TBD Meeting (4663-24)

Lowering the recommended age for baseline prostate-specific antigen (PSA) would reduce prostate cancer deaths by about 30% in Black men without significantly increasing the rate of overdiagnosis, according to new screening guidelines from the Prostate Cancer Foundation.

Specifically, baseline PSA testing in Black men should begin at age 40-45, sooner than current guidelines recommend, and should be followed by regular screening intervals, preferably annually, at least until age 70, a multidisciplinary panel of experts and patient advocates determined based on a comprehensive literature review.

The panel’s findings were presented in a poster at the ASCO Genitourinary Cancers Symposium.

“Black men in the United States are considered a high-risk population for being diagnosed with and dying from prostate cancer,” wrote lead author Isla Garraway, MD, PhD, of the University of California, Los Angeles, and colleagues. Specifically, Black men are about two times more likely to be diagnosed with and die from prostate cancer than White men. But, the authors continued, “few guidelines have outlined specific recommendations for PSA-based prostate cancer screening among Black men.”

The US Preventive Services Task Force recommendations, which are currently being updated, set the PSA screening start age at 55. The task force recommendations, which dictate insurance coverage in the United States, acknowledged “a potential mortality benefit for African American men when beginning screening before age 55 years” but did not explicitly recommend screening earlier.

Current guidelines from the American Cancer Society call for discussions about screening in average-risk men to begin at age 50-55. The recommendations do specify lowering the age to 45 for those at a high risk for prostate cancer, which includes Black men as well as those with a first-degree relative diagnosed with prostate cancer before age 65. In some cases, screening can begin at age 40 in the highest risk men — those with more than one first-degree relative who had prostate cancer at a young age.

The Prostate Cancer Foundation “wanted to address the confusion around different guideline statements and the lack of clarity around screening recommendations for Black men,” said William K. Oh, MD, of The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, who chaired the panel for the new guidelines. “We thus convened a distinguished panel of experts from diverse backgrounds and expertise to create six guidelines statements to help Black men, their families, and their healthcare providers to consider options for prostate cancer screening based on the best available evidence.”

After reviewing 287, the expert panel developed six new guideline statements, reaching at least 80% consensus among panel members, addressing screening for Black men:

• Because Black men are at a high risk for prostate cancer, the benefits of screening generally outweigh the risks.
• PSA testing should be considered first line for prostate cancer screening, although some providers may recommend an optional digital rectal exam in addition to the PSA test.
• Black men should engage in shared decision-making with their healthcare providers and other trusted sources of information to learn about the pros and cons of screening.
• For Black men who elect screening, a baseline PSA test should be done between ages 40 and 45, and annual PSA screening should be strongly considered based on the PSA value and the individual’s health status.
• Black men over age 70 who have been undergoing prostate cancer screening should talk with their healthcare provider about whether to continue PSA testing and make an informed decision based on their age, life expectancy, health status, family history, and prior PSA levels.
• Black men who are at even higher risk due to a strong family history and/or known carriers of high-risk genetic variants should consider initiating annual PSA screening as early as age 40.

These statements are based on “the best available evidence, which overwhelmingly supports the conclusion that Black men in the US could benefit from a risk-adapted PSA screening,” the investigators concluded, noting that the latest evidence “warrants revisiting current recommendations for early [prostate cancer] detection in Black men from other national guideline groups.”

“We believe that the outcome of these more directed guidelines will be to give clarity to these men,” added Oh, who is also chief medical officer for the Prostate Cancer Foundation.

This research was funded by the Prostate Cancer Foundation, National Cancer Institute, Veterans Affairs, Jean Perkins Foundation, and Department of Defense. Garraway reported having no disclosures.
 

A version of this article appeared on Medscape.com.

Lowering the recommended age for baseline prostate-specific antigen (PSA) would reduce prostate cancer deaths by about 30% in Black men without significantly increasing the rate of overdiagnosis, according to new screening guidelines from the Prostate Cancer Foundation.

Specifically, baseline PSA testing in Black men should begin at age 40-45, sooner than current guidelines recommend, and should be followed by regular screening intervals, preferably annually, at least until age 70, a multidisciplinary panel of experts and patient advocates determined based on a comprehensive literature review.

The panel’s findings were presented in a poster at the ASCO Genitourinary Cancers Symposium.

“Black men in the United States are considered a high-risk population for being diagnosed with and dying from prostate cancer,” wrote lead author Isla Garraway, MD, PhD, of the University of California, Los Angeles, and colleagues. Specifically, Black men are about two times more likely to be diagnosed with and die from prostate cancer than White men. But, the authors continued, “few guidelines have outlined specific recommendations for PSA-based prostate cancer screening among Black men.”

The US Preventive Services Task Force recommendations, which are currently being updated, set the PSA screening start age at 55. The task force recommendations, which dictate insurance coverage in the United States, acknowledged “a potential mortality benefit for African American men when beginning screening before age 55 years” but did not explicitly recommend screening earlier.

Current guidelines from the American Cancer Society call for discussions about screening in average-risk men to begin at age 50-55. The recommendations do specify lowering the age to 45 for those at a high risk for prostate cancer, which includes Black men as well as those with a first-degree relative diagnosed with prostate cancer before age 65. In some cases, screening can begin at age 40 in the highest risk men — those with more than one first-degree relative who had prostate cancer at a young age.

The Prostate Cancer Foundation “wanted to address the confusion around different guideline statements and the lack of clarity around screening recommendations for Black men,” said William K. Oh, MD, of The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, who chaired the panel for the new guidelines. “We thus convened a distinguished panel of experts from diverse backgrounds and expertise to create six guidelines statements to help Black men, their families, and their healthcare providers to consider options for prostate cancer screening based on the best available evidence.”

After reviewing 287, the expert panel developed six new guideline statements, reaching at least 80% consensus among panel members, addressing screening for Black men:

• Because Black men are at a high risk for prostate cancer, the benefits of screening generally outweigh the risks.
• PSA testing should be considered first line for prostate cancer screening, although some providers may recommend an optional digital rectal exam in addition to the PSA test.
• Black men should engage in shared decision-making with their healthcare providers and other trusted sources of information to learn about the pros and cons of screening.
• For Black men who elect screening, a baseline PSA test should be done between ages 40 and 45, and annual PSA screening should be strongly considered based on the PSA value and the individual’s health status.
• Black men over age 70 who have been undergoing prostate cancer screening should talk with their healthcare provider about whether to continue PSA testing and make an informed decision based on their age, life expectancy, health status, family history, and prior PSA levels.
• Black men who are at even higher risk due to a strong family history and/or known carriers of high-risk genetic variants should consider initiating annual PSA screening as early as age 40.

These statements are based on “the best available evidence, which overwhelmingly supports the conclusion that Black men in the US could benefit from a risk-adapted PSA screening,” the investigators concluded, noting that the latest evidence “warrants revisiting current recommendations for early [prostate cancer] detection in Black men from other national guideline groups.”

“We believe that the outcome of these more directed guidelines will be to give clarity to these men,” added Oh, who is also chief medical officer for the Prostate Cancer Foundation.

This research was funded by the Prostate Cancer Foundation, National Cancer Institute, Veterans Affairs, Jean Perkins Foundation, and Department of Defense. Garraway reported having no disclosures.
 

A version of this article appeared on Medscape.com.

Lowering the recommended age for baseline prostate-specific antigen (PSA) would reduce prostate cancer deaths by about 30% in Black men without significantly increasing the rate of overdiagnosis, according to new screening guidelines from the Prostate Cancer Foundation.

Specifically, baseline PSA testing in Black men should begin at age 40-45, sooner than current guidelines recommend, and should be followed by regular screening intervals, preferably annually, at least until age 70, a multidisciplinary panel of experts and patient advocates determined based on a comprehensive literature review.

The panel’s findings were presented in a poster at the ASCO Genitourinary Cancers Symposium.

“Black men in the United States are considered a high-risk population for being diagnosed with and dying from prostate cancer,” wrote lead author Isla Garraway, MD, PhD, of the University of California, Los Angeles, and colleagues. Specifically, Black men are about two times more likely to be diagnosed with and die from prostate cancer than White men. But, the authors continued, “few guidelines have outlined specific recommendations for PSA-based prostate cancer screening among Black men.”

The US Preventive Services Task Force recommendations, which are currently being updated, set the PSA screening start age at 55. The task force recommendations, which dictate insurance coverage in the United States, acknowledged “a potential mortality benefit for African American men when beginning screening before age 55 years” but did not explicitly recommend screening earlier.

Current guidelines from the American Cancer Society call for discussions about screening in average-risk men to begin at age 50-55. The recommendations do specify lowering the age to 45 for those at a high risk for prostate cancer, which includes Black men as well as those with a first-degree relative diagnosed with prostate cancer before age 65. In some cases, screening can begin at age 40 in the highest risk men — those with more than one first-degree relative who had prostate cancer at a young age.

The Prostate Cancer Foundation “wanted to address the confusion around different guideline statements and the lack of clarity around screening recommendations for Black men,” said William K. Oh, MD, of The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, who chaired the panel for the new guidelines. “We thus convened a distinguished panel of experts from diverse backgrounds and expertise to create six guidelines statements to help Black men, their families, and their healthcare providers to consider options for prostate cancer screening based on the best available evidence.”

After reviewing 287, the expert panel developed six new guideline statements, reaching at least 80% consensus among panel members, addressing screening for Black men:

• Because Black men are at a high risk for prostate cancer, the benefits of screening generally outweigh the risks.
• PSA testing should be considered first line for prostate cancer screening, although some providers may recommend an optional digital rectal exam in addition to the PSA test.
• Black men should engage in shared decision-making with their healthcare providers and other trusted sources of information to learn about the pros and cons of screening.
• For Black men who elect screening, a baseline PSA test should be done between ages 40 and 45, and annual PSA screening should be strongly considered based on the PSA value and the individual’s health status.
• Black men over age 70 who have been undergoing prostate cancer screening should talk with their healthcare provider about whether to continue PSA testing and make an informed decision based on their age, life expectancy, health status, family history, and prior PSA levels.
• Black men who are at even higher risk due to a strong family history and/or known carriers of high-risk genetic variants should consider initiating annual PSA screening as early as age 40.

These statements are based on “the best available evidence, which overwhelmingly supports the conclusion that Black men in the US could benefit from a risk-adapted PSA screening,” the investigators concluded, noting that the latest evidence “warrants revisiting current recommendations for early [prostate cancer] detection in Black men from other national guideline groups.”

“We believe that the outcome of these more directed guidelines will be to give clarity to these men,” added Oh, who is also chief medical officer for the Prostate Cancer Foundation.

This research was funded by the Prostate Cancer Foundation, National Cancer Institute, Veterans Affairs, Jean Perkins Foundation, and Department of Defense. Garraway reported having no disclosures.
 

A version of this article appeared on Medscape.com.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.

Two drugs delivered in combination are better than one after the other for the first-line treatment of men with metastatic castration-resistant prostate cancer bearing homologous recombination-repair mutations.

That’s the conclusion of investigators in the phase 2 BRCAAway trial, which compared a combination of abiraterone (Zytiga) and prednisone plus olaparib (Lynparza) against sequential therapy with the same agents.

At the time of data cutoff, median progression-free survival (PFS), the primary endpoint, was 39 months for patients randomized to the combination, compared with 8.4 months for those assigned to abiraterone/prednisone, and 14 months for those assigned to olaparib monotherapy, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center in Chicago.

“In patients with metastatic castration-resistant prostate cancer [mCRPC] and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs. single-agent olaparib or abiraterone/prednisone,” she said in an oral abstract presentation at the ASCO Genitourinary Cancers Symposium.

Although the study allowed crossover between the single-agent arms at the time of progression, only a few patients made the switch. Nonetheless, in these patients the PFS with the frontline combination was superior to that of sequential therapy, she noted.
 

Study Rationale and Design

Germline or somatic mutations in genes encoding for homologous recombination-repair occur in about 20% of men with mCRPC. Olaparib, a PARP1 (poly-adp ribose polymerase-1) inhibitor, interacts with androgen signaling, and preclinical studies have shown that castration-resistant prostate tumor cells have increased PARP1 activity. In addition, PARP1 has been shown preclinically to synergize with androgen receptor pathway inhibitors (ARPIs) such as abiraterone, Dr. Hussain explained.

The BRCAAway trial was designed to test whether co-targeting the androgen receptor and PARP1 could result in higher and more durable responses than current frontline therapies in patients with mCRPC with DNA-damage response mutations.

Patients with mCRPC with no prior exposure to either a PARP1 inhibitor, androgen receptor inhibitor, or mCRPC-directed chemotherapy underwent next-generation sequencing and germline testing of tumor tissues, and those patients found to have inactivating BRCA1/2 and/or ATM alterations were randomized on a 1:1:1 basis to either abiraterone 1000 mg daily plus prednisone 5 mg twice daily (19 patients); olaparib 300 mg twice daily (21 patients); or to the combination (21 patients).

The primary endpoint was radiographic PFS according to RECIST 1.1 criteria, Prostate Cancer Working Group 3 criteria, clinical assessment, or death.

As noted, the median PFS was 8.4 months with abiraterone/prednisone, 14 months with olaparib, and 39 months with the combination.

Secondary endpoints also favored the combination therapy arm, with objective response rates of 22%, 14%, and 33%, respectively; PSA response rates of 61%, 67% and 95%; and undetectable PSA response rates of 17%, 14%, and 33%.

A total of 8 of 19 patients on abiraterone were crossed over to olaparib, and 8 of 21 initially assigned to olaparib were crossed over to abiraterone. In these patients the median PFS from crossover was 8.3 and 7.2 months, respectively. In each crossover group the median PFS from the time of randomization was 16 months.

There were no grade 4 adverse events or treatment-related deaths reported in any of the study arms, and “essentially when you look at the adverse events, they pretty much are consistent with what you would expect to see with these particular agents,” Dr. Hussain said.

“Overall the patients were tolerating the treatment well,” she added.
 

Practice Changing with Caveats

Kim N. Chi, MD, FRCPC, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant, said that the strengths of the study included an olaparib monotherapy arm — something that was missing from phase 3 trials — that provides insights into how PARP inhibitors perform in this population. He also applauded the inclusion of clinical assessment as a primary endpoint, noting that “this is what we do in routine practice, and therefore, the generalizability of the trial becomes more evident.”

The crossover design provides important information about whether an upfront combination or a sequential therapy approach is more effective, as well, he added.

He pointed out, however, that the trial was limited by small sample size and by its “horse race” design rather than as a comparison trial.

“So how does the BRCAAway trial change our practice? Despite the limitations, I think it does support an upfront PARP inhibitor-ARPI combination as firstline therapy for HRR gene-mutated metastatic CRPC. These data suggest synergy, and most importantly, there is no loss of opportunity [for more effective therapies]. However, the limitations of the trial will not end this debate today,” he said.

The trial was funded by AstraZeneca. Both Dr. Hussain and Dr. Chi disclosed honoraria, consulting/advising, and institutional research funding from AstraZeneca and others.

Lowering the recommended age for baseline prostate-specific antigen (PSA) would reduce prostate cancer deaths by about 30% in Black men without significantly increasing the rate of overdiagnosis, according to new screening guidelines from the Prostate Cancer Foundation.

Specifically, baseline PSA testing in Black men should begin at age 40-45, sooner than current guidelines recommend, and should be followed by regular screening intervals, preferably annually, at least until age 70, a multidisciplinary panel of experts and patient advocates determined based on a comprehensive literature review.

The panel’s findings were presented in a poster at the ASCO Genitourinary Symposium.

“Black men in the United States are considered a high-risk population for being diagnosed with and dying from prostate cancer,” lead author Isla Garraway, MD, PhD, of the University of California, Los Angeles, and colleagues wrote. Specifically, Black men are about two times more likely to be diagnosed with and die from prostate cancer than White men. But, the authors continued, “few guidelines have outlined specific recommendations for PSA-based prostate cancer screening among Black men.”

The US Preventive Services Taskforce recommendations, which are currently being updated, set the PSA screening start age at 55. The task force recommendations, which dictate insurance coverage in the United States, acknowledged “a potential mortality benefit for African American men when beginning screening before age 55 years” but did not explicitly recommend screening earlier.

Current guidelines from the American Cancer Society call for discussions about screening in average-risk men to begin at age 50-55. The recommendations do specify lowering the age to 45 for those at a high risk for prostate cancer, which includes Black men as well as those with a first-degree relative diagnosed with prostate cancer before age 65. In some cases, screening can begin at age 40 in the highest risk men — those with more than one first-degree relative who had prostate cancer at a young age.

The Prostate Cancer Foundation “wanted to address the confusion around different guideline statements and the lack of clarity around screening recommendations for Black men,” said William K. Oh, MD, of The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, who chaired the panel for the new guidelines. “We thus convened a distinguished panel of experts from diverse backgrounds and expertise to create six guidelines statements to help Black men, their families, and their healthcare providers to consider options for prostate cancer screening based on the best available evidence.”

After reviewing 287, the expert panel developed six new guideline statements, reaching at least 80% consensus among panel members, addressing screening for Black men:

Because Black men are at a high risk for prostate cancer, the benefits of screening generally outweigh the risks.

PSA testing should be considered first line for prostate cancer screening, although some providers may recommend an optional digital rectal exam in addition to the PSA test.

Black men should engage in shared decision-making with their healthcare providers and other trusted sources of information to learn about the pros and cons of screening.

For Black men who elect screening, a baseline PSA test should be done between ages 40 and 45, and annual PSA screening should be strongly considered based on the PSA value and the individual’s health status.

Black men over age 70 who have been undergoing prostate cancer screening should talk with their healthcare provider about whether to continue PSA testing and make an informed decision based on their age, life expectancy, health status, family history, and prior PSA levels.

Black men who are at even higher risk due to a strong family history and/or known carriers of high-risk genetic variants should consider initiating annual PSA screening as early as age 40.

These statements are based on “the best available evidence, which overwhelmingly supports the conclusion that Black men in the US could benefit from a risk-adapted PSA screening,” the investigators concluded, noting that the latest evidence “warrants revisiting current recommendations for early [prostate cancer] detection in Black men from other national guideline groups.”

“We believe that the outcome of these more directed guidelines will be to give clarity to these men,” Dr. Oh added.

This research was funded by the Prostate Cancer Foundation, National Cancer Institute, Veterans Affairs, Jean Perkins Foundation, and Department of Defense. Dr. Garraway reported having no disclosures.

A version of this article appeared on Medscape.com.

Lowering the recommended age for baseline prostate-specific antigen (PSA) would reduce prostate cancer deaths by about 30% in Black men without significantly increasing the rate of overdiagnosis, according to new screening guidelines from the Prostate Cancer Foundation.

Specifically, baseline PSA testing in Black men should begin at age 40-45, sooner than current guidelines recommend, and should be followed by regular screening intervals, preferably annually, at least until age 70, a multidisciplinary panel of experts and patient advocates determined based on a comprehensive literature review.

The panel’s findings were presented in a poster at the ASCO Genitourinary Symposium.

“Black men in the United States are considered a high-risk population for being diagnosed with and dying from prostate cancer,” lead author Isla Garraway, MD, PhD, of the University of California, Los Angeles, and colleagues wrote. Specifically, Black men are about two times more likely to be diagnosed with and die from prostate cancer than White men. But, the authors continued, “few guidelines have outlined specific recommendations for PSA-based prostate cancer screening among Black men.”

The US Preventive Services Taskforce recommendations, which are currently being updated, set the PSA screening start age at 55. The task force recommendations, which dictate insurance coverage in the United States, acknowledged “a potential mortality benefit for African American men when beginning screening before age 55 years” but did not explicitly recommend screening earlier.

Current guidelines from the American Cancer Society call for discussions about screening in average-risk men to begin at age 50-55. The recommendations do specify lowering the age to 45 for those at a high risk for prostate cancer, which includes Black men as well as those with a first-degree relative diagnosed with prostate cancer before age 65. In some cases, screening can begin at age 40 in the highest risk men — those with more than one first-degree relative who had prostate cancer at a young age.

The Prostate Cancer Foundation “wanted to address the confusion around different guideline statements and the lack of clarity around screening recommendations for Black men,” said William K. Oh, MD, of The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, who chaired the panel for the new guidelines. “We thus convened a distinguished panel of experts from diverse backgrounds and expertise to create six guidelines statements to help Black men, their families, and their healthcare providers to consider options for prostate cancer screening based on the best available evidence.”

After reviewing 287, the expert panel developed six new guideline statements, reaching at least 80% consensus among panel members, addressing screening for Black men:

Because Black men are at a high risk for prostate cancer, the benefits of screening generally outweigh the risks.

PSA testing should be considered first line for prostate cancer screening, although some providers may recommend an optional digital rectal exam in addition to the PSA test.

Black men should engage in shared decision-making with their healthcare providers and other trusted sources of information to learn about the pros and cons of screening.

For Black men who elect screening, a baseline PSA test should be done between ages 40 and 45, and annual PSA screening should be strongly considered based on the PSA value and the individual’s health status.

Black men over age 70 who have been undergoing prostate cancer screening should talk with their healthcare provider about whether to continue PSA testing and make an informed decision based on their age, life expectancy, health status, family history, and prior PSA levels.

Black men who are at even higher risk due to a strong family history and/or known carriers of high-risk genetic variants should consider initiating annual PSA screening as early as age 40.

These statements are based on “the best available evidence, which overwhelmingly supports the conclusion that Black men in the US could benefit from a risk-adapted PSA screening,” the investigators concluded, noting that the latest evidence “warrants revisiting current recommendations for early [prostate cancer] detection in Black men from other national guideline groups.”

“We believe that the outcome of these more directed guidelines will be to give clarity to these men,” Dr. Oh added.

This research was funded by the Prostate Cancer Foundation, National Cancer Institute, Veterans Affairs, Jean Perkins Foundation, and Department of Defense. Dr. Garraway reported having no disclosures.

A version of this article appeared on Medscape.com.

Lowering the recommended age for baseline prostate-specific antigen (PSA) would reduce prostate cancer deaths by about 30% in Black men without significantly increasing the rate of overdiagnosis, according to new screening guidelines from the Prostate Cancer Foundation.

Specifically, baseline PSA testing in Black men should begin at age 40-45, sooner than current guidelines recommend, and should be followed by regular screening intervals, preferably annually, at least until age 70, a multidisciplinary panel of experts and patient advocates determined based on a comprehensive literature review.

The panel’s findings were presented in a poster at the ASCO Genitourinary Symposium.

“Black men in the United States are considered a high-risk population for being diagnosed with and dying from prostate cancer,” lead author Isla Garraway, MD, PhD, of the University of California, Los Angeles, and colleagues wrote. Specifically, Black men are about two times more likely to be diagnosed with and die from prostate cancer than White men. But, the authors continued, “few guidelines have outlined specific recommendations for PSA-based prostate cancer screening among Black men.”

The US Preventive Services Taskforce recommendations, which are currently being updated, set the PSA screening start age at 55. The task force recommendations, which dictate insurance coverage in the United States, acknowledged “a potential mortality benefit for African American men when beginning screening before age 55 years” but did not explicitly recommend screening earlier.

Current guidelines from the American Cancer Society call for discussions about screening in average-risk men to begin at age 50-55. The recommendations do specify lowering the age to 45 for those at a high risk for prostate cancer, which includes Black men as well as those with a first-degree relative diagnosed with prostate cancer before age 65. In some cases, screening can begin at age 40 in the highest risk men — those with more than one first-degree relative who had prostate cancer at a young age.

The Prostate Cancer Foundation “wanted to address the confusion around different guideline statements and the lack of clarity around screening recommendations for Black men,” said William K. Oh, MD, of The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, who chaired the panel for the new guidelines. “We thus convened a distinguished panel of experts from diverse backgrounds and expertise to create six guidelines statements to help Black men, their families, and their healthcare providers to consider options for prostate cancer screening based on the best available evidence.”

After reviewing 287, the expert panel developed six new guideline statements, reaching at least 80% consensus among panel members, addressing screening for Black men:

Because Black men are at a high risk for prostate cancer, the benefits of screening generally outweigh the risks.

PSA testing should be considered first line for prostate cancer screening, although some providers may recommend an optional digital rectal exam in addition to the PSA test.

Black men should engage in shared decision-making with their healthcare providers and other trusted sources of information to learn about the pros and cons of screening.

For Black men who elect screening, a baseline PSA test should be done between ages 40 and 45, and annual PSA screening should be strongly considered based on the PSA value and the individual’s health status.

Black men over age 70 who have been undergoing prostate cancer screening should talk with their healthcare provider about whether to continue PSA testing and make an informed decision based on their age, life expectancy, health status, family history, and prior PSA levels.

Black men who are at even higher risk due to a strong family history and/or known carriers of high-risk genetic variants should consider initiating annual PSA screening as early as age 40.

These statements are based on “the best available evidence, which overwhelmingly supports the conclusion that Black men in the US could benefit from a risk-adapted PSA screening,” the investigators concluded, noting that the latest evidence “warrants revisiting current recommendations for early [prostate cancer] detection in Black men from other national guideline groups.”

“We believe that the outcome of these more directed guidelines will be to give clarity to these men,” Dr. Oh added.

This research was funded by the Prostate Cancer Foundation, National Cancer Institute, Veterans Affairs, Jean Perkins Foundation, and Department of Defense. Dr. Garraway reported having no disclosures.

A version of this article appeared on Medscape.com.

The Stockholm3 (A3P Biomedical) multiparametic blood test has shown accuracy in assessing the risk of prostate cancer, exceeding that of the standard prostate-specific antigen (PSA)-based test, in Swedish patients. That improved accuracy was observed across diverse racial and ethnic groups, in a new study.

“The Stockholm3 outperformed the PSA test overall and in every subcohort, with an impressive reduction of unnecessary biopsies of 40% to 50%, while maintaining relative sensitivity,” first author Scott E. Eggener, MD, said in presenting the findings at the ASCO Genitourinary Cancers Symposium. The test “has attractive characteristics in a diverse cohort, including within various racial and ethnic subgroups,” added Dr. Eggener, professor of surgery and radiology at the University of Chicago.

While the PSA test, the standard-of-care in prostate cancer risk assessment, reduces mortality, the test is known to have a risk for false positive results, leading to unnecessary prostate biopsies, as well as overdiagnosis of low-risk prostate cancers, Dr. Eggener explained in his talk.

Randomized trials do show “fewer men die from prostate cancer with screening [with PSA testing], however, the likelihood of unnecessarily finding out about a cancer, undergoing treatment, and exposure to potential treatment-related side effects is significantly higher,” Dr. Eggener said in a interview.

The Stockholm3 clinical diagnostic prostate cancer test, which has been used in Sweden and Norway since 2017, was validated in a sample of nearly 60,000 men in the STHLM3 study (doi: 10.1016/S1470-2045[15]00361-7), which was published in The Lancet Oncology in December 2015. That study showed significant improvement over PSA alone detection of prostate cancers with a Gleason score of at least 7 (P < .0001), Dr. Eggener explained.

The test combines five plasma protein markers, including total and free PSA, PSP94, GDF-15 and KLK2, along with 101 genetic markers and clinical patient data, including age, previous biopsy results and family history.

Because the Stockholm3 test was validated in a Swedish population cohort, evidence on the accuracy of the test in other racial and ethnic populations is lacking, the authors noted in the abstract.

Study Methods and Results

To further investigate, Dr. Eggener and his colleagues conducted the prospective SEPTA trial, involving 2,129 men with no known prostate cancer but clinical indications for prostate biopsy, who were referred for prostate biopsy at 17 North American sites between 2019 and 2023.

Among the men, 24% were self-identified as African American/Black; 46% were White/Caucasian; 14% were Hispanic/Latina; and 16% were Asian. The men’s median age was 63; their median PSA value was 6.1 ng/mL, according to the abstract.

Of the patients, 16% received magnetic resonance imaging (MRI)-targeted biopsies and 20% had prior benign biopsies, the abstract notes.

Biopsy results showed that clinically significant prostate cancer, defined as International Society of Urological Pathology (ISUP) Gleason Grade group ≥ 2, was detected in 29% of patients, with 14% having ISUP 1 cancer and 57% of cases having been benign, according to the abstract.

Overall detection rates of grade 2 or higher were 37% for African American/Black, 28% for White/Caucasian, 29% for Hispanic/Latino, and 21% Asian.

In terms of sensitivity of the two tests, the Stockholm3 (cut-point of ≥ 15) was noninferior compared with the traditional PSA cut-point of ≥ 4 ng/mL (relative sensitivity 0.95).

Results were consistent across ethnic subgroups: noninferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70), the abstract authors reported.

Compared with the use of the PSA test’s cut-point of ≥ 4 ng/mL, the use of Stockholm3’s cut-point of ≥ 15 or higher would have reduced unnecessary biopsies by 45% overall, including by 46% among Asian and Black/African American patients, by 53% in Hispanic patients and 42% in White patients, according to the abstract.

Overall, “utilization of Stockholm3 improves the net benefit:harm ratio of PSA screening by identifying nearly all men with Gleason Grade 2 or higher, while minimizing the number of men undergoing biopsy who show no cancer or an indolent cancer (Gleason Grade 1),” Dr. Eggener said in an interview.
 

Stockholm3 Expected to be Available in U.S. This Year

The test, which has been available in Sweden since 2018, is expected to become commercially available in the United States in early 2024. Dr. Eggener noted that “cost of the test hasn’t been finalized, but will be considerably more expensive than PSA, which is very cheap.”

Commenting on the findings, Bradley McGregor, MD, of the Dana Farber Cancer Institute and an ASCO oncology expert, noted that “ultimately, the goal [of prostate screening] is to be able to better decide when a biopsy is going to yield a clinically relevant prostate cancer, [and] this study gives us some insight of the use of the Stockholm3 tool in a more diverse population.

“How the tool will be utilized in the clinic and in guidelines is something that is a work in progress,” he added. “But I think this provides some reassurances that this will have implications beyond just the homogeneous populations in the original studies.”

Dr. McGregor noted that considerations of the issue of cost should be weighed against the potential costs involved in unnecessary biopsies and a host of other costs that can arise with an inaccurate risk assessment.

“If there is a way to avoid those costs and help us have more confidence in the prostate test results and intervene at an earlier stage, I think that’s exciting,” he said.

Dr. Eggener has consulted for A3P Biomedical but had no financial relationship with the company to disclose.

The Stockholm3 (A3P Biomedical) multiparametic blood test has shown accuracy in assessing the risk of prostate cancer, exceeding that of the standard prostate-specific antigen (PSA)-based test, in Swedish patients. That improved accuracy was observed across diverse racial and ethnic groups, in a new study.

“The Stockholm3 outperformed the PSA test overall and in every subcohort, with an impressive reduction of unnecessary biopsies of 40% to 50%, while maintaining relative sensitivity,” first author Scott E. Eggener, MD, said in presenting the findings at the ASCO Genitourinary Cancers Symposium. The test “has attractive characteristics in a diverse cohort, including within various racial and ethnic subgroups,” added Dr. Eggener, professor of surgery and radiology at the University of Chicago.

While the PSA test, the standard-of-care in prostate cancer risk assessment, reduces mortality, the test is known to have a risk for false positive results, leading to unnecessary prostate biopsies, as well as overdiagnosis of low-risk prostate cancers, Dr. Eggener explained in his talk.

Randomized trials do show “fewer men die from prostate cancer with screening [with PSA testing], however, the likelihood of unnecessarily finding out about a cancer, undergoing treatment, and exposure to potential treatment-related side effects is significantly higher,” Dr. Eggener said in a interview.

The Stockholm3 clinical diagnostic prostate cancer test, which has been used in Sweden and Norway since 2017, was validated in a sample of nearly 60,000 men in the STHLM3 study (doi: 10.1016/S1470-2045[15]00361-7), which was published in The Lancet Oncology in December 2015. That study showed significant improvement over PSA alone detection of prostate cancers with a Gleason score of at least 7 (P < .0001), Dr. Eggener explained.

The test combines five plasma protein markers, including total and free PSA, PSP94, GDF-15 and KLK2, along with 101 genetic markers and clinical patient data, including age, previous biopsy results and family history.

Because the Stockholm3 test was validated in a Swedish population cohort, evidence on the accuracy of the test in other racial and ethnic populations is lacking, the authors noted in the abstract.

Study Methods and Results

To further investigate, Dr. Eggener and his colleagues conducted the prospective SEPTA trial, involving 2,129 men with no known prostate cancer but clinical indications for prostate biopsy, who were referred for prostate biopsy at 17 North American sites between 2019 and 2023.

Among the men, 24% were self-identified as African American/Black; 46% were White/Caucasian; 14% were Hispanic/Latina; and 16% were Asian. The men’s median age was 63; their median PSA value was 6.1 ng/mL, according to the abstract.

Of the patients, 16% received magnetic resonance imaging (MRI)-targeted biopsies and 20% had prior benign biopsies, the abstract notes.

Biopsy results showed that clinically significant prostate cancer, defined as International Society of Urological Pathology (ISUP) Gleason Grade group ≥ 2, was detected in 29% of patients, with 14% having ISUP 1 cancer and 57% of cases having been benign, according to the abstract.

Overall detection rates of grade 2 or higher were 37% for African American/Black, 28% for White/Caucasian, 29% for Hispanic/Latino, and 21% Asian.

In terms of sensitivity of the two tests, the Stockholm3 (cut-point of ≥ 15) was noninferior compared with the traditional PSA cut-point of ≥ 4 ng/mL (relative sensitivity 0.95).

Results were consistent across ethnic subgroups: noninferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70), the abstract authors reported.

Compared with the use of the PSA test’s cut-point of ≥ 4 ng/mL, the use of Stockholm3’s cut-point of ≥ 15 or higher would have reduced unnecessary biopsies by 45% overall, including by 46% among Asian and Black/African American patients, by 53% in Hispanic patients and 42% in White patients, according to the abstract.

Overall, “utilization of Stockholm3 improves the net benefit:harm ratio of PSA screening by identifying nearly all men with Gleason Grade 2 or higher, while minimizing the number of men undergoing biopsy who show no cancer or an indolent cancer (Gleason Grade 1),” Dr. Eggener said in an interview.
 

Stockholm3 Expected to be Available in U.S. This Year

The test, which has been available in Sweden since 2018, is expected to become commercially available in the United States in early 2024. Dr. Eggener noted that “cost of the test hasn’t been finalized, but will be considerably more expensive than PSA, which is very cheap.”

Commenting on the findings, Bradley McGregor, MD, of the Dana Farber Cancer Institute and an ASCO oncology expert, noted that “ultimately, the goal [of prostate screening] is to be able to better decide when a biopsy is going to yield a clinically relevant prostate cancer, [and] this study gives us some insight of the use of the Stockholm3 tool in a more diverse population.

“How the tool will be utilized in the clinic and in guidelines is something that is a work in progress,” he added. “But I think this provides some reassurances that this will have implications beyond just the homogeneous populations in the original studies.”

Dr. McGregor noted that considerations of the issue of cost should be weighed against the potential costs involved in unnecessary biopsies and a host of other costs that can arise with an inaccurate risk assessment.

“If there is a way to avoid those costs and help us have more confidence in the prostate test results and intervene at an earlier stage, I think that’s exciting,” he said.

Dr. Eggener has consulted for A3P Biomedical but had no financial relationship with the company to disclose.

The Stockholm3 (A3P Biomedical) multiparametic blood test has shown accuracy in assessing the risk of prostate cancer, exceeding that of the standard prostate-specific antigen (PSA)-based test, in Swedish patients. That improved accuracy was observed across diverse racial and ethnic groups, in a new study.

“The Stockholm3 outperformed the PSA test overall and in every subcohort, with an impressive reduction of unnecessary biopsies of 40% to 50%, while maintaining relative sensitivity,” first author Scott E. Eggener, MD, said in presenting the findings at the ASCO Genitourinary Cancers Symposium. The test “has attractive characteristics in a diverse cohort, including within various racial and ethnic subgroups,” added Dr. Eggener, professor of surgery and radiology at the University of Chicago.

While the PSA test, the standard-of-care in prostate cancer risk assessment, reduces mortality, the test is known to have a risk for false positive results, leading to unnecessary prostate biopsies, as well as overdiagnosis of low-risk prostate cancers, Dr. Eggener explained in his talk.

Randomized trials do show “fewer men die from prostate cancer with screening [with PSA testing], however, the likelihood of unnecessarily finding out about a cancer, undergoing treatment, and exposure to potential treatment-related side effects is significantly higher,” Dr. Eggener said in a interview.

The Stockholm3 clinical diagnostic prostate cancer test, which has been used in Sweden and Norway since 2017, was validated in a sample of nearly 60,000 men in the STHLM3 study (doi: 10.1016/S1470-2045[15]00361-7), which was published in The Lancet Oncology in December 2015. That study showed significant improvement over PSA alone detection of prostate cancers with a Gleason score of at least 7 (P < .0001), Dr. Eggener explained.

The test combines five plasma protein markers, including total and free PSA, PSP94, GDF-15 and KLK2, along with 101 genetic markers and clinical patient data, including age, previous biopsy results and family history.

Because the Stockholm3 test was validated in a Swedish population cohort, evidence on the accuracy of the test in other racial and ethnic populations is lacking, the authors noted in the abstract.

Study Methods and Results

To further investigate, Dr. Eggener and his colleagues conducted the prospective SEPTA trial, involving 2,129 men with no known prostate cancer but clinical indications for prostate biopsy, who were referred for prostate biopsy at 17 North American sites between 2019 and 2023.

Among the men, 24% were self-identified as African American/Black; 46% were White/Caucasian; 14% were Hispanic/Latina; and 16% were Asian. The men’s median age was 63; their median PSA value was 6.1 ng/mL, according to the abstract.

Of the patients, 16% received magnetic resonance imaging (MRI)-targeted biopsies and 20% had prior benign biopsies, the abstract notes.

Biopsy results showed that clinically significant prostate cancer, defined as International Society of Urological Pathology (ISUP) Gleason Grade group ≥ 2, was detected in 29% of patients, with 14% having ISUP 1 cancer and 57% of cases having been benign, according to the abstract.

Overall detection rates of grade 2 or higher were 37% for African American/Black, 28% for White/Caucasian, 29% for Hispanic/Latino, and 21% Asian.

In terms of sensitivity of the two tests, the Stockholm3 (cut-point of ≥ 15) was noninferior compared with the traditional PSA cut-point of ≥ 4 ng/mL (relative sensitivity 0.95).

Results were consistent across ethnic subgroups: noninferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70), the abstract authors reported.

Compared with the use of the PSA test’s cut-point of ≥ 4 ng/mL, the use of Stockholm3’s cut-point of ≥ 15 or higher would have reduced unnecessary biopsies by 45% overall, including by 46% among Asian and Black/African American patients, by 53% in Hispanic patients and 42% in White patients, according to the abstract.

Overall, “utilization of Stockholm3 improves the net benefit:harm ratio of PSA screening by identifying nearly all men with Gleason Grade 2 or higher, while minimizing the number of men undergoing biopsy who show no cancer or an indolent cancer (Gleason Grade 1),” Dr. Eggener said in an interview.
 

Stockholm3 Expected to be Available in U.S. This Year

The test, which has been available in Sweden since 2018, is expected to become commercially available in the United States in early 2024. Dr. Eggener noted that “cost of the test hasn’t been finalized, but will be considerably more expensive than PSA, which is very cheap.”

Commenting on the findings, Bradley McGregor, MD, of the Dana Farber Cancer Institute and an ASCO oncology expert, noted that “ultimately, the goal [of prostate screening] is to be able to better decide when a biopsy is going to yield a clinically relevant prostate cancer, [and] this study gives us some insight of the use of the Stockholm3 tool in a more diverse population.

“How the tool will be utilized in the clinic and in guidelines is something that is a work in progress,” he added. “But I think this provides some reassurances that this will have implications beyond just the homogeneous populations in the original studies.”

Dr. McGregor noted that considerations of the issue of cost should be weighed against the potential costs involved in unnecessary biopsies and a host of other costs that can arise with an inaccurate risk assessment.

“If there is a way to avoid those costs and help us have more confidence in the prostate test results and intervene at an earlier stage, I think that’s exciting,” he said.

Dr. Eggener has consulted for A3P Biomedical but had no financial relationship with the company to disclose.

In ongoing efforts to better understand the predictive value of circulating tumor DNA (ctDNA) in cancer treatment response, new research shows ctDNA clearance following neoadjuvant treatment of muscle-invasive urothelial cancer is a better predictor of the risk of relapse than a 50% reduction in ctDNA variant allele frequency (VAF).

The combination of ctDNA with other baseline biomarkers shows further accuracy in predicting treatment response, the study also shows.

Matthew Nicholas Young, MD, of Barts Cancer Institute, London, presented the research at the ASCO Genitourinary Cancers Symposium.

“We found that ctDNA and tissue-based biomarkers improved biomarker accuracy,” Dr. Young, first author of the study, said at the meeting.

Furthermore, “ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse,” the authors said in their abstract.

“This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint,” they wrote.

Dr. Young and his colleagues have previously shown ctDNA clearance to be an important predictive marker of treatment response or relapse.

To better understand the predictive value in combination with other biomarkers, as well as whether a reduction in ctDNA variant allele frequency could be used as a surrogate predictor of relapse compared with ctDNA clearance, the authors conducted an exploratory biomarker analysis of the phase 2, multicenter ABACUS trial.
 

Methods and Results

In the study, 95 patients with inoperable, muscle-invasive urothelial cancer who were either not eligible for or refused neoadjuvant cisplatin-based chemotherapy, each received two cycles of atezolizumab, followed by radical cystectomy.

Previously published results show the study met its primary endpoint of a pathological complete response (pCR) of 31%, and the 2-year disease-free survival and overall survival rates were 68% and 77%, respectively.

Of the 95 patients, 40 had sequential DNA analysis that could be evaluated in the current analysis; 43% of those patients achieved a pCR, while 20% experienced a relapse.

At baseline, 63% of patients were ctDNA-positive, and after treatment, 8% achieved ctDNA clearance, while 40% had a ctDNA response of a 50% VAF reduction.

All patients who had ctDNA clearance achieved pCR and none relapsed. In comparison, 30% of patients with a 50% VAF reduction experienced relapse and only 40% achieved pCR.

In terms of correlations with baseline biomarkers, the combination of ctDNA with activated T cells was significantly associated with outcomes (P = .02), as was the combination with PDL-1 status (P = .004).

However, combination with tumor mutation burden, already weak as a predictive biomarker, remained weak when combined with ctDNA status (P = .2), Dr. Young reported.

In terms of baseline expression of ctDNA, patients who were positive at baseline showed an increase in innate and adaptive immune signaling, in a profile aligning with increased PD-L1 at baseline in ctDNA-positive patients.

In addition, decreased immune signaling was observed in ctDNA-positive patients who relapsed.
 

Results May Be ‘Hypothesis-Generating’

Asked during the session whether the results imply that patients with no detectable ctDNA prior to the start of therapy may not need or benefit from neoadjuvant therapy, Dr. Young said the small sample size of ctDNA patients in the study was an important limitation.

“I think [the results] are hypothesis-generating, as we know that some patients will not benefit from neoadjuvant therapy and the goal of this work is to try to identify patterns among those who may not need treatment,” he said.

Of the patients with ctDNA analysis, “only those who were ctDNA-positive at baseline relapsed, [as well as] those who were ctDNA-positive following cystectomy, so I think [the possibility that a lack of detectable ctDNA prior to the start of therapy could suggest that the patient may not need or benefit from neoadjuvant therapy] is an interesting hypothesis that has come from this work,” Dr. Young said.

Overall, the findings show that, “in ctDNA-positive patients, increased immune signals appear to be associated with better outcomes with atezolizumab,” he concluded.

“Combining immune and circulating biomarkers may be required to accurately predict response to therapy,” Dr. Young added.

The ABACUS trial was supported by Roche.

In ongoing efforts to better understand the predictive value of circulating tumor DNA (ctDNA) in cancer treatment response, new research shows ctDNA clearance following neoadjuvant treatment of muscle-invasive urothelial cancer is a better predictor of the risk of relapse than a 50% reduction in ctDNA variant allele frequency (VAF).

The combination of ctDNA with other baseline biomarkers shows further accuracy in predicting treatment response, the study also shows.

Matthew Nicholas Young, MD, of Barts Cancer Institute, London, presented the research at the ASCO Genitourinary Cancers Symposium.

“We found that ctDNA and tissue-based biomarkers improved biomarker accuracy,” Dr. Young, first author of the study, said at the meeting.

Furthermore, “ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse,” the authors said in their abstract.

“This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint,” they wrote.

Dr. Young and his colleagues have previously shown ctDNA clearance to be an important predictive marker of treatment response or relapse.

To better understand the predictive value in combination with other biomarkers, as well as whether a reduction in ctDNA variant allele frequency could be used as a surrogate predictor of relapse compared with ctDNA clearance, the authors conducted an exploratory biomarker analysis of the phase 2, multicenter ABACUS trial.
 

Methods and Results

In the study, 95 patients with inoperable, muscle-invasive urothelial cancer who were either not eligible for or refused neoadjuvant cisplatin-based chemotherapy, each received two cycles of atezolizumab, followed by radical cystectomy.

Previously published results show the study met its primary endpoint of a pathological complete response (pCR) of 31%, and the 2-year disease-free survival and overall survival rates were 68% and 77%, respectively.

Of the 95 patients, 40 had sequential DNA analysis that could be evaluated in the current analysis; 43% of those patients achieved a pCR, while 20% experienced a relapse.

At baseline, 63% of patients were ctDNA-positive, and after treatment, 8% achieved ctDNA clearance, while 40% had a ctDNA response of a 50% VAF reduction.

All patients who had ctDNA clearance achieved pCR and none relapsed. In comparison, 30% of patients with a 50% VAF reduction experienced relapse and only 40% achieved pCR.

In terms of correlations with baseline biomarkers, the combination of ctDNA with activated T cells was significantly associated with outcomes (P = .02), as was the combination with PDL-1 status (P = .004).

However, combination with tumor mutation burden, already weak as a predictive biomarker, remained weak when combined with ctDNA status (P = .2), Dr. Young reported.

In terms of baseline expression of ctDNA, patients who were positive at baseline showed an increase in innate and adaptive immune signaling, in a profile aligning with increased PD-L1 at baseline in ctDNA-positive patients.

In addition, decreased immune signaling was observed in ctDNA-positive patients who relapsed.
 

Results May Be ‘Hypothesis-Generating’

Asked during the session whether the results imply that patients with no detectable ctDNA prior to the start of therapy may not need or benefit from neoadjuvant therapy, Dr. Young said the small sample size of ctDNA patients in the study was an important limitation.

“I think [the results] are hypothesis-generating, as we know that some patients will not benefit from neoadjuvant therapy and the goal of this work is to try to identify patterns among those who may not need treatment,” he said.

Of the patients with ctDNA analysis, “only those who were ctDNA-positive at baseline relapsed, [as well as] those who were ctDNA-positive following cystectomy, so I think [the possibility that a lack of detectable ctDNA prior to the start of therapy could suggest that the patient may not need or benefit from neoadjuvant therapy] is an interesting hypothesis that has come from this work,” Dr. Young said.

Overall, the findings show that, “in ctDNA-positive patients, increased immune signals appear to be associated with better outcomes with atezolizumab,” he concluded.

“Combining immune and circulating biomarkers may be required to accurately predict response to therapy,” Dr. Young added.

The ABACUS trial was supported by Roche.

In ongoing efforts to better understand the predictive value of circulating tumor DNA (ctDNA) in cancer treatment response, new research shows ctDNA clearance following neoadjuvant treatment of muscle-invasive urothelial cancer is a better predictor of the risk of relapse than a 50% reduction in ctDNA variant allele frequency (VAF).

The combination of ctDNA with other baseline biomarkers shows further accuracy in predicting treatment response, the study also shows.

Matthew Nicholas Young, MD, of Barts Cancer Institute, London, presented the research at the ASCO Genitourinary Cancers Symposium.

“We found that ctDNA and tissue-based biomarkers improved biomarker accuracy,” Dr. Young, first author of the study, said at the meeting.

Furthermore, “ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse,” the authors said in their abstract.

“This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint,” they wrote.

Dr. Young and his colleagues have previously shown ctDNA clearance to be an important predictive marker of treatment response or relapse.

To better understand the predictive value in combination with other biomarkers, as well as whether a reduction in ctDNA variant allele frequency could be used as a surrogate predictor of relapse compared with ctDNA clearance, the authors conducted an exploratory biomarker analysis of the phase 2, multicenter ABACUS trial.
 

Methods and Results

In the study, 95 patients with inoperable, muscle-invasive urothelial cancer who were either not eligible for or refused neoadjuvant cisplatin-based chemotherapy, each received two cycles of atezolizumab, followed by radical cystectomy.

Previously published results show the study met its primary endpoint of a pathological complete response (pCR) of 31%, and the 2-year disease-free survival and overall survival rates were 68% and 77%, respectively.

Of the 95 patients, 40 had sequential DNA analysis that could be evaluated in the current analysis; 43% of those patients achieved a pCR, while 20% experienced a relapse.

At baseline, 63% of patients were ctDNA-positive, and after treatment, 8% achieved ctDNA clearance, while 40% had a ctDNA response of a 50% VAF reduction.

All patients who had ctDNA clearance achieved pCR and none relapsed. In comparison, 30% of patients with a 50% VAF reduction experienced relapse and only 40% achieved pCR.

In terms of correlations with baseline biomarkers, the combination of ctDNA with activated T cells was significantly associated with outcomes (P = .02), as was the combination with PDL-1 status (P = .004).

However, combination with tumor mutation burden, already weak as a predictive biomarker, remained weak when combined with ctDNA status (P = .2), Dr. Young reported.

In terms of baseline expression of ctDNA, patients who were positive at baseline showed an increase in innate and adaptive immune signaling, in a profile aligning with increased PD-L1 at baseline in ctDNA-positive patients.

In addition, decreased immune signaling was observed in ctDNA-positive patients who relapsed.
 

Results May Be ‘Hypothesis-Generating’

Asked during the session whether the results imply that patients with no detectable ctDNA prior to the start of therapy may not need or benefit from neoadjuvant therapy, Dr. Young said the small sample size of ctDNA patients in the study was an important limitation.

“I think [the results] are hypothesis-generating, as we know that some patients will not benefit from neoadjuvant therapy and the goal of this work is to try to identify patterns among those who may not need treatment,” he said.

Of the patients with ctDNA analysis, “only those who were ctDNA-positive at baseline relapsed, [as well as] those who were ctDNA-positive following cystectomy, so I think [the possibility that a lack of detectable ctDNA prior to the start of therapy could suggest that the patient may not need or benefit from neoadjuvant therapy] is an interesting hypothesis that has come from this work,” Dr. Young said.

Overall, the findings show that, “in ctDNA-positive patients, increased immune signals appear to be associated with better outcomes with atezolizumab,” he concluded.

“Combining immune and circulating biomarkers may be required to accurately predict response to therapy,” Dr. Young added.

The ABACUS trial was supported by Roche.