dissection (RPLND) may be having organs unnecessarily removed at the time, a retrospective analysis suggests.

However, determining which of these patients do not require adjunct resection remains challenging, according to Tim Nestler, MD, of the University Hospital of Cologne in Germany.

Dr. Nestler presented the retrospective analysis at the the 2020 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Nestler and his colleagues analyzed the frequency and pathologic findings of adjunctive organ resection (encompassing organs, blood vessels, and bones) among 1,181 men undergoing postchemotherapy RPLND during 2008-2018.

Adjunctive organ resection was performed in 20% of patients. Pathologic evaluation of the resection specimens showed viable germ cell tumors in 21.7% of these patients, teratomas in 38.7%, and necrosis or fibrosis in 39.6%. The prevalence of necrosis/fibrosis was generally similar across various organs, blood vessels, and bones.

At a median follow-up of 22 months, 27% of the study cohort experienced a relapse. The 5-year rate of relapse-free survival was 18% for patients with viable germ cell tumors in adjunctively resected organs, 54% for those with teratomas, and 81% for those with necrosis/fibrosis.

“Within this cohort, about 40% of all resections finally showed necrosis/fibrosis, and these are patients that were kind of unnecessarily treated from the oncological standpoint,” Dr. Nestler said, although he noted that such resections should continue until there is a reliable way to identify this subset of patients.

“We are thinking of increasing the rate of frozen sections within surgery, especially to avoid nephrectomies, hepatectomies, and vascular resections,” he said. “Or, if we are thinking about bone metastasis, then we also might think about presurgical biopsies.”

Stepping back even further, clinicians could do “a more accurate presurgical work-up to identify those patients that are really in need of postchemotherapy RPLND, compared to those who will have a high chance of showing necrosis/fibrosis,” Dr. Nestler said. “Here, we are currently working on means like radiomics and molecular markers.”
 

Implications for patient counseling

“The problem is, and this is the central crux of the issue, that we cannot accurately identify ‘cancer or teratoma’ from ‘not cancer or teratoma’ prior to surgery,” said session cochair Brant A. Inman, MD, of the Duke Prostate and Urologic Cancer Center in Durham, N.C.

Preoperative biopsies are not helpful in differentiating these groups because of their technical difficulty and very high false-negative rate, Dr. Inman said. And intraoperative biopsies with frozen sections have the same sampling problem, plus problems of diagnostic accuracy and differentiation of live from dead tumor.

“This research is mainly helpful for preoperative patient counseling,” Dr. Inman said. “You have to tell your patient prior to RPLND, especially if they have a large postchemotherapy mass, several things.”

Specifically, patients should be informed about the probability of needing adjunctive resection and what that entails, he said. If this additional surgery is needed, patients should be informed of the probability that the tissues removed will not contain any cancer or teratoma. Moreover, “if this is the case, the blood vessel or organ will likely have been removed without benefit to you,” he added.

Finally, patients should be told that “there is no accurate way presently to distinguish cancer/teratoma from necrosis/fibrosis preoperatively or intraoperatively, including imaging and biopsies,” Dr. Inman said. “New technologies, like microRNA tests, are being developed to help sort this out.”

There was no funding for this research. Dr. Nestler disclosed no relevant conflicts of interest. Dr. Inman disclosed relationships with several pharmaceutical companies as well as patents or royalties for soluble B7-H1.

SOURCE: Nestler T et al. GUCS 2020, Abstract 388.

SAN FRANCISCO – A large share of men with testicular cancer undergoing postchemotherapy retroperitoneal lymph node dissection (RPLND) may be having organs unnecessarily removed at the time, a retrospective analysis suggests.

However, determining which of these patients do not require adjunct resection remains challenging, according to Tim Nestler, MD, of the University Hospital of Cologne in Germany.

Dr. Nestler presented the retrospective analysis at the the 2020 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Nestler and his colleagues analyzed the frequency and pathologic findings of adjunctive organ resection (encompassing organs, blood vessels, and bones) among 1,181 men undergoing postchemotherapy RPLND during 2008-2018.

Adjunctive organ resection was performed in 20% of patients. Pathologic evaluation of the resection specimens showed viable germ cell tumors in 21.7% of these patients, teratomas in 38.7%, and necrosis or fibrosis in 39.6%. The prevalence of necrosis/fibrosis was generally similar across various organs, blood vessels, and bones.

At a median follow-up of 22 months, 27% of the study cohort experienced a relapse. The 5-year rate of relapse-free survival was 18% for patients with viable germ cell tumors in adjunctively resected organs, 54% for those with teratomas, and 81% for those with necrosis/fibrosis.

“Within this cohort, about 40% of all resections finally showed necrosis/fibrosis, and these are patients that were kind of unnecessarily treated from the oncological standpoint,” Dr. Nestler said, although he noted that such resections should continue until there is a reliable way to identify this subset of patients.

“We are thinking of increasing the rate of frozen sections within surgery, especially to avoid nephrectomies, hepatectomies, and vascular resections,” he said. “Or, if we are thinking about bone metastasis, then we also might think about presurgical biopsies.”

Stepping back even further, clinicians could do “a more accurate presurgical work-up to identify those patients that are really in need of postchemotherapy RPLND, compared to those who will have a high chance of showing necrosis/fibrosis,” Dr. Nestler said. “Here, we are currently working on means like radiomics and molecular markers.”
 

Implications for patient counseling

“The problem is, and this is the central crux of the issue, that we cannot accurately identify ‘cancer or teratoma’ from ‘not cancer or teratoma’ prior to surgery,” said session cochair Brant A. Inman, MD, of the Duke Prostate and Urologic Cancer Center in Durham, N.C.

Preoperative biopsies are not helpful in differentiating these groups because of their technical difficulty and very high false-negative rate, Dr. Inman said. And intraoperative biopsies with frozen sections have the same sampling problem, plus problems of diagnostic accuracy and differentiation of live from dead tumor.

“This research is mainly helpful for preoperative patient counseling,” Dr. Inman said. “You have to tell your patient prior to RPLND, especially if they have a large postchemotherapy mass, several things.”

Specifically, patients should be informed about the probability of needing adjunctive resection and what that entails, he said. If this additional surgery is needed, patients should be informed of the probability that the tissues removed will not contain any cancer or teratoma. Moreover, “if this is the case, the blood vessel or organ will likely have been removed without benefit to you,” he added.

Finally, patients should be told that “there is no accurate way presently to distinguish cancer/teratoma from necrosis/fibrosis preoperatively or intraoperatively, including imaging and biopsies,” Dr. Inman said. “New technologies, like microRNA tests, are being developed to help sort this out.”

There was no funding for this research. Dr. Nestler disclosed no relevant conflicts of interest. Dr. Inman disclosed relationships with several pharmaceutical companies as well as patents or royalties for soluble B7-H1.

SOURCE: Nestler T et al. GUCS 2020, Abstract 388.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.

SAN FRANCISCO – A novel gene therapy may expand treatment options for non–muscle invasive bladder cancer that does not respond to Bacillus Calmette-Guerin (BCG), new research suggests.

Susan London/MDedge News

The therapy, nadofaragene firadenovec, is a recombinant adenovirus that is instilled into the bladder and delivers the human interferon alpha-2b gene, leading to expression of the immune cytokine.

At 3 months, nadofaragene firadenovec had produced a complete response in 53.4% of patients with carcinoma in situ (CIS), and the rate of high-grade recurrence-free survival was 59.6% in all patients. Although most patients (70.1%) experienced adverse events in this trial, few had serious events (1.9%).

Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minn., presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“The optimal management for patients with BCG-unresponsive non–muscle invasive bladder cancer remains to be established,” Dr. Boorjian said. “National and organizational guidelines recommend radical cystectomy in this setting, but we have to acknowledge that many of our patients will be either unwilling or unfit to undergo what is often a highly morbid operation.”

Dr. Boorjian and coinvestigators tested nadofaragene firadenovec in 107 patients with CIS, with or without high-grade Ta or T1 papillary disease, as well as 50 patients with high-grade Ta or T1 papillary disease only.

All patients received nadofaragene firadenovec once every 3 months for up four doses, with additional dosing at the investigator’s discretion. Although the trial was designated as phase 3, it did not have the typical randomized comparative design.

“The challenge in the BCG-unresponsive disease state is that, historically, there has been no validated good comparator to use here; there’s no standard of care for these patients,” Dr. Boorjian explained, noting that the design was chosen after discussion with the Food and Drug Administration.
 

Efficacy

The complete response rate among CIS patients at any time after instillation, the trial’s primary objective, was 53.4%. All of these responses occurred after a single dose of nadofaragene firadenovec. Responses were considered durable, as 45.5% of CIS patients who had a complete response at 3 months still had a complete response at 12 months.

The rate of high-grade recurrence-free survival at 3 months was 59.6% in the overall population, 53.4% in patients with CIS, and 72.9% in patients with papillary disease. At 12 months, the rate of high-grade recurrence-free survival was 30.5%, 24.3%, and 43.8%, respectively.

The rate of high-grade recurrence without muscle invasive bladder cancer was 71.8% in the CIS group and 52.1% in the papillary group. The rate of progression to muscle invasive bladder cancer or more advanced disease was 4.9% and 6.3%, respectively. The overall 2-year rate of cystectomy-free survival was 64%, and there were no bladder cancer deaths.
 

Safety

Nadofaragene firadenovec was considered safe and well tolerated. The most common study drug–related adverse events were irritative voiding symptoms, such as discharge, bladder spasm, micturition urgency, and hematuria.

Although 70.1% of patients experienced a local or systemic adverse event related to the study drug or procedure, few experienced serious adverse events (1.9%), grade 3 adverse events (3.8%), or treatment-emergent adverse events leading to discontinuation (1.9%). The serious adverse events were sepsis, syncope, and hematuria.
 

Next steps

“Nadofaragene firadenovec represents a promising option for patients with BCG-unresponsive [non–muscle invasive bladder cancer],” Dr. Boorjian said. “What we want to see going forward is durability of response, cystectomy-free survival, and metastasis-free and cancer-specific survival. Those are the harder endpoints that, as these data mature, we will want to see so that we are able to counsel our patients accordingly.”

Susan London/MDedge News

The FDA recently approved pembrolizumab for this patient population, noted session cochair Guru Sonpavde, MD, of the Dana-Farber Cancer Institute in Boston.

“But nadofaragene firadenovec is much less toxic, it is given intravesically, and it’s only given once every 3 months,” he said. “The outcomes at the 1-year point look similar in terms of the durable complete response rate. So we hope that this therapy will be able to get to the clinic, but we have to wait for the FDA to decide.”

It remains to be seen how nadofaragene firadenovec compares with other emerging therapies for high-risk BCG-unresponsive non–muscle invasive bladder cancer, including pembrolizumab and potentially intravesical oportuzumab monatox (a targeted immunotoxin) and intravesical combination BCG and superagonist interleukin-15 (ALT-803), according to Dr. Boorjian.

“A unique feature of the trial I presented was that the results were validated by a mandatory 12-month study biopsy, which has not been the case in other trials,” he pointed out. “So this separates it a little bit when you are looking at pathologic response rates and high-grade recurrence–free rates. They are based on pathologic confirmation.”

Evaluators will ultimately compare these therapies on safety, efficacy, ease of administration, delivery schedule, and cost, Dr. Boorjian said. “At this stage, it’s very difficult to start to say which agent is going to be placed where in our management paradigm. We have to go step by step: Do the trial that we did, show our data, put it out for review, and then allow the community to engage in a discussion about which agent, and why, for which patient.”

This trial was funded by FKD Therapies Oy. Dr. Boorjian disclosed relationships with Ferring and Sanofi. Dr. Sonpavde disclosed relationships with many companies.

SOURCE: Boorjian SA et al. GUCS 2020, Abstract 442.

SAN FRANCISCO – Early use of the androgen receptor antagonist apalutamide for metastatic castration-sensitive prostate cancer has a sustained carry-over benefit regardless of subsequent therapy, an exploratory analysis of the TITAN trial suggests.

Susan London/MDedge News

Previous trial results for all 1,052 men randomized showed significant improvements in radiographic progression-free survival and overall survival from adding apalutamide versus placebo to androgen deprivation therapy (N Engl J Med. 2019;381:13-24), leading to recent Food and Drug Administration approval of the drug for metastatic castration-sensitive prostate cancer.

In the new analysis, investigators assessed progression-free survival 2 (PFS2), measured from time of randomization to investigator-determined disease progression or death, among the 277 men who went on to receive a subsequent life-prolonging therapy after progression on their trial therapy.

Results reported at the 2020 Genitourinary Cancers Symposium showed that the risk of PFS2 events was similarly reduced for patients who had initially received apalutamide vs. placebo regardless of whether their next therapy was a new hormonal therapy (32% reduction in risk) or a taxane (37% reduction in risk).

“The PFS2 benefit is an indicator of effective early intensification of treatment, is consistent with the overall survival benefit we have seen with this agent, and together shows totality of the treatment trajectory,” reported Neeraj Agarwal, MD, the study’s lead investigator. “These results may assist with counseling of patients with metastatic castration-sensitive prostate cancer who are contemplating various treatment options.”

The analysis was performed post hoc, and the subsequent therapy was left up to the treating clinicians, acknowledged Dr. Agarwal, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

“A small number of events on subsequent therapy and the nonrandomized treatment decision preclude determination of best subsequent therapy based on these data,” he said. “We need further events and for data to mature more in order to pursue additional in-depth analysis.”

Some caveats

As only about a fifth of patients experienced PFS2 events, “these findings need to be interpreted with some caution,” said invited discussant Dana E. Rathkopf, MD, a genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center in New York.

Another caveat is that the cohort analyzed comprised poor responders, who had experienced progression at a median of roughly 12 months whether on apalutamide or placebo, she noted. “If the patients were all on treatment for about 12 months, it does make me wonder why the apalutamide patients responded better than placebo patients to a second hormonal therapy, because you might think that, in the setting of poor response to upfront apalutamide, these patients may develop some type of intrinsic resistance that would suggest they would not respond to a second-line androgen receptor inhibitor relative to a taxane.”

Patients in TITAN were stratified on prior receipt of docetaxel before undergoing randomization. But simply by chance, among those receiving subsequent hormonal therapy, a larger share of those initially treated with apalutamide than of those initially treated with placebo had received the taxane (33% vs. 16%), which may have influenced outcomes, Dr. Rathkopf added.

“Further maturation of the data will tell us more,” she said. “But clearly, apalutamide in both the SPARTAN and TITAN trials improved PFS2 relative to placebo, and this begs the question of how we can better select treatment using predictive markers.”
 

Study details

Among the 277 men experiencing progression on their trial therapy and going on to receive a life-prolonging subsequent therapy, about 30% later received a new hormonal therapy – abiraterone or enzalutamide – and 35% subsequently received a taxane – docetaxel or cabazitaxel.

Overall, PFS2 was significantly better for men initially randomized to apalutamide, compared with counterparts initially randomized to placebo (hazard ratio for events, 0.66; P = .0026), Dr. Agarwal reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In stratified analyses, PFS2 was also significantly better with initial apalutamide vs. placebo whether patients went on to receive a new hormonal therapy (hazard ratio for events, 0.684; P = .0326) or taxane chemotherapy (hazard ratio for events, 0.634; P = .0062). Median values were not reached.

The trial was funded by Janssen Research & Development. Dr. Agarwal and Dr. Rathkopf each disclosed relationships with numerous pharmaceutical companies, including Janssen.

SOURCE: Agarwal N et al. GUCS 2020. Abstract 82.

SAN FRANCISCO – Early use of the androgen receptor antagonist apalutamide for metastatic castration-sensitive prostate cancer has a sustained carry-over benefit regardless of subsequent therapy, an exploratory analysis of the TITAN trial suggests.

Susan London/MDedge News

Previous trial results for all 1,052 men randomized showed significant improvements in radiographic progression-free survival and overall survival from adding apalutamide versus placebo to androgen deprivation therapy (N Engl J Med. 2019;381:13-24), leading to recent Food and Drug Administration approval of the drug for metastatic castration-sensitive prostate cancer.

In the new analysis, investigators assessed progression-free survival 2 (PFS2), measured from time of randomization to investigator-determined disease progression or death, among the 277 men who went on to receive a subsequent life-prolonging therapy after progression on their trial therapy.

Results reported at the 2020 Genitourinary Cancers Symposium showed that the risk of PFS2 events was similarly reduced for patients who had initially received apalutamide vs. placebo regardless of whether their next therapy was a new hormonal therapy (32% reduction in risk) or a taxane (37% reduction in risk).

“The PFS2 benefit is an indicator of effective early intensification of treatment, is consistent with the overall survival benefit we have seen with this agent, and together shows totality of the treatment trajectory,” reported Neeraj Agarwal, MD, the study’s lead investigator. “These results may assist with counseling of patients with metastatic castration-sensitive prostate cancer who are contemplating various treatment options.”

The analysis was performed post hoc, and the subsequent therapy was left up to the treating clinicians, acknowledged Dr. Agarwal, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

“A small number of events on subsequent therapy and the nonrandomized treatment decision preclude determination of best subsequent therapy based on these data,” he said. “We need further events and for data to mature more in order to pursue additional in-depth analysis.”

Some caveats

As only about a fifth of patients experienced PFS2 events, “these findings need to be interpreted with some caution,” said invited discussant Dana E. Rathkopf, MD, a genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center in New York.

Another caveat is that the cohort analyzed comprised poor responders, who had experienced progression at a median of roughly 12 months whether on apalutamide or placebo, she noted. “If the patients were all on treatment for about 12 months, it does make me wonder why the apalutamide patients responded better than placebo patients to a second hormonal therapy, because you might think that, in the setting of poor response to upfront apalutamide, these patients may develop some type of intrinsic resistance that would suggest they would not respond to a second-line androgen receptor inhibitor relative to a taxane.”

Patients in TITAN were stratified on prior receipt of docetaxel before undergoing randomization. But simply by chance, among those receiving subsequent hormonal therapy, a larger share of those initially treated with apalutamide than of those initially treated with placebo had received the taxane (33% vs. 16%), which may have influenced outcomes, Dr. Rathkopf added.

“Further maturation of the data will tell us more,” she said. “But clearly, apalutamide in both the SPARTAN and TITAN trials improved PFS2 relative to placebo, and this begs the question of how we can better select treatment using predictive markers.”
 

Study details

Among the 277 men experiencing progression on their trial therapy and going on to receive a life-prolonging subsequent therapy, about 30% later received a new hormonal therapy – abiraterone or enzalutamide – and 35% subsequently received a taxane – docetaxel or cabazitaxel.

Overall, PFS2 was significantly better for men initially randomized to apalutamide, compared with counterparts initially randomized to placebo (hazard ratio for events, 0.66; P = .0026), Dr. Agarwal reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In stratified analyses, PFS2 was also significantly better with initial apalutamide vs. placebo whether patients went on to receive a new hormonal therapy (hazard ratio for events, 0.684; P = .0326) or taxane chemotherapy (hazard ratio for events, 0.634; P = .0062). Median values were not reached.

The trial was funded by Janssen Research & Development. Dr. Agarwal and Dr. Rathkopf each disclosed relationships with numerous pharmaceutical companies, including Janssen.

SOURCE: Agarwal N et al. GUCS 2020. Abstract 82.

SAN FRANCISCO – Early use of the androgen receptor antagonist apalutamide for metastatic castration-sensitive prostate cancer has a sustained carry-over benefit regardless of subsequent therapy, an exploratory analysis of the TITAN trial suggests.

Susan London/MDedge News

Previous trial results for all 1,052 men randomized showed significant improvements in radiographic progression-free survival and overall survival from adding apalutamide versus placebo to androgen deprivation therapy (N Engl J Med. 2019;381:13-24), leading to recent Food and Drug Administration approval of the drug for metastatic castration-sensitive prostate cancer.

In the new analysis, investigators assessed progression-free survival 2 (PFS2), measured from time of randomization to investigator-determined disease progression or death, among the 277 men who went on to receive a subsequent life-prolonging therapy after progression on their trial therapy.

Results reported at the 2020 Genitourinary Cancers Symposium showed that the risk of PFS2 events was similarly reduced for patients who had initially received apalutamide vs. placebo regardless of whether their next therapy was a new hormonal therapy (32% reduction in risk) or a taxane (37% reduction in risk).

“The PFS2 benefit is an indicator of effective early intensification of treatment, is consistent with the overall survival benefit we have seen with this agent, and together shows totality of the treatment trajectory,” reported Neeraj Agarwal, MD, the study’s lead investigator. “These results may assist with counseling of patients with metastatic castration-sensitive prostate cancer who are contemplating various treatment options.”

The analysis was performed post hoc, and the subsequent therapy was left up to the treating clinicians, acknowledged Dr. Agarwal, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.

“A small number of events on subsequent therapy and the nonrandomized treatment decision preclude determination of best subsequent therapy based on these data,” he said. “We need further events and for data to mature more in order to pursue additional in-depth analysis.”

Some caveats

As only about a fifth of patients experienced PFS2 events, “these findings need to be interpreted with some caution,” said invited discussant Dana E. Rathkopf, MD, a genitourinary medical oncologist at Memorial Sloan Kettering Cancer Center in New York.

Another caveat is that the cohort analyzed comprised poor responders, who had experienced progression at a median of roughly 12 months whether on apalutamide or placebo, she noted. “If the patients were all on treatment for about 12 months, it does make me wonder why the apalutamide patients responded better than placebo patients to a second hormonal therapy, because you might think that, in the setting of poor response to upfront apalutamide, these patients may develop some type of intrinsic resistance that would suggest they would not respond to a second-line androgen receptor inhibitor relative to a taxane.”

Patients in TITAN were stratified on prior receipt of docetaxel before undergoing randomization. But simply by chance, among those receiving subsequent hormonal therapy, a larger share of those initially treated with apalutamide than of those initially treated with placebo had received the taxane (33% vs. 16%), which may have influenced outcomes, Dr. Rathkopf added.

“Further maturation of the data will tell us more,” she said. “But clearly, apalutamide in both the SPARTAN and TITAN trials improved PFS2 relative to placebo, and this begs the question of how we can better select treatment using predictive markers.”
 

Study details

Among the 277 men experiencing progression on their trial therapy and going on to receive a life-prolonging subsequent therapy, about 30% later received a new hormonal therapy – abiraterone or enzalutamide – and 35% subsequently received a taxane – docetaxel or cabazitaxel.

Overall, PFS2 was significantly better for men initially randomized to apalutamide, compared with counterparts initially randomized to placebo (hazard ratio for events, 0.66; P = .0026), Dr. Agarwal reported at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In stratified analyses, PFS2 was also significantly better with initial apalutamide vs. placebo whether patients went on to receive a new hormonal therapy (hazard ratio for events, 0.684; P = .0326) or taxane chemotherapy (hazard ratio for events, 0.634; P = .0062). Median values were not reached.

The trial was funded by Janssen Research & Development. Dr. Agarwal and Dr. Rathkopf each disclosed relationships with numerous pharmaceutical companies, including Janssen.

SOURCE: Agarwal N et al. GUCS 2020. Abstract 82.

SAN FRANCISCO – Use of FDG-PET early in the course of chemotherapy can identify men with low-volume seminoma who have highly chemosensitive disease, enabling them to safely skip the standard chemotherapy regimen with its toxicity. This was among key findings of the phase 2 SEMITEP trial reported at the 2020 Genitourinary Cancers Symposium.

Susan London/MDedge News

Although four cycles of etoposide-cisplatin cure almost all cases of good-prognosis metastatic seminoma (Eur Urol. 2014;65:381-6), long-term cisplatin toxicity in this predominantly young population remains problematic, noted lead investigator Yohann Loriot, MD, PhD, a medical oncologist at Gustave Roussy Institute, Villejuif, France.

In SEMITEP, he and his colleagues tested a risk-adapted strategy among 98 patients with metastatic seminoma who met International Germ Cell Cancer Collaboration Group criteria for good prognosis and had not received any chemotherapy or radiotherapy.

Fully 68.4% had a negative FDG-PET result after two cycles of etoposide-cisplatin and were given only one cycle of carboplatin to complete treatment (based on that drug’s activity in low-volume disease), Dr. Loriot reported. The rest went on to receive an additional two cycles of etoposide-cisplatin, completing the standard regimen.

At 3 years, 9 in 10 patients were alive and free of progression in both the deescalated chemotherapy group and the standard chemotherapy group. The cumulative incidence of peripheral neuropathy, however, was about 10 times higher in the standard chemotherapy group.

“Deescalating chemotherapy based on an early FDG-PET is safe and feasible in metastatic seminoma,” Dr. Loriot said. “This strategy provides shorter treatment, reduces neuropathy, and eliminates need for bleomycin and its associated toxicity. SEMITEP supports the deescalating strategy in metastatic seminoma.”

Ready for prime time?

The SEMITEP trial achieved the main goal of reducing toxicity but had several noteworthy caveats, according to invited discussant Peter Albers, MD, professor and chairman of the department of urology, Heinrich-Heine University Düsseldorf, Germany.

Susan London/MDedge News

First, in an “astonishing” feat, FDG-PET was performed and evaluable after just two cycles of chemotherapy, or 3 weeks, when typical practice is to wait until 8 or 10 weeks, he said.

“Second, I really don’t understand why carboplatin was given in an FDG-PET–negative seminoma,” Dr. Albers said. “There is, in my view, no reason to add another chemotherapy agent to this patient population if you really claim this to be a biomarker. Carboplatin is known to be inferior to cisplatin in metastatic seminoma.”

Third, enrolled patients predominantly had low-volume disease, with about two-thirds having clinical stage IIA or IIB. “So this study is not representative for all metastatic seminoma patients,” Dr. Albers cautioned. “But obviously, it gives a good signal, and those patients who had IIC disease in the deescalation arm have shown no recurrences so far.

“This trial is important and obviously accurately done, but to my mind, it’s not yet practice-changing. We need a clear comparison to standard treatment before we introduce FDG-PET as a biomarker in this indication,” he concluded, recommending that, for now, risk-stratified approaches should be limited to clinical trials.

Study details

Although 72% of patients in SEMITEP had a negative early FDG-PET result, four of them requested standard chemotherapy anyway and were analyzed in that group, Dr. Loriot noted at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

With a median follow-up of 33.9 months, the 36-month rate of progression-free survival was 89.9% in the deescalated chemotherapy group, essentially the same as the 90% in the standard chemotherapy group. There were no deaths during follow-up in either group.

During chemotherapy, the deescalation group had lower rates of grade 3 or 4 nausea and vomiting and ototoxicity, and a higher rate of grade 3 or 4 thrombocytopenia.

At 3 years, the cumulative incidence of any-grade peripheral neuropathy was less than 5% in the deescalated chemotherapy group, compared with about 50% in the standard chemotherapy group (P less than .001). There was also a trend toward a lower incidence of ototoxicity with deescalation.

The trial was funded by Institut National du Cancer (Programme Hospitalier de Recherche Clinique). Dr. Loriot disclosed no relevant conflicts of interest. Dr. Albers disclosed relationships with Sanofi, Roche, and Merck Sharp & Dohme Corp.

SOURCE: Loriot Y et al. GUCS 2020. Abstract 387.

SAN FRANCISCO – Use of FDG-PET early in the course of chemotherapy can identify men with low-volume seminoma who have highly chemosensitive disease, enabling them to safely skip the standard chemotherapy regimen with its toxicity. This was among key findings of the phase 2 SEMITEP trial reported at the 2020 Genitourinary Cancers Symposium.

Susan London/MDedge News

Although four cycles of etoposide-cisplatin cure almost all cases of good-prognosis metastatic seminoma (Eur Urol. 2014;65:381-6), long-term cisplatin toxicity in this predominantly young population remains problematic, noted lead investigator Yohann Loriot, MD, PhD, a medical oncologist at Gustave Roussy Institute, Villejuif, France.

In SEMITEP, he and his colleagues tested a risk-adapted strategy among 98 patients with metastatic seminoma who met International Germ Cell Cancer Collaboration Group criteria for good prognosis and had not received any chemotherapy or radiotherapy.

Fully 68.4% had a negative FDG-PET result after two cycles of etoposide-cisplatin and were given only one cycle of carboplatin to complete treatment (based on that drug’s activity in low-volume disease), Dr. Loriot reported. The rest went on to receive an additional two cycles of etoposide-cisplatin, completing the standard regimen.

At 3 years, 9 in 10 patients were alive and free of progression in both the deescalated chemotherapy group and the standard chemotherapy group. The cumulative incidence of peripheral neuropathy, however, was about 10 times higher in the standard chemotherapy group.

“Deescalating chemotherapy based on an early FDG-PET is safe and feasible in metastatic seminoma,” Dr. Loriot said. “This strategy provides shorter treatment, reduces neuropathy, and eliminates need for bleomycin and its associated toxicity. SEMITEP supports the deescalating strategy in metastatic seminoma.”

Ready for prime time?

The SEMITEP trial achieved the main goal of reducing toxicity but had several noteworthy caveats, according to invited discussant Peter Albers, MD, professor and chairman of the department of urology, Heinrich-Heine University Düsseldorf, Germany.

Susan London/MDedge News

First, in an “astonishing” feat, FDG-PET was performed and evaluable after just two cycles of chemotherapy, or 3 weeks, when typical practice is to wait until 8 or 10 weeks, he said.

“Second, I really don’t understand why carboplatin was given in an FDG-PET–negative seminoma,” Dr. Albers said. “There is, in my view, no reason to add another chemotherapy agent to this patient population if you really claim this to be a biomarker. Carboplatin is known to be inferior to cisplatin in metastatic seminoma.”

Third, enrolled patients predominantly had low-volume disease, with about two-thirds having clinical stage IIA or IIB. “So this study is not representative for all metastatic seminoma patients,” Dr. Albers cautioned. “But obviously, it gives a good signal, and those patients who had IIC disease in the deescalation arm have shown no recurrences so far.

“This trial is important and obviously accurately done, but to my mind, it’s not yet practice-changing. We need a clear comparison to standard treatment before we introduce FDG-PET as a biomarker in this indication,” he concluded, recommending that, for now, risk-stratified approaches should be limited to clinical trials.

Study details

Although 72% of patients in SEMITEP had a negative early FDG-PET result, four of them requested standard chemotherapy anyway and were analyzed in that group, Dr. Loriot noted at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

With a median follow-up of 33.9 months, the 36-month rate of progression-free survival was 89.9% in the deescalated chemotherapy group, essentially the same as the 90% in the standard chemotherapy group. There were no deaths during follow-up in either group.

During chemotherapy, the deescalation group had lower rates of grade 3 or 4 nausea and vomiting and ototoxicity, and a higher rate of grade 3 or 4 thrombocytopenia.

At 3 years, the cumulative incidence of any-grade peripheral neuropathy was less than 5% in the deescalated chemotherapy group, compared with about 50% in the standard chemotherapy group (P less than .001). There was also a trend toward a lower incidence of ototoxicity with deescalation.

The trial was funded by Institut National du Cancer (Programme Hospitalier de Recherche Clinique). Dr. Loriot disclosed no relevant conflicts of interest. Dr. Albers disclosed relationships with Sanofi, Roche, and Merck Sharp & Dohme Corp.

SOURCE: Loriot Y et al. GUCS 2020. Abstract 387.

SAN FRANCISCO – Use of FDG-PET early in the course of chemotherapy can identify men with low-volume seminoma who have highly chemosensitive disease, enabling them to safely skip the standard chemotherapy regimen with its toxicity. This was among key findings of the phase 2 SEMITEP trial reported at the 2020 Genitourinary Cancers Symposium.

Susan London/MDedge News

Although four cycles of etoposide-cisplatin cure almost all cases of good-prognosis metastatic seminoma (Eur Urol. 2014;65:381-6), long-term cisplatin toxicity in this predominantly young population remains problematic, noted lead investigator Yohann Loriot, MD, PhD, a medical oncologist at Gustave Roussy Institute, Villejuif, France.

In SEMITEP, he and his colleagues tested a risk-adapted strategy among 98 patients with metastatic seminoma who met International Germ Cell Cancer Collaboration Group criteria for good prognosis and had not received any chemotherapy or radiotherapy.

Fully 68.4% had a negative FDG-PET result after two cycles of etoposide-cisplatin and were given only one cycle of carboplatin to complete treatment (based on that drug’s activity in low-volume disease), Dr. Loriot reported. The rest went on to receive an additional two cycles of etoposide-cisplatin, completing the standard regimen.

At 3 years, 9 in 10 patients were alive and free of progression in both the deescalated chemotherapy group and the standard chemotherapy group. The cumulative incidence of peripheral neuropathy, however, was about 10 times higher in the standard chemotherapy group.

“Deescalating chemotherapy based on an early FDG-PET is safe and feasible in metastatic seminoma,” Dr. Loriot said. “This strategy provides shorter treatment, reduces neuropathy, and eliminates need for bleomycin and its associated toxicity. SEMITEP supports the deescalating strategy in metastatic seminoma.”

Ready for prime time?

The SEMITEP trial achieved the main goal of reducing toxicity but had several noteworthy caveats, according to invited discussant Peter Albers, MD, professor and chairman of the department of urology, Heinrich-Heine University Düsseldorf, Germany.

Susan London/MDedge News

First, in an “astonishing” feat, FDG-PET was performed and evaluable after just two cycles of chemotherapy, or 3 weeks, when typical practice is to wait until 8 or 10 weeks, he said.

“Second, I really don’t understand why carboplatin was given in an FDG-PET–negative seminoma,” Dr. Albers said. “There is, in my view, no reason to add another chemotherapy agent to this patient population if you really claim this to be a biomarker. Carboplatin is known to be inferior to cisplatin in metastatic seminoma.”

Third, enrolled patients predominantly had low-volume disease, with about two-thirds having clinical stage IIA or IIB. “So this study is not representative for all metastatic seminoma patients,” Dr. Albers cautioned. “But obviously, it gives a good signal, and those patients who had IIC disease in the deescalation arm have shown no recurrences so far.

“This trial is important and obviously accurately done, but to my mind, it’s not yet practice-changing. We need a clear comparison to standard treatment before we introduce FDG-PET as a biomarker in this indication,” he concluded, recommending that, for now, risk-stratified approaches should be limited to clinical trials.

Study details

Although 72% of patients in SEMITEP had a negative early FDG-PET result, four of them requested standard chemotherapy anyway and were analyzed in that group, Dr. Loriot noted at the symposium, which was sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

With a median follow-up of 33.9 months, the 36-month rate of progression-free survival was 89.9% in the deescalated chemotherapy group, essentially the same as the 90% in the standard chemotherapy group. There were no deaths during follow-up in either group.

During chemotherapy, the deescalation group had lower rates of grade 3 or 4 nausea and vomiting and ototoxicity, and a higher rate of grade 3 or 4 thrombocytopenia.

At 3 years, the cumulative incidence of any-grade peripheral neuropathy was less than 5% in the deescalated chemotherapy group, compared with about 50% in the standard chemotherapy group (P less than .001). There was also a trend toward a lower incidence of ototoxicity with deescalation.

The trial was funded by Institut National du Cancer (Programme Hospitalier de Recherche Clinique). Dr. Loriot disclosed no relevant conflicts of interest. Dr. Albers disclosed relationships with Sanofi, Roche, and Merck Sharp & Dohme Corp.

SOURCE: Loriot Y et al. GUCS 2020. Abstract 387.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

SAN FRANCISCO – Using stereotactic body radiation therapy (SBRT) to stimulate the immune response may boost the efficacy of immunotherapy in metastatic renal cell carcinoma (RCC), results of the RADVAX RCC trial suggest.

Susan London/MDedge News

More than half of patients (56%) who received SBRT plus nivolumab and ipilimumab achieved a response in nonirradiated lesions, but the prespecified threshold for efficacy was not met (70%). Still, the combination was active and well tolerated, and it warrants further investigation, according to Hans J. Hammers, MD, PhD, of the University of Texas, Dallas.

Dr. Hammers presented results from the RADVAX RCC trial at the 2020 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Study details

The phase 2 trial enrolled 25 patients with metastatic clear-cell RCC. They had at least two metastatic sites, one of which was measurable for response. Forty percent had received at least one prior line of systemic therapy, and 30% had tumors positive for programmed death–ligand 1 expression. Almost a third had not undergone nephrectomy and therefore still had their primary tumor.

Patients received SBRT (50 Gy in five fractions) at one or two sites while also receiving nivolumab and ipilimumab. SBRT was given right after the first of four nivolumab-ipilimumab treatments and was delivered to lesions in the lung (56% of patients), lymph nodes (20%), bone or soft tissue (12%), and kidney (12%). Patients went on to receive maintenance nivolumab monotherapy.

At a median follow-up of 24 months, 56% of patients achieved a response in nonirradiated lesions. All were partial responses.

The 56% response rate fell short of the trial’s predefined efficacy endpoint of 70%. However, “we felt that an increase to around 60% [with the addition of SBRT] would probably be a reasonable signal for this small signal-finding study,” Dr. Hammers said, noting that this would be in line with the increase seen with intratumoral injections of immune stimulators.

“I would say we are not that far off if the numbers are real,” he added. “That certainly needs to be confirmed and expanded. And I’m sure we can make it more intelligent by choosing which tumors we go after because, right now, we are doing it completely blindly.”

The lack of any complete responses is likely explained, in part, by the large share of patients still having their primary tumor, Dr. Hammers said.

The median duration of response was not reached. The median progression-free survival was 8.21 months, and the median overall survival was not reached.

Thirty-six percent of patients experienced grade 3-4 adverse events, all gastrointestinal. Of the two patients (8%) experiencing grade 2 radiation pneumonitis, one was a case of radiation recall. Some patients needed high-dose corticosteroids (40%) and additional immune suppression (28%) for side effect management.

Should SBRT move forward in RCC?

“We feel that the combination of SBRT with dual immune checkpoint inhibition is feasible and associated with an acceptable safety profile,” Dr. Hammers said. “We do see an encouraging antitumor activity that we believe warrants further investigation.”

A proposed RADVAX II trial would assess programmed death–ligand 1 expression across tumor sites using PET. “We would then direct the radiation to the cold [noninflamed] tumors to derive potentially the maximum benefit in the sense of in situ vaccination,” Dr. Hammers explained.

Susan London/MDedge News

Invited discussant Thomas Powles, MD, PhD, of the Barts Cancer Institute in London, questioned whether SBRT plus immunotherapy should move forward in RCC patients. He noted that the abscopal effect was first described in the 1950s, but evidence of its clinical efficacy remains limited and inconsistent.

“We are in an era where we are keen to believe that this [phenomenon] exists,” Dr. Powles said. “But just because we can do SBRT in our hospitals doesn’t mean we should be doing it without robust data. The robustness of this data in renal cancer is not there at the moment.”

The 56% response rate seen in the RADVAX RCC trial was somewhat better than the 42% response rate seen in the CheckMate 214 trial with nivolumab and ipilimumab alone among patients with metastatic RCC treated in the first-line setting (Lancet Oncol. 2019;20:1370-85), Dr. Powles noted, while acknowledging the limitations of a cross-trial comparison.

“[However,] there were no complete responses, and this is therefore not a home run, in my opinion,” he said. “Progression-free survival was modest. Clearly, tolerability was okay.”

“In this work, the null hypothesis has not been rejected,” he added. “That’s an English way of saying it didn’t work very well. The question I put to you is, if [SBRT and immunotherapy] were a drug combination, would we be taking it further in randomized trials? And I suspect the answer to that is probably no.”

This trial was funded by KidneyCAN. Dr. Hammers and Dr. Powles disclosed relationships with Bristol-Myers Squibb, which markets nivolumab and ipilimumab, as well as other companies.

SOURCE: Hammers HJ et al. GUCS 2020, Abstract 614.

SAN FRANCISCO – Using stereotactic body radiation therapy (SBRT) to stimulate the immune response may boost the efficacy of immunotherapy in metastatic renal cell carcinoma (RCC), results of the RADVAX RCC trial suggest.

Susan London/MDedge News

More than half of patients (56%) who received SBRT plus nivolumab and ipilimumab achieved a response in nonirradiated lesions, but the prespecified threshold for efficacy was not met (70%). Still, the combination was active and well tolerated, and it warrants further investigation, according to Hans J. Hammers, MD, PhD, of the University of Texas, Dallas.

Dr. Hammers presented results from the RADVAX RCC trial at the 2020 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Study details

The phase 2 trial enrolled 25 patients with metastatic clear-cell RCC. They had at least two metastatic sites, one of which was measurable for response. Forty percent had received at least one prior line of systemic therapy, and 30% had tumors positive for programmed death–ligand 1 expression. Almost a third had not undergone nephrectomy and therefore still had their primary tumor.

Patients received SBRT (50 Gy in five fractions) at one or two sites while also receiving nivolumab and ipilimumab. SBRT was given right after the first of four nivolumab-ipilimumab treatments and was delivered to lesions in the lung (56% of patients), lymph nodes (20%), bone or soft tissue (12%), and kidney (12%). Patients went on to receive maintenance nivolumab monotherapy.

At a median follow-up of 24 months, 56% of patients achieved a response in nonirradiated lesions. All were partial responses.

The 56% response rate fell short of the trial’s predefined efficacy endpoint of 70%. However, “we felt that an increase to around 60% [with the addition of SBRT] would probably be a reasonable signal for this small signal-finding study,” Dr. Hammers said, noting that this would be in line with the increase seen with intratumoral injections of immune stimulators.

“I would say we are not that far off if the numbers are real,” he added. “That certainly needs to be confirmed and expanded. And I’m sure we can make it more intelligent by choosing which tumors we go after because, right now, we are doing it completely blindly.”

The lack of any complete responses is likely explained, in part, by the large share of patients still having their primary tumor, Dr. Hammers said.

The median duration of response was not reached. The median progression-free survival was 8.21 months, and the median overall survival was not reached.

Thirty-six percent of patients experienced grade 3-4 adverse events, all gastrointestinal. Of the two patients (8%) experiencing grade 2 radiation pneumonitis, one was a case of radiation recall. Some patients needed high-dose corticosteroids (40%) and additional immune suppression (28%) for side effect management.

Should SBRT move forward in RCC?

“We feel that the combination of SBRT with dual immune checkpoint inhibition is feasible and associated with an acceptable safety profile,” Dr. Hammers said. “We do see an encouraging antitumor activity that we believe warrants further investigation.”

A proposed RADVAX II trial would assess programmed death–ligand 1 expression across tumor sites using PET. “We would then direct the radiation to the cold [noninflamed] tumors to derive potentially the maximum benefit in the sense of in situ vaccination,” Dr. Hammers explained.

Susan London/MDedge News

Invited discussant Thomas Powles, MD, PhD, of the Barts Cancer Institute in London, questioned whether SBRT plus immunotherapy should move forward in RCC patients. He noted that the abscopal effect was first described in the 1950s, but evidence of its clinical efficacy remains limited and inconsistent.

“We are in an era where we are keen to believe that this [phenomenon] exists,” Dr. Powles said. “But just because we can do SBRT in our hospitals doesn’t mean we should be doing it without robust data. The robustness of this data in renal cancer is not there at the moment.”

The 56% response rate seen in the RADVAX RCC trial was somewhat better than the 42% response rate seen in the CheckMate 214 trial with nivolumab and ipilimumab alone among patients with metastatic RCC treated in the first-line setting (Lancet Oncol. 2019;20:1370-85), Dr. Powles noted, while acknowledging the limitations of a cross-trial comparison.

“[However,] there were no complete responses, and this is therefore not a home run, in my opinion,” he said. “Progression-free survival was modest. Clearly, tolerability was okay.”

“In this work, the null hypothesis has not been rejected,” he added. “That’s an English way of saying it didn’t work very well. The question I put to you is, if [SBRT and immunotherapy] were a drug combination, would we be taking it further in randomized trials? And I suspect the answer to that is probably no.”

This trial was funded by KidneyCAN. Dr. Hammers and Dr. Powles disclosed relationships with Bristol-Myers Squibb, which markets nivolumab and ipilimumab, as well as other companies.

SOURCE: Hammers HJ et al. GUCS 2020, Abstract 614.

SAN FRANCISCO – Using stereotactic body radiation therapy (SBRT) to stimulate the immune response may boost the efficacy of immunotherapy in metastatic renal cell carcinoma (RCC), results of the RADVAX RCC trial suggest.

Susan London/MDedge News

More than half of patients (56%) who received SBRT plus nivolumab and ipilimumab achieved a response in nonirradiated lesions, but the prespecified threshold for efficacy was not met (70%). Still, the combination was active and well tolerated, and it warrants further investigation, according to Hans J. Hammers, MD, PhD, of the University of Texas, Dallas.

Dr. Hammers presented results from the RADVAX RCC trial at the 2020 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
 

Study details

The phase 2 trial enrolled 25 patients with metastatic clear-cell RCC. They had at least two metastatic sites, one of which was measurable for response. Forty percent had received at least one prior line of systemic therapy, and 30% had tumors positive for programmed death–ligand 1 expression. Almost a third had not undergone nephrectomy and therefore still had their primary tumor.

Patients received SBRT (50 Gy in five fractions) at one or two sites while also receiving nivolumab and ipilimumab. SBRT was given right after the first of four nivolumab-ipilimumab treatments and was delivered to lesions in the lung (56% of patients), lymph nodes (20%), bone or soft tissue (12%), and kidney (12%). Patients went on to receive maintenance nivolumab monotherapy.

At a median follow-up of 24 months, 56% of patients achieved a response in nonirradiated lesions. All were partial responses.

The 56% response rate fell short of the trial’s predefined efficacy endpoint of 70%. However, “we felt that an increase to around 60% [with the addition of SBRT] would probably be a reasonable signal for this small signal-finding study,” Dr. Hammers said, noting that this would be in line with the increase seen with intratumoral injections of immune stimulators.

“I would say we are not that far off if the numbers are real,” he added. “That certainly needs to be confirmed and expanded. And I’m sure we can make it more intelligent by choosing which tumors we go after because, right now, we are doing it completely blindly.”

The lack of any complete responses is likely explained, in part, by the large share of patients still having their primary tumor, Dr. Hammers said.

The median duration of response was not reached. The median progression-free survival was 8.21 months, and the median overall survival was not reached.

Thirty-six percent of patients experienced grade 3-4 adverse events, all gastrointestinal. Of the two patients (8%) experiencing grade 2 radiation pneumonitis, one was a case of radiation recall. Some patients needed high-dose corticosteroids (40%) and additional immune suppression (28%) for side effect management.

Should SBRT move forward in RCC?

“We feel that the combination of SBRT with dual immune checkpoint inhibition is feasible and associated with an acceptable safety profile,” Dr. Hammers said. “We do see an encouraging antitumor activity that we believe warrants further investigation.”

A proposed RADVAX II trial would assess programmed death–ligand 1 expression across tumor sites using PET. “We would then direct the radiation to the cold [noninflamed] tumors to derive potentially the maximum benefit in the sense of in situ vaccination,” Dr. Hammers explained.

Susan London/MDedge News

Invited discussant Thomas Powles, MD, PhD, of the Barts Cancer Institute in London, questioned whether SBRT plus immunotherapy should move forward in RCC patients. He noted that the abscopal effect was first described in the 1950s, but evidence of its clinical efficacy remains limited and inconsistent.

“We are in an era where we are keen to believe that this [phenomenon] exists,” Dr. Powles said. “But just because we can do SBRT in our hospitals doesn’t mean we should be doing it without robust data. The robustness of this data in renal cancer is not there at the moment.”

The 56% response rate seen in the RADVAX RCC trial was somewhat better than the 42% response rate seen in the CheckMate 214 trial with nivolumab and ipilimumab alone among patients with metastatic RCC treated in the first-line setting (Lancet Oncol. 2019;20:1370-85), Dr. Powles noted, while acknowledging the limitations of a cross-trial comparison.

“[However,] there were no complete responses, and this is therefore not a home run, in my opinion,” he said. “Progression-free survival was modest. Clearly, tolerability was okay.”

“In this work, the null hypothesis has not been rejected,” he added. “That’s an English way of saying it didn’t work very well. The question I put to you is, if [SBRT and immunotherapy] were a drug combination, would we be taking it further in randomized trials? And I suspect the answer to that is probably no.”

This trial was funded by KidneyCAN. Dr. Hammers and Dr. Powles disclosed relationships with Bristol-Myers Squibb, which markets nivolumab and ipilimumab, as well as other companies.

SOURCE: Hammers HJ et al. GUCS 2020, Abstract 614.

SAN FRANCISCO – In men with localized prostate cancer, a hypofractionated radiotherapy regimen that cuts treatment time in half continues to have noninferior efficacy long-term relative to a conventional radiotherapy regimen, an update of the CHHiP trial shows.

Susan London/MDedge News

The 3,216 men in the phase 3 trial had node-negative T1b-T3a prostate cancer and were evenly assigned to a conventional regimen of 74 Gy delivered in 37 fractions, a hypofractionated regimen of 60 Gy in 20 fractions, or a hypofractionated regimen of 57 Gy in 19 fractions. All regimens were delivered with intensity-modulated techniques.

The trial’s 5-year results, previously reported, showed noninferiority of the 60-Gy regimen, compared with the 74-Gy regimen on risk of biochemical or clinical failure (hazard ratio, 0.84), prompting recommendation of the former as a new standard of care for localized prostate cancer (Lancet Oncol. 2016;17:1047-60). Noninferiority could not be established for the 57-Gy regimen.

The 8-year results were essentially the same, confirming noninferiority of the 60-Gy regimen (HR, 0.85) but not the 57-Gy regimen. Meanwhile, bowel and bladder toxicity continued to be low across regimens.

David P. Dearnaley, MB BCh, MD, of the Royal Marsden NHS Foundation Trust, London, reported the 8-year results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Study details

At a median follow-up of 9.3 years, the 8-year rate of freedom from biochemical failure (defined by Phoenix consensus guidelines) or clinical failure (cancer recurrence) was 80.6% with 74 Gy, 83.7% with 60 Gy, and 78.5% with 57 Gy, Dr. Dearnaley reported.

Analyses confirmed noninferiority of the 60-Gy regimen (HR, 0.85; 95% confidence interval, 0.72-1.01; P = .11), but not the 57-Gy regimen (HR, 1.17; 95% CI, 1.00-1.36; P = .10), as the upper bound of the confidence interval crossed the predefined 1.21 boundary for noninferiority.

In an unplanned analysis, the pattern among men younger than 75 years was similar to that in the entire trial population. But among men 75 years of age and older, the 57-Gy arm is actually outperforming the 74-Gy arm (HR, 0.77).

The three regimens yielded a similarly high rate of freedom from metastases, at about 95% in each arm. The 60-Gy regimen had an edge in overall survival relative to the 74-Gy regimen (88.6% vs. 85.9%; HR, 0.84) that is hard to explain, according to Dr. Dearnaley.

“Because there is an 8:1 ratio of non–prostate cancer deaths to prostate cancer deaths, you would have to postulate something other than prostate cancer being affected by the radiotherapy fractionation,” he said. “The answers on a postcard, because I can’t think of one.”

On central pathology review, nearly a fifth of evaluated trial patients had high-risk disease. “I know everybody wants to know about high-risk patients, but I’d rather take the trial results as a whole and look to see if there is any heterogeneity between those groups rather than perform a specific high-risk subgroup analysis,” Dr. Dearnaley said, expressing concern about performing too many subgroup analyses.

That said, older patients on the trial tended to have higher risk. “It does seem hypofractionation was particularly useful in those patients,” he noted. “Now, whether that’s anything to do with their pathology or whether it’s due to their age per se, I really don’t know.”

There were no differences between groups on rates of Radiation Therapy Oncology Group toxicity at 5 years, with grade 2 or worse bowel toxicity and bladder toxicity each seen in about 2% of patients.

There were no significant differences in rates of patient-reported “moderate or big” bowel bother (roughly 5%-8%) and urinary bother (roughly 7%-9%). For all regimens, bowel and urinary symptoms remained stable from 2-5 years.

Reassuring for practice

These updated findings “support the continued use of 60 Gy in 20 fractions as the standard of care,” Dr. Dearnaley said.

When the math is run to permit comparison, efficacy findings of the CHHiP trial show “amazing agreement” with those of the similar multinational PROFIT trial, he noted (J Clin Oncol. 2017 Jun 10;35(17):1884-90).

The absolute advantage in the failure-free rate of 3.1% and the overall survival rate of 2.7% for the 60-Gy regimen in CHHiP generated interest among symposium attendees about its possible superiority. “I think the 60 Gy is marginally more effective than the 74 Gy,” Dr. Dearnaley said, but he acknowledged that there are no statistics to prove that.

Susan London/MDedge News

“This CHHiP update is fantastic,” said session cochair Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston. “It is very reassuring that the initial results the investigators presented several years ago still hold up in the long term. It’s even more reassuring for the use of hypofractionation, and it’s great to know that we can use it across the age spectrum and it works well.”

This trial is the only noninferiority hypofractionation trial in prostate cancer that includes a sizable share of patients at high risk for poor outcomes, a population for whom efficacy of this strategy is of particular interest, Dr. Nguyen noted.

“That’s always been a question,” he said. “The majority of the data from the noninferiority trials is for the low- and intermediate-risk patients. So it really would be interesting to learn whatever we can about high-risk patients from this trial.”

The trial was funded by Cancer Research UK, Department of Health (UK), and the National Institute for Health Research Cancer Research Network. Dr. Dearnaley and Dr. Nguyen disclosed relationships with a range of pharmaceutical companies.
 

SOURCE: Dearnaley DP et al. GUCS 2020. Abstract 325.

SAN FRANCISCO – In men with localized prostate cancer, a hypofractionated radiotherapy regimen that cuts treatment time in half continues to have noninferior efficacy long-term relative to a conventional radiotherapy regimen, an update of the CHHiP trial shows.

Susan London/MDedge News

The 3,216 men in the phase 3 trial had node-negative T1b-T3a prostate cancer and were evenly assigned to a conventional regimen of 74 Gy delivered in 37 fractions, a hypofractionated regimen of 60 Gy in 20 fractions, or a hypofractionated regimen of 57 Gy in 19 fractions. All regimens were delivered with intensity-modulated techniques.

The trial’s 5-year results, previously reported, showed noninferiority of the 60-Gy regimen, compared with the 74-Gy regimen on risk of biochemical or clinical failure (hazard ratio, 0.84), prompting recommendation of the former as a new standard of care for localized prostate cancer (Lancet Oncol. 2016;17:1047-60). Noninferiority could not be established for the 57-Gy regimen.

The 8-year results were essentially the same, confirming noninferiority of the 60-Gy regimen (HR, 0.85) but not the 57-Gy regimen. Meanwhile, bowel and bladder toxicity continued to be low across regimens.

David P. Dearnaley, MB BCh, MD, of the Royal Marsden NHS Foundation Trust, London, reported the 8-year results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Study details

At a median follow-up of 9.3 years, the 8-year rate of freedom from biochemical failure (defined by Phoenix consensus guidelines) or clinical failure (cancer recurrence) was 80.6% with 74 Gy, 83.7% with 60 Gy, and 78.5% with 57 Gy, Dr. Dearnaley reported.

Analyses confirmed noninferiority of the 60-Gy regimen (HR, 0.85; 95% confidence interval, 0.72-1.01; P = .11), but not the 57-Gy regimen (HR, 1.17; 95% CI, 1.00-1.36; P = .10), as the upper bound of the confidence interval crossed the predefined 1.21 boundary for noninferiority.

In an unplanned analysis, the pattern among men younger than 75 years was similar to that in the entire trial population. But among men 75 years of age and older, the 57-Gy arm is actually outperforming the 74-Gy arm (HR, 0.77).

The three regimens yielded a similarly high rate of freedom from metastases, at about 95% in each arm. The 60-Gy regimen had an edge in overall survival relative to the 74-Gy regimen (88.6% vs. 85.9%; HR, 0.84) that is hard to explain, according to Dr. Dearnaley.

“Because there is an 8:1 ratio of non–prostate cancer deaths to prostate cancer deaths, you would have to postulate something other than prostate cancer being affected by the radiotherapy fractionation,” he said. “The answers on a postcard, because I can’t think of one.”

On central pathology review, nearly a fifth of evaluated trial patients had high-risk disease. “I know everybody wants to know about high-risk patients, but I’d rather take the trial results as a whole and look to see if there is any heterogeneity between those groups rather than perform a specific high-risk subgroup analysis,” Dr. Dearnaley said, expressing concern about performing too many subgroup analyses.

That said, older patients on the trial tended to have higher risk. “It does seem hypofractionation was particularly useful in those patients,” he noted. “Now, whether that’s anything to do with their pathology or whether it’s due to their age per se, I really don’t know.”

There were no differences between groups on rates of Radiation Therapy Oncology Group toxicity at 5 years, with grade 2 or worse bowel toxicity and bladder toxicity each seen in about 2% of patients.

There were no significant differences in rates of patient-reported “moderate or big” bowel bother (roughly 5%-8%) and urinary bother (roughly 7%-9%). For all regimens, bowel and urinary symptoms remained stable from 2-5 years.

Reassuring for practice

These updated findings “support the continued use of 60 Gy in 20 fractions as the standard of care,” Dr. Dearnaley said.

When the math is run to permit comparison, efficacy findings of the CHHiP trial show “amazing agreement” with those of the similar multinational PROFIT trial, he noted (J Clin Oncol. 2017 Jun 10;35(17):1884-90).

The absolute advantage in the failure-free rate of 3.1% and the overall survival rate of 2.7% for the 60-Gy regimen in CHHiP generated interest among symposium attendees about its possible superiority. “I think the 60 Gy is marginally more effective than the 74 Gy,” Dr. Dearnaley said, but he acknowledged that there are no statistics to prove that.

Susan London/MDedge News

“This CHHiP update is fantastic,” said session cochair Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston. “It is very reassuring that the initial results the investigators presented several years ago still hold up in the long term. It’s even more reassuring for the use of hypofractionation, and it’s great to know that we can use it across the age spectrum and it works well.”

This trial is the only noninferiority hypofractionation trial in prostate cancer that includes a sizable share of patients at high risk for poor outcomes, a population for whom efficacy of this strategy is of particular interest, Dr. Nguyen noted.

“That’s always been a question,” he said. “The majority of the data from the noninferiority trials is for the low- and intermediate-risk patients. So it really would be interesting to learn whatever we can about high-risk patients from this trial.”

The trial was funded by Cancer Research UK, Department of Health (UK), and the National Institute for Health Research Cancer Research Network. Dr. Dearnaley and Dr. Nguyen disclosed relationships with a range of pharmaceutical companies.
 

SOURCE: Dearnaley DP et al. GUCS 2020. Abstract 325.

SAN FRANCISCO – In men with localized prostate cancer, a hypofractionated radiotherapy regimen that cuts treatment time in half continues to have noninferior efficacy long-term relative to a conventional radiotherapy regimen, an update of the CHHiP trial shows.

Susan London/MDedge News

The 3,216 men in the phase 3 trial had node-negative T1b-T3a prostate cancer and were evenly assigned to a conventional regimen of 74 Gy delivered in 37 fractions, a hypofractionated regimen of 60 Gy in 20 fractions, or a hypofractionated regimen of 57 Gy in 19 fractions. All regimens were delivered with intensity-modulated techniques.

The trial’s 5-year results, previously reported, showed noninferiority of the 60-Gy regimen, compared with the 74-Gy regimen on risk of biochemical or clinical failure (hazard ratio, 0.84), prompting recommendation of the former as a new standard of care for localized prostate cancer (Lancet Oncol. 2016;17:1047-60). Noninferiority could not be established for the 57-Gy regimen.

The 8-year results were essentially the same, confirming noninferiority of the 60-Gy regimen (HR, 0.85) but not the 57-Gy regimen. Meanwhile, bowel and bladder toxicity continued to be low across regimens.

David P. Dearnaley, MB BCh, MD, of the Royal Marsden NHS Foundation Trust, London, reported the 8-year results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Study details

At a median follow-up of 9.3 years, the 8-year rate of freedom from biochemical failure (defined by Phoenix consensus guidelines) or clinical failure (cancer recurrence) was 80.6% with 74 Gy, 83.7% with 60 Gy, and 78.5% with 57 Gy, Dr. Dearnaley reported.

Analyses confirmed noninferiority of the 60-Gy regimen (HR, 0.85; 95% confidence interval, 0.72-1.01; P = .11), but not the 57-Gy regimen (HR, 1.17; 95% CI, 1.00-1.36; P = .10), as the upper bound of the confidence interval crossed the predefined 1.21 boundary for noninferiority.

In an unplanned analysis, the pattern among men younger than 75 years was similar to that in the entire trial population. But among men 75 years of age and older, the 57-Gy arm is actually outperforming the 74-Gy arm (HR, 0.77).

The three regimens yielded a similarly high rate of freedom from metastases, at about 95% in each arm. The 60-Gy regimen had an edge in overall survival relative to the 74-Gy regimen (88.6% vs. 85.9%; HR, 0.84) that is hard to explain, according to Dr. Dearnaley.

“Because there is an 8:1 ratio of non–prostate cancer deaths to prostate cancer deaths, you would have to postulate something other than prostate cancer being affected by the radiotherapy fractionation,” he said. “The answers on a postcard, because I can’t think of one.”

On central pathology review, nearly a fifth of evaluated trial patients had high-risk disease. “I know everybody wants to know about high-risk patients, but I’d rather take the trial results as a whole and look to see if there is any heterogeneity between those groups rather than perform a specific high-risk subgroup analysis,” Dr. Dearnaley said, expressing concern about performing too many subgroup analyses.

That said, older patients on the trial tended to have higher risk. “It does seem hypofractionation was particularly useful in those patients,” he noted. “Now, whether that’s anything to do with their pathology or whether it’s due to their age per se, I really don’t know.”

There were no differences between groups on rates of Radiation Therapy Oncology Group toxicity at 5 years, with grade 2 or worse bowel toxicity and bladder toxicity each seen in about 2% of patients.

There were no significant differences in rates of patient-reported “moderate or big” bowel bother (roughly 5%-8%) and urinary bother (roughly 7%-9%). For all regimens, bowel and urinary symptoms remained stable from 2-5 years.

Reassuring for practice

These updated findings “support the continued use of 60 Gy in 20 fractions as the standard of care,” Dr. Dearnaley said.

When the math is run to permit comparison, efficacy findings of the CHHiP trial show “amazing agreement” with those of the similar multinational PROFIT trial, he noted (J Clin Oncol. 2017 Jun 10;35(17):1884-90).

The absolute advantage in the failure-free rate of 3.1% and the overall survival rate of 2.7% for the 60-Gy regimen in CHHiP generated interest among symposium attendees about its possible superiority. “I think the 60 Gy is marginally more effective than the 74 Gy,” Dr. Dearnaley said, but he acknowledged that there are no statistics to prove that.

Susan London/MDedge News

“This CHHiP update is fantastic,” said session cochair Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston. “It is very reassuring that the initial results the investigators presented several years ago still hold up in the long term. It’s even more reassuring for the use of hypofractionation, and it’s great to know that we can use it across the age spectrum and it works well.”

This trial is the only noninferiority hypofractionation trial in prostate cancer that includes a sizable share of patients at high risk for poor outcomes, a population for whom efficacy of this strategy is of particular interest, Dr. Nguyen noted.

“That’s always been a question,” he said. “The majority of the data from the noninferiority trials is for the low- and intermediate-risk patients. So it really would be interesting to learn whatever we can about high-risk patients from this trial.”

The trial was funded by Cancer Research UK, Department of Health (UK), and the National Institute for Health Research Cancer Research Network. Dr. Dearnaley and Dr. Nguyen disclosed relationships with a range of pharmaceutical companies.
 

SOURCE: Dearnaley DP et al. GUCS 2020. Abstract 325.

SAN FRANCISCO – The molecular subtype of metastatic hormone-sensitive prostate cancer dictates the benefit of adding docetaxel to androgen deprivation therapy (ADT), according to a correlative analysis of the CHAARTED trial.

Susan London/MDedge News

Researchers found that adding docetaxel to ADT reduced the risk of death by 55% among men with luminal B subtype tumors, which corresponded to about 22 more months of life on average. In contrast, there was no significant reduction in risk of death among men with the basal subtype.

Anis Hamid, MD, of the Dana-Farber Cancer Institute in Boston, presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The phase 3, randomized CHAARTED trial included 790 men with newly diagnosed, metastatic, hormone-sensitive prostate cancer. Previously reported results showed a survival benefit of adding six cycles of docetaxel to ADT (N Engl J Med. 2015;373:737-46), with long-term durability driven by benefit in men with high-volume disease (J Clin Oncol. 2018;36:1080-7).

These findings, along with those from similar chemotherapy trials, changed the treatment paradigm for metastatic hormone-sensitive disease, Dr. Hamid noted. Androgen receptor signaling inhibitors and prostate radiation have since entered this treatment space as well.

“There is a critical need to identify and better understand patients who do and do not benefit from upfront chemotherapy or potent hormonal therapy in order to guide optimal therapy selection,” Dr. Hamid said. “It is hypothesized that understanding the underlying biology will provide critical insights.”

Study details

Dr. Hamid and colleagues analyzed primary biopsies obtained at the time of metastatic diagnosis, before ADT exposure, in 160 patients treated on the CHAARTED trial. The researchers performed whole-transcriptome profiling and classification using the PAM50 gene set.

Tumors were classified as basal subtype in 52.1% of patients, as luminal B subtype in 46.1%, and as luminal A subtype in 1.8%.

Among patients given ADT alone, those with luminal B subtype tended to have poorer overall survival than those with basal subtype (hazard ratio, 1.75; P = .052). Among patients who received ADT plus docetaxel, there was no significant difference in overall survival according to subtype (HR, 0.92; P = .14).

The addition of docetaxel to ADT significantly prolonged median overall survival among men with luminal B subtype (52.1 months vs. 29.8 months; HR, 0.45; P = .007) but not among men with basal subtype (49.2 months vs. 47.1 months; HR, 0.85; P = .60). Findings were similar in an analysis restricted to patients with high-volume disease, according to Dr. Hamid.

“Luminal B tumors are associated with a poorer prognosis on ADT alone but significantly benefit from the addition of docetaxel chemotherapy upfront,” he said. “Conversely, basal subtype predicts for a lack of survival benefit with docetaxel.”

Dr. Hamid and colleagues also found that adding docetaxel significantly prolonged median time to castration-resistant prostate cancer, regardless of whether the subtype was luminal B (16.9 months vs. 8.0 months; HR, 0.43; P = .001) or basal (17.7 months vs. 6.4 months; HR, 0.51; P = .013).

Dr. Hamid acknowledged that prediction of treatment response is likely to be more complex than this research suggests and additionally influenced by as-yet-unidentified biomarkers.

“I await more biological information from CHAARTED but also independent metastatic cohorts,” he said. “I don’t think it’s likely there will be just one particular very discrete story like we have presented today. The effect size that we saw in the luminal B tumors, for example, with respect to the benefit of docetaxel, wasn’t subtle. It was big, and I am ever keen to know what is driving that.”

Clinical implications

“The landscape of treatments for metastatic hormone-sensitive prostate cancer is very complicated, and there are many, many good options and probably more than one best answer for each patient,” said invited discussant Dana E. Rathkopf, MD, of the Memorial Sloan Kettering Cancer Center in New York.

Susan London/MDedge News

Historically, the luminal B subtype has been associated with a good response to ADT but also with a high proliferation rate and fairly poor prognosis. “So maybe the luminal B response to ADT was good, but it wasn’t good enough, given the underlying biology of this poor prognostic subtype,” Dr. Rathkopf said.

She added that the efficacy of ADT alone may have been worse than expected in the luminal B group, making the addition of docetaxel appear more favorable, as overall survival with ADT plus docetaxel was similar between these subtypes, at about 50 months.

“But still, it looks like the addition of docetaxel added benefit to these luminal B cells regardless of whether they did better or worse than was expected on the ADT,” Dr. Rathkopf said. Taken together, the findings identify luminal B subtype as a predictive biomarker of response to docetaxel in men with metastatic hormone-sensitive prostate cancer, she added.

“Can this help select patients who should and should not receive docetaxel? I think we would all agree that further validation is needed before we move this into clinical practice,” Dr. Rathkopf said. “It’s not that easy, and there are probably additional tests and additional molecular factors that we need to incorporate into these types of models.”

“As a clinician, if I see a patient tomorrow with newly diagnosed metastatic hormone-sensitive prostate cancer who is basal subtype on PAM50, I certainly wouldn’t withhold docetaxel,” Dr. Hamid said. “Withholding a proven life-prolonging therapy needs to meet a very high bar of biomarker discovery and validation independently for us to confidently translate that to the clinics.”

This research was funded by Decipher Biosciences and the National Institutes of Health. The CHAARTED trial was funded by the ECOG-ACRIN Cancer Research Group in collaboration with the National Cancer Institute.

Dr. Hamid disclosed relationships with Bayer and Merck Sharp and Dohme. Dr. Rathkopf disclosed relationships with AstraZeneca, Genentech/Roche, Janssen, Celgene, Ferring, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma.
 

SOURCE: Hamid A et al. GUCS 2020. Abstract 162.

SAN FRANCISCO – The molecular subtype of metastatic hormone-sensitive prostate cancer dictates the benefit of adding docetaxel to androgen deprivation therapy (ADT), according to a correlative analysis of the CHAARTED trial.

Susan London/MDedge News

Researchers found that adding docetaxel to ADT reduced the risk of death by 55% among men with luminal B subtype tumors, which corresponded to about 22 more months of life on average. In contrast, there was no significant reduction in risk of death among men with the basal subtype.

Anis Hamid, MD, of the Dana-Farber Cancer Institute in Boston, presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The phase 3, randomized CHAARTED trial included 790 men with newly diagnosed, metastatic, hormone-sensitive prostate cancer. Previously reported results showed a survival benefit of adding six cycles of docetaxel to ADT (N Engl J Med. 2015;373:737-46), with long-term durability driven by benefit in men with high-volume disease (J Clin Oncol. 2018;36:1080-7).

These findings, along with those from similar chemotherapy trials, changed the treatment paradigm for metastatic hormone-sensitive disease, Dr. Hamid noted. Androgen receptor signaling inhibitors and prostate radiation have since entered this treatment space as well.

“There is a critical need to identify and better understand patients who do and do not benefit from upfront chemotherapy or potent hormonal therapy in order to guide optimal therapy selection,” Dr. Hamid said. “It is hypothesized that understanding the underlying biology will provide critical insights.”

Study details

Dr. Hamid and colleagues analyzed primary biopsies obtained at the time of metastatic diagnosis, before ADT exposure, in 160 patients treated on the CHAARTED trial. The researchers performed whole-transcriptome profiling and classification using the PAM50 gene set.

Tumors were classified as basal subtype in 52.1% of patients, as luminal B subtype in 46.1%, and as luminal A subtype in 1.8%.

Among patients given ADT alone, those with luminal B subtype tended to have poorer overall survival than those with basal subtype (hazard ratio, 1.75; P = .052). Among patients who received ADT plus docetaxel, there was no significant difference in overall survival according to subtype (HR, 0.92; P = .14).

The addition of docetaxel to ADT significantly prolonged median overall survival among men with luminal B subtype (52.1 months vs. 29.8 months; HR, 0.45; P = .007) but not among men with basal subtype (49.2 months vs. 47.1 months; HR, 0.85; P = .60). Findings were similar in an analysis restricted to patients with high-volume disease, according to Dr. Hamid.

“Luminal B tumors are associated with a poorer prognosis on ADT alone but significantly benefit from the addition of docetaxel chemotherapy upfront,” he said. “Conversely, basal subtype predicts for a lack of survival benefit with docetaxel.”

Dr. Hamid and colleagues also found that adding docetaxel significantly prolonged median time to castration-resistant prostate cancer, regardless of whether the subtype was luminal B (16.9 months vs. 8.0 months; HR, 0.43; P = .001) or basal (17.7 months vs. 6.4 months; HR, 0.51; P = .013).

Dr. Hamid acknowledged that prediction of treatment response is likely to be more complex than this research suggests and additionally influenced by as-yet-unidentified biomarkers.

“I await more biological information from CHAARTED but also independent metastatic cohorts,” he said. “I don’t think it’s likely there will be just one particular very discrete story like we have presented today. The effect size that we saw in the luminal B tumors, for example, with respect to the benefit of docetaxel, wasn’t subtle. It was big, and I am ever keen to know what is driving that.”

Clinical implications

“The landscape of treatments for metastatic hormone-sensitive prostate cancer is very complicated, and there are many, many good options and probably more than one best answer for each patient,” said invited discussant Dana E. Rathkopf, MD, of the Memorial Sloan Kettering Cancer Center in New York.

Susan London/MDedge News

Historically, the luminal B subtype has been associated with a good response to ADT but also with a high proliferation rate and fairly poor prognosis. “So maybe the luminal B response to ADT was good, but it wasn’t good enough, given the underlying biology of this poor prognostic subtype,” Dr. Rathkopf said.

She added that the efficacy of ADT alone may have been worse than expected in the luminal B group, making the addition of docetaxel appear more favorable, as overall survival with ADT plus docetaxel was similar between these subtypes, at about 50 months.

“But still, it looks like the addition of docetaxel added benefit to these luminal B cells regardless of whether they did better or worse than was expected on the ADT,” Dr. Rathkopf said. Taken together, the findings identify luminal B subtype as a predictive biomarker of response to docetaxel in men with metastatic hormone-sensitive prostate cancer, she added.

“Can this help select patients who should and should not receive docetaxel? I think we would all agree that further validation is needed before we move this into clinical practice,” Dr. Rathkopf said. “It’s not that easy, and there are probably additional tests and additional molecular factors that we need to incorporate into these types of models.”

“As a clinician, if I see a patient tomorrow with newly diagnosed metastatic hormone-sensitive prostate cancer who is basal subtype on PAM50, I certainly wouldn’t withhold docetaxel,” Dr. Hamid said. “Withholding a proven life-prolonging therapy needs to meet a very high bar of biomarker discovery and validation independently for us to confidently translate that to the clinics.”

This research was funded by Decipher Biosciences and the National Institutes of Health. The CHAARTED trial was funded by the ECOG-ACRIN Cancer Research Group in collaboration with the National Cancer Institute.

Dr. Hamid disclosed relationships with Bayer and Merck Sharp and Dohme. Dr. Rathkopf disclosed relationships with AstraZeneca, Genentech/Roche, Janssen, Celgene, Ferring, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma.
 

SOURCE: Hamid A et al. GUCS 2020. Abstract 162.

SAN FRANCISCO – The molecular subtype of metastatic hormone-sensitive prostate cancer dictates the benefit of adding docetaxel to androgen deprivation therapy (ADT), according to a correlative analysis of the CHAARTED trial.

Susan London/MDedge News

Researchers found that adding docetaxel to ADT reduced the risk of death by 55% among men with luminal B subtype tumors, which corresponded to about 22 more months of life on average. In contrast, there was no significant reduction in risk of death among men with the basal subtype.

Anis Hamid, MD, of the Dana-Farber Cancer Institute in Boston, presented these results at the 2020 Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

The phase 3, randomized CHAARTED trial included 790 men with newly diagnosed, metastatic, hormone-sensitive prostate cancer. Previously reported results showed a survival benefit of adding six cycles of docetaxel to ADT (N Engl J Med. 2015;373:737-46), with long-term durability driven by benefit in men with high-volume disease (J Clin Oncol. 2018;36:1080-7).

These findings, along with those from similar chemotherapy trials, changed the treatment paradigm for metastatic hormone-sensitive disease, Dr. Hamid noted. Androgen receptor signaling inhibitors and prostate radiation have since entered this treatment space as well.

“There is a critical need to identify and better understand patients who do and do not benefit from upfront chemotherapy or potent hormonal therapy in order to guide optimal therapy selection,” Dr. Hamid said. “It is hypothesized that understanding the underlying biology will provide critical insights.”

Study details

Dr. Hamid and colleagues analyzed primary biopsies obtained at the time of metastatic diagnosis, before ADT exposure, in 160 patients treated on the CHAARTED trial. The researchers performed whole-transcriptome profiling and classification using the PAM50 gene set.

Tumors were classified as basal subtype in 52.1% of patients, as luminal B subtype in 46.1%, and as luminal A subtype in 1.8%.

Among patients given ADT alone, those with luminal B subtype tended to have poorer overall survival than those with basal subtype (hazard ratio, 1.75; P = .052). Among patients who received ADT plus docetaxel, there was no significant difference in overall survival according to subtype (HR, 0.92; P = .14).

The addition of docetaxel to ADT significantly prolonged median overall survival among men with luminal B subtype (52.1 months vs. 29.8 months; HR, 0.45; P = .007) but not among men with basal subtype (49.2 months vs. 47.1 months; HR, 0.85; P = .60). Findings were similar in an analysis restricted to patients with high-volume disease, according to Dr. Hamid.

“Luminal B tumors are associated with a poorer prognosis on ADT alone but significantly benefit from the addition of docetaxel chemotherapy upfront,” he said. “Conversely, basal subtype predicts for a lack of survival benefit with docetaxel.”

Dr. Hamid and colleagues also found that adding docetaxel significantly prolonged median time to castration-resistant prostate cancer, regardless of whether the subtype was luminal B (16.9 months vs. 8.0 months; HR, 0.43; P = .001) or basal (17.7 months vs. 6.4 months; HR, 0.51; P = .013).

Dr. Hamid acknowledged that prediction of treatment response is likely to be more complex than this research suggests and additionally influenced by as-yet-unidentified biomarkers.

“I await more biological information from CHAARTED but also independent metastatic cohorts,” he said. “I don’t think it’s likely there will be just one particular very discrete story like we have presented today. The effect size that we saw in the luminal B tumors, for example, with respect to the benefit of docetaxel, wasn’t subtle. It was big, and I am ever keen to know what is driving that.”

Clinical implications

“The landscape of treatments for metastatic hormone-sensitive prostate cancer is very complicated, and there are many, many good options and probably more than one best answer for each patient,” said invited discussant Dana E. Rathkopf, MD, of the Memorial Sloan Kettering Cancer Center in New York.

Susan London/MDedge News

Historically, the luminal B subtype has been associated with a good response to ADT but also with a high proliferation rate and fairly poor prognosis. “So maybe the luminal B response to ADT was good, but it wasn’t good enough, given the underlying biology of this poor prognostic subtype,” Dr. Rathkopf said.

She added that the efficacy of ADT alone may have been worse than expected in the luminal B group, making the addition of docetaxel appear more favorable, as overall survival with ADT plus docetaxel was similar between these subtypes, at about 50 months.

“But still, it looks like the addition of docetaxel added benefit to these luminal B cells regardless of whether they did better or worse than was expected on the ADT,” Dr. Rathkopf said. Taken together, the findings identify luminal B subtype as a predictive biomarker of response to docetaxel in men with metastatic hormone-sensitive prostate cancer, she added.

“Can this help select patients who should and should not receive docetaxel? I think we would all agree that further validation is needed before we move this into clinical practice,” Dr. Rathkopf said. “It’s not that easy, and there are probably additional tests and additional molecular factors that we need to incorporate into these types of models.”

“As a clinician, if I see a patient tomorrow with newly diagnosed metastatic hormone-sensitive prostate cancer who is basal subtype on PAM50, I certainly wouldn’t withhold docetaxel,” Dr. Hamid said. “Withholding a proven life-prolonging therapy needs to meet a very high bar of biomarker discovery and validation independently for us to confidently translate that to the clinics.”

This research was funded by Decipher Biosciences and the National Institutes of Health. The CHAARTED trial was funded by the ECOG-ACRIN Cancer Research Group in collaboration with the National Cancer Institute.

Dr. Hamid disclosed relationships with Bayer and Merck Sharp and Dohme. Dr. Rathkopf disclosed relationships with AstraZeneca, Genentech/Roche, Janssen, Celgene, Ferring, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma.
 

SOURCE: Hamid A et al. GUCS 2020. Abstract 162.

Men with low-volume, advanced prostate cancer who carry one or more adrenal-permissive alleles of the HSD3B1 gene have worse prognosis than do men with adrenal-restrictive alleles of HSD3B1, a retrospective analysis suggests.

Among 475 white men in the CHAARTED trial, those with the adrenal-permissive allele, HSD3B1(1245C), had a nearly twofold greater risk for developing early castration-resistant prostate cancer (CRPC) and for lower overall survival, compared with men who had the adrenal-restrictive allele, HSD3B1(1245A).

“Our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume, metastatic prostate cancer,” Jason W.D. Hearn, MD, of the University of Michigan in Ann Arbor and colleagues wrote in JAMA Oncology.

HSD3B1 encodes for an enzyme involved in regulating the rate of metabolic conversion of the precursor hormone dehydroepiandrosterone into testosterone and dihydrotestosterone in prostate tissues. A common missense-encoding germline mutation in the gene leads to variant metabolic phenotypes, including the adrenal-permissive type that allows for ramped-up conversion of the precursor hormone into dihydrotestosterone and the adrenal-restrictive type that results in more rapid enzyme degradation, limiting the conversion from the precursor into the active hormone.

“The population frequency of the adrenal-permissive HSD3B1(1245C) allele varies tremendously by race and is disproportionally high in white men (e.g., carried in approximately 70% of Italian and Spanish men and only about 9% of Yoruba Nigerian men),” Dr. Hearn and colleagues wrote.

Previous studies have suggested that men with both metastatic and nonmetastatic prostate cancer who inherit the adrenal permissive HSD3B1(1245C) allele have worse clinical outcomes, compared with men without that allele.

To validate these findings, Dr. Hearn and colleagues retrospectively determined the germline genotype of HSD3B1 for 475 white men enrolled in CHAARTED. In that trial, men with metastatic, hormone-sensitive prostate cancer were randomized to either castration alone or castration plus docetaxel. The current analysis showed that 270 of those patients carried the adrenal-permissive allele.

Among patients with low-volume disease, the adrenal-permissive genotype was associated with significantly lower freedom from CRPC at 2 years, compared with the adrenal-restrictive genotype: 51% and 70.5%, respectively (hazard ratio, 1.89; P = .02). The 5-year overall survival rate was significantly lower for adrenal-permissive allele carriers than adrenal-restrictive allele carriers: 57.5% and 70.8%, respectively (HR, 1.74; P = .045).

Among men with high-volume disease, there was no association between HSD3B1 genotypes and outcomes, and there was no interaction between genotype and benefit from docetaxel. High-volume disease was defined as the presence of visceral metastases or four or more bone metastases with one or more lesions beyond the pelvis and vertebral bodies.

“Regardless of genotype, men with high-volume disease achieved better outcomes when docetaxel was added to ADT [androgen deprivation therapy], whereas outcomes in men with low-volume disease varied only by genotype, with no clear benefit from docetaxel,” the investigators wrote.

The trial was funded by the National Cancer Institute. The authors disclosed relationships with several pharmaceutical companies. One author is a coinventor on a patent for a treatment method based on HSD3B1.

SOURCE: Hearn JWD et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6496.

Men with low-volume, advanced prostate cancer who carry one or more adrenal-permissive alleles of the HSD3B1 gene have worse prognosis than do men with adrenal-restrictive alleles of HSD3B1, a retrospective analysis suggests.

Among 475 white men in the CHAARTED trial, those with the adrenal-permissive allele, HSD3B1(1245C), had a nearly twofold greater risk for developing early castration-resistant prostate cancer (CRPC) and for lower overall survival, compared with men who had the adrenal-restrictive allele, HSD3B1(1245A).

“Our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume, metastatic prostate cancer,” Jason W.D. Hearn, MD, of the University of Michigan in Ann Arbor and colleagues wrote in JAMA Oncology.

HSD3B1 encodes for an enzyme involved in regulating the rate of metabolic conversion of the precursor hormone dehydroepiandrosterone into testosterone and dihydrotestosterone in prostate tissues. A common missense-encoding germline mutation in the gene leads to variant metabolic phenotypes, including the adrenal-permissive type that allows for ramped-up conversion of the precursor hormone into dihydrotestosterone and the adrenal-restrictive type that results in more rapid enzyme degradation, limiting the conversion from the precursor into the active hormone.

“The population frequency of the adrenal-permissive HSD3B1(1245C) allele varies tremendously by race and is disproportionally high in white men (e.g., carried in approximately 70% of Italian and Spanish men and only about 9% of Yoruba Nigerian men),” Dr. Hearn and colleagues wrote.

Previous studies have suggested that men with both metastatic and nonmetastatic prostate cancer who inherit the adrenal permissive HSD3B1(1245C) allele have worse clinical outcomes, compared with men without that allele.

To validate these findings, Dr. Hearn and colleagues retrospectively determined the germline genotype of HSD3B1 for 475 white men enrolled in CHAARTED. In that trial, men with metastatic, hormone-sensitive prostate cancer were randomized to either castration alone or castration plus docetaxel. The current analysis showed that 270 of those patients carried the adrenal-permissive allele.

Among patients with low-volume disease, the adrenal-permissive genotype was associated with significantly lower freedom from CRPC at 2 years, compared with the adrenal-restrictive genotype: 51% and 70.5%, respectively (hazard ratio, 1.89; P = .02). The 5-year overall survival rate was significantly lower for adrenal-permissive allele carriers than adrenal-restrictive allele carriers: 57.5% and 70.8%, respectively (HR, 1.74; P = .045).

Among men with high-volume disease, there was no association between HSD3B1 genotypes and outcomes, and there was no interaction between genotype and benefit from docetaxel. High-volume disease was defined as the presence of visceral metastases or four or more bone metastases with one or more lesions beyond the pelvis and vertebral bodies.

“Regardless of genotype, men with high-volume disease achieved better outcomes when docetaxel was added to ADT [androgen deprivation therapy], whereas outcomes in men with low-volume disease varied only by genotype, with no clear benefit from docetaxel,” the investigators wrote.

The trial was funded by the National Cancer Institute. The authors disclosed relationships with several pharmaceutical companies. One author is a coinventor on a patent for a treatment method based on HSD3B1.

SOURCE: Hearn JWD et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6496.

Men with low-volume, advanced prostate cancer who carry one or more adrenal-permissive alleles of the HSD3B1 gene have worse prognosis than do men with adrenal-restrictive alleles of HSD3B1, a retrospective analysis suggests.

Among 475 white men in the CHAARTED trial, those with the adrenal-permissive allele, HSD3B1(1245C), had a nearly twofold greater risk for developing early castration-resistant prostate cancer (CRPC) and for lower overall survival, compared with men who had the adrenal-restrictive allele, HSD3B1(1245A).

“Our findings suggest that the HSD3B1 genotype can be used to risk stratify white men with low-volume, metastatic prostate cancer,” Jason W.D. Hearn, MD, of the University of Michigan in Ann Arbor and colleagues wrote in JAMA Oncology.

HSD3B1 encodes for an enzyme involved in regulating the rate of metabolic conversion of the precursor hormone dehydroepiandrosterone into testosterone and dihydrotestosterone in prostate tissues. A common missense-encoding germline mutation in the gene leads to variant metabolic phenotypes, including the adrenal-permissive type that allows for ramped-up conversion of the precursor hormone into dihydrotestosterone and the adrenal-restrictive type that results in more rapid enzyme degradation, limiting the conversion from the precursor into the active hormone.

“The population frequency of the adrenal-permissive HSD3B1(1245C) allele varies tremendously by race and is disproportionally high in white men (e.g., carried in approximately 70% of Italian and Spanish men and only about 9% of Yoruba Nigerian men),” Dr. Hearn and colleagues wrote.

Previous studies have suggested that men with both metastatic and nonmetastatic prostate cancer who inherit the adrenal permissive HSD3B1(1245C) allele have worse clinical outcomes, compared with men without that allele.

To validate these findings, Dr. Hearn and colleagues retrospectively determined the germline genotype of HSD3B1 for 475 white men enrolled in CHAARTED. In that trial, men with metastatic, hormone-sensitive prostate cancer were randomized to either castration alone or castration plus docetaxel. The current analysis showed that 270 of those patients carried the adrenal-permissive allele.

Among patients with low-volume disease, the adrenal-permissive genotype was associated with significantly lower freedom from CRPC at 2 years, compared with the adrenal-restrictive genotype: 51% and 70.5%, respectively (hazard ratio, 1.89; P = .02). The 5-year overall survival rate was significantly lower for adrenal-permissive allele carriers than adrenal-restrictive allele carriers: 57.5% and 70.8%, respectively (HR, 1.74; P = .045).

Among men with high-volume disease, there was no association between HSD3B1 genotypes and outcomes, and there was no interaction between genotype and benefit from docetaxel. High-volume disease was defined as the presence of visceral metastases or four or more bone metastases with one or more lesions beyond the pelvis and vertebral bodies.

“Regardless of genotype, men with high-volume disease achieved better outcomes when docetaxel was added to ADT [androgen deprivation therapy], whereas outcomes in men with low-volume disease varied only by genotype, with no clear benefit from docetaxel,” the investigators wrote.

The trial was funded by the National Cancer Institute. The authors disclosed relationships with several pharmaceutical companies. One author is a coinventor on a patent for a treatment method based on HSD3B1.

SOURCE: Hearn JWD et al. JAMA Oncol. 2020 Feb 13. doi: 10.1001/jamaoncol.2019.6496.