Genitourinary Cancer

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

BARCELONA – Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to standard platinum-based chemotherapy was associated with a small but statistically significant progression-free survival benefit for patients with previously untreated metastatic urothelial carcinoma, investigators in the IMvigor130 trial found.

Neil Osterweil/MDedge News

Among 1,213 patients with newly diagnosed metastatic urothelial carcinoma assigned to receive either atezolizumab monotherapy or chemotherapy with a platinum compound and gemcitabine plus either atezolizumab or placebo, the median progression-free survival (PFS) at a median follow-up of 11.8 months was 8.2 months with atezolizumab/chemotherapy, compared with 6.3 months with chemotherapy plus placebo, reported Enrique Grande, MD, of MD Anderson Cancer Center Madrid.

“IMvigor130 is the first immune checkpoint inhibitor study to demonstrate an improvement in progression-free survival over the standard of care in first-line metastatic urothelial carcinoma. At this interim analysis, we observed a clinically meaningful improvement in the overall survival for the combination of atezolizumab plus chemotherapy that did not meet the prespecified interim boundary for significance,” he said at the European Society for Medical Oncology Congress.

Median overall survival (OS) at the interim analysis was 16.0 months in the atezolizumab arm, vs. 13.4 months in the placebo arm, translating into a hazard ratio (HR) of 0.83 trending in favor of the combination. But as noted by Dr. Grande, the P value was .027, which did not reach the interim efficacy boundary of .007.

IMvigor130 investigators enrolled patients with locally advanced metastatic urothelial carcinoma with no prior systemic therapy in the metastatic setting who had good performance status (ECOG 2 or less) and were eligible for chemotherapy with either cisplatin or carboplatin plus gemcitabine.

The patients were stratified by programmed death ligand-1 (PD-L1) status, prognostic (Bajorin) risk factor scores, and investigator choice of cisplatin or carboplatin, and then randomized to either atezolizumab plus chemotherapy, atezolizumab monotherapy, or placebo plus chemotherapy.

As noted, the co-primary endpoint of PFS in the chemotherapy arms in the intention-to-treat population was statistically significant at the preplanned interim analysis, but the other primary endpoint of OS had not reached significance.

At the time of the data cutoff in May 2019, the stratified HR for progression with atezolizumab was 0.82 (P = .007).

An analysis by subgroup showed either significant benefit or a trend favoring atezolizumab across all stratification factors, Dr. Grande said.

A hierarchical analysis of atezolizumab monotherapy vs. chemotherapy in the placebo-control arm showed a median OS of 15.7 vs. 13.1 months, respectively, with a hazard ratio of 1.02 (nonsignificant).

The benefit of atezolizumab appeared to be almost entirely among patients whose tumors had higher levels of PD-L1 expression according to immunohistochemistry (IC). The interim OS among patients with PD-L1 IC0/1 was a median of 13.5 months with atezolizumab vs. 12.9 months with chemotherapy alone, with an unstratified HR of 1.07 (nonsignificant). In contrast, among patients with PD-L1 IC2/3 status, the median OS was not reached for patients in the atezolizumab arm, vs. 17.8 months in the chemotherapy alone arm, for a stratified HR of 0.68, although this too did not reach statistical significance.

Responses were similar between the two chemotherapy arms, with an overall response rate (ORR) of 47% with atezolizumab added, vs. 44% with placebo added. The complete response (CR) rates were 13% and 7%, respectively. The ORR in the monotherapy arm was 23%, consisting of 6% complete and 17% partial responses.

Grade 3 or 4 treatment-related adverse events occurred in 81% of patients in each chemotherapy arm, compared with 15% in the atezolizumab monotherapy arm. Nine patients in the atezolizumab/chemotherapy arm died from a treatment-related cause, compared with four in the chemotherapy alone arm, and three in the atezolizumab monotherapy arm.

Adverse events leading to treatment discontinuation occurred in one-fourth of patients in each chemotherapy-containing arm, vs. less than 1% of patients in the monotherapy arm.

“The results from the IMvigor130 trial support the use of atezolizumab in combination with chemotherapy as an important new treatment option for patients with untreated metastatic urothelial carcinoma,” Dr. Grande concluded.

But invited discussant Thomas Powles, MD, of Barts Cancer Institute in London, cautioned that more data are needed to conclude that the addition of atezolizumab should become a standard of care.

Neil Osterweil/MDedge News

“Does this change practice? Well, the for and against: significant delay in PFS, but how meaningful is that? OS trending the right way, but not significant yet. CR rates, yes with 13% CRs, but response rates weren’t very different from one another, and as response rates are similar, it’s hard to argue that the two are synergistic together, for example,” he said.

He added that the adverse event profiles “actually are very acceptable to me, and I’m really looking forward to the quality-of-life data.”

The IMvigor130 study is sponsored by F. Hoffman-La Roche. Dr. Grande disclosed honoraria and research grants from Roche and others. Dr. Powles disclosed research funding, honoraria, and travel costs from Roche and others.
 

SOURCE: Grande E et al. ESMO 2019. Abstract LBA14_PR.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

A new analysis of 40 years of U.S. cancer data underscores the importance of looking at multiple metrics to discern the complex interplay of factors influencing cancer burden in the population. Findings showed that the epidemiologic signature – a composite of two or three key metrics – differed across cancer types and was favorable in some cases and unfavorable in others.

“Epidemiologic signatures that illustrate trends in population-based data on cancer burden provide insight into true cancer occurrence, overdiagnosis, and treatment advances,” explain the analysts, led by H. Gilbert Welch, MD, MPH, Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston. “They are important indicators of the potential contribution of environmental exposures, primary preventive interventions, new treatments, and changing diagnostic and screening practices.”

Dr. Welch and colleagues analyzed data for the years 1975 through 2015, assessing juxtaposed trends in incidence, mortality, and, when available, metastatic incidence (cancer already metastatic at diagnosis) for 11 cancers individually and for all cancers combined. Incidence data combining invasive and in situ cancers were obtained from the original nine Surveillance, Epidemiology, and End Results (SEER) registries, and mortality data were obtained from the National Vital Statistics System.

The analysts then explored implications of the epidemiologic signatures as they pertain to true cancer occurrence (the underlying incidence of clinically meaningful cancer), overdiagnosis (detection of cancers that will not cause symptoms or death), and treatment advances.
 

Individual cancers

Findings of the analysis, published in a special report in the New England Journal of Medicine, revealed three broad categories of epidemiologic signatures having different implications for the public health and oncology fields.

Desirable signatures showed, for example, declining mortality against a backdrop of stable incidence over the 40-year period, signaling improved treatment, as seen for chronic myeloid leukemia following introduction of imatinib (Gleevec), according to the analysts. Lung cancer incidence and mortality rose and fell in tandem, reflecting an increase in smoking followed by a decrease in response to prevention efforts. Stomach, cervical, and colorectal cancers had both falling incidence – likely reflecting a true decline in occurrence related to prevention and/or screening detection and subsequent treatment of precancerous lesions – and falling mortality.

Undesirable signatures showed a rising incidence juxtaposed with stable mortality and stable or rising metastatic incidence, signaling likely overdiagnosis, Dr. Welch and colleagues proposed. Three cancers—thyroid cancer, kidney cancer, and melanoma—fell into this category; for thyroid cancer and melanoma, fairly recent upticks in metastatic incidence may reflect upstaging.

Finally, some signatures showed mixed signals, with rising incidence and falling mortality. Breast cancer incidence rose and stabilized, coinciding with introduction of screening mammography, and possibly reflecting an increase in true cancer occurrence or overdiagnosis (with stable metastatic incidence favoring the latter), the analysts speculate. Declining mortality since the 1990s may be due to improved treatment or screening, or both. Prostate cancer incidence rose sharply with introduction of prostate-specific antigen screening but then fell to initial levels, suggesting sensitivity of this cancer to diagnostic scrutiny. Falling metastatic incidence indicates screening leads to earlier diagnosis in some cases, while declining mortality starting in the 1990s may again reflect improved treatment or screening, or both.
 

All cancers

The epidemiologic signature for all cancers combined differed somewhat by sex. Women had a rising incidence during the 1980s that was mainly driven by lung and breast cancers, according to Dr. Welch and colleagues; a continued rise since the mid-1990s was largely driven by melanoma, kidney cancer, and thyroid cancer. Declining mortality since 1990 has been primarily due to reductions in deaths from breast and colorectal cancers, and, more recently, lung cancer.

Men had a “volatile pattern” in the incidence of all cancers combined that was attributable to prostate cancer trends; drops in lung and colorectal cancer incidences were offset by rises in melanoma and kidney cancer incidences, the analysts proposed. Declining mortality since 1990 was more marked than that among women and reflects a longer period of decline in lung cancer mortality, plus reductions in deaths from prostate cancer and colorectal cancer.

“Falling mortality means that there has been real progress against cancer in the past 40 years – largely reflecting improved treatment and the decline of a uniquely powerful causal factor: cigarette smoking,” Dr. Welch and colleagues noted. “The lack of an accompanying fall in incidence is an unfortunate side effect of early cancer-detection efforts.”

Dr. Welch reported that he had no relevant disclosures. The analysis did not receive any specific funding.

SOURCE: Welch HG et al. N Engl J Med. 2019;381:1378-86. doi: 10.1056/NEJMsr1905447.

There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.

Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.

“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.

The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.

Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.

At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.

The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.

After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.

“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”

Dr. Dudani had no financial disclosures.

SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
 

There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.

Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.

“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.

The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.

Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.

At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.

The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.

After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.

“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”

Dr. Dudani had no financial disclosures.

SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
 

There is no significant difference in response or survival rates between the combination of ipilimumab/nivolumab (ipi-nivo) and immuno-oncology plus vascular endothelial growth factor inhibition (IOVE) for patients with metastatic renal cell carcinoma.

Therefore, the treatment should probably be directed by patient preferences, among other things, Shaan Dudani, MD, and colleagues wrote in European Oncology.

“Given the current lack of evidence to suggest a difference in efficacy between treatment strategies, patients, clinicians and policy makers are likely to take into account other considerations, such as toxicity, cost, logistics, prognostic categories, and patient preferences in deciding between the various front-line [immuno-oncology] combination regimens,” wrote Dr. Dudani, of the University of Calgary, and coauthors.

The team examined response rates among 263 patients with metastatic renal cell carcinoma from the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) dataset. Patients treated with any first-line IOVE combination (n = 113) were compared with those treated with ipi-nivo (n = 75). Patients were about 62 years old. The most common sites of metastasis were liver (about 20%) and bone (about 33%), and about 20% had sarcomatoid features (about 20%). Most (about 75%) had multiple metastatic sites.

Thirty percent of those in the IOVE group and 40% in the ipi-nivo group had received second-line treatments. These included axitinib, levantinib plus severolimus, nivolumab alone, pazopanib, and sunitinib, as well as other treatments.

At a mean follow-up of 11.7 months, the response rates were 33% for IOVE and 40% for ipi-nivo. This difference was not statistically significant (between group difference, 7%; 95% confidence interval, –8% to 22%; P = .4). Complete response occurred in 2% in IOVE and 5% of the ipi-nivo group.

The time to treatment failure was 14.3 months for IOVE and 10.2 months for ipi-nivo – again not a significant difference (P = .2). Time to next treatment also was not significantly different (19.7 vs. 17.9 months; P = .4). Neither group met the study’s overall survival goal.

After adjustment for IMDC risk score, hazard ratios for death were 0.71 for IOVE and 1.74 for ipi-nivo. There were no significant between-group differences when comparing intermediate- and poor-risk patients or when the analysis was restricted only to favorable-risk patients. Among 55 who received second-line therapy, there was also no significant difference in time to treatment failure.

“It was interesting, though not surprising, to observe that the majority [88%] of second-line therapies in this cohort were VEGF-based following ipi-nivo vs. IOVE combinations,” the authors noted. “The higher response rates observed in patients receiving second-line VEGF combinations is noteworthy and thought provoking. Biologically, it is plausible that VEGF-based second-line therapy would be more likely to be effective in the VEGF-naive ipi-nivo cohort. It remains to be seen whether the numerical difference in time to treatment failure becomes significant with increased sample size and further follow-up, and whether this contributes to differences in overall survival, which ultimately impacts treatment selections in the first-line setting.”

Dr. Dudani had no financial disclosures.

SOURCE: Dudani S et al. Euro Onc. 2019 Aug 22. doi: 10.1016/j.eururo.2019.07.048.
 

BARCELONA – PARP inhibitors may be able to do for men with advanced castration-resistant prostate cancer what they currently do for women with breast or ovarian cancers linked to BRCA mutations, investigators report.

Neil Osterweil/MDedge News

Among men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed on prior therapy with either abiraterone (Zytiga) or enzalutamide (Xtandi) and that bore DNA-repair mutations (BRCA1, BRCA2, or ATM), those who were randomized in the PROfound trial to receive olaparib (Lynparza) had significant improvement in radiographic progression-free survival (rPFS) compared with patients assigned to the physician’s choice of a new hormonal agent, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.

“PROfound is the first positive biomarker-selected phase 3 study evaluating a molecularly-targeted therapy in men with metastatic castration-resistant prostate cancer, highlighting the importance of genomic testing in this population, and also importantly highlighting the feasibility of precision-medicine trials in this disease,” she said at the European Society for Medical Oncology (ESMO) Congress.

Approximately 25% of men with mCRPC have loss-of-function mutations or alterations in homologous recombinant repair (HRR) genes, especially BRCA1, BRCA2, and ATM. Breast and ovarian cancers bearing these mutations are known to be sensitive to PARP (poly ADP ribose polymerase) inhibitors such as olaparib.

To see whether men with mCRPC could derive a similar benefit, the investigators enrolled patients who had experienced disease progression on abiraterone or enzalutamiude and whose tumors had one or more alterations in any qualifying gene with direct or indirect role in homologous recombinant DNA repair.

Patients were stratified by previous taxane use and measurable disease, and then two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (in BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L).

The median age in cohort A was 68, and in cohort B it was 67, with men 86 years of age at the upper end of the range.

“I think it’s remarkable that men in their late 80s and even early 90s were eligible, were able to be enter this study and be treated on it, and I think that’s an important point here,” Dr. Hussain said.

Nearly one-fourth of patients in the trial had metastatic disease at their initial diagnosis, she noted.

Patients in each cohort were randomized on a 2:1 basis to receive either open-label olaparib 300 mg twice daily, or the treating physician’s choice of abireraterone or enzalutamide, plus predisone.

Upon blinded independent central review (BICR) showing disease progression, patients were allowed to cross over to the olaparib arm, which more than 80% of patients eventually did.

Radiographic PFS in the BRCA1, BRCA2 and ATM cohort according to BICR, the primary endpoint, was a median of 7.39 months with olaparib, compared with 3.55 months with the other therapies, for a hazard ratio (HR) for progression on olaparib of 0.34 (P less than .0001).

A somewhat smaller but still significant benefit was seen for olaparib in the overall population (both cohorts), with a median rPFS of 5.82 months vs. 3.52 months, respectively (HR 0.49, P less than .0001).

Among patients in cohort A, the objective response rate was 33.3% with olaparib, compared with 2.3% for the other agents, resulting in an odds ratio for response of 20.86 (P less than .0001)

Olaparib was also associated with longer time to pain progression in patients in cohort A, with the median not reached compared with 9.92 months with the hormonal agents (HR 0.44, P = .0192).

Among patients in the physician’s choice arm who had disease progression, 80.6% in cohort A and 84.6% in cohort B were crossed over to olaparib.

At this interim analysis, median overall survival was 18.5 months with olaparib, compared with 15.11 months with the other agents, but this difference was not statistically significant. Further follow-up will be needed before a difference in overall survival becomes evident, Dr. Hussain said.

“I think this study has demonstrated that now prostate cancer can be treated with a targeted therapy approach,” said Ignacio Duran, MD, of Hospital Universitario Marques de Valdecilla in Santander, Spain. He was the invited discussant and moderator of a briefing where Dr. Hussain outlined the study details prior to presentation in a symposium.

Neil Osterweil/MDedge News

“Not all prostate cancer patients have the same tumors, and this is the first time we’ve been able to identify that we can more precisely characterize the molecular biology, the genetic background of these tumors, and that is going to determine how we treat them,” he said.

The PROfound trial made “a double hit: superiority in terms of efficacy, and it has proved a new concept that in prostate cancer has not been proved before,” he added.

“This is a truly practice-changing study, not just for our practice and our patients, but also for the study design,” said Eleni Efstathiou, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant at the symposium where Dr. Hussain presented the full trial data.

Neil Osterweil/MDedge News

She lauded the use of a validated genomic testing tissue-based assay (FoundationOne CDx next-generation sequencing test) to identify patients who might benefit from olaparib.

She said that the PARP inhibition-specific strategy of the trial appears to have paid off, with statistically significant, clinically meaningful improvement in outcomes and an acceptable safety profile.

“And when it comes to a prostate cancer therapy strategry? Well, we’re starting to enter into the targeted therapy era,” she said.

The PROfound trial was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck. Dr. Hussain disclosed travel and/or accommodation support, honoraria, consulting/advisory fees and research support from AstraZeneca and others. Dr. Duran disclosed advisory board fees from Roche and BMS, and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck. Dr. Efstathiou disclosed research support and honoraria from various companies, not including AstraZeneca or Merck.

SOURCE: Hussain M et al. ESMO 2019, Abstract LBA-12.

BARCELONA – PARP inhibitors may be able to do for men with advanced castration-resistant prostate cancer what they currently do for women with breast or ovarian cancers linked to BRCA mutations, investigators report.

Neil Osterweil/MDedge News

Among men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed on prior therapy with either abiraterone (Zytiga) or enzalutamide (Xtandi) and that bore DNA-repair mutations (BRCA1, BRCA2, or ATM), those who were randomized in the PROfound trial to receive olaparib (Lynparza) had significant improvement in radiographic progression-free survival (rPFS) compared with patients assigned to the physician’s choice of a new hormonal agent, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.

“PROfound is the first positive biomarker-selected phase 3 study evaluating a molecularly-targeted therapy in men with metastatic castration-resistant prostate cancer, highlighting the importance of genomic testing in this population, and also importantly highlighting the feasibility of precision-medicine trials in this disease,” she said at the European Society for Medical Oncology (ESMO) Congress.

Approximately 25% of men with mCRPC have loss-of-function mutations or alterations in homologous recombinant repair (HRR) genes, especially BRCA1, BRCA2, and ATM. Breast and ovarian cancers bearing these mutations are known to be sensitive to PARP (poly ADP ribose polymerase) inhibitors such as olaparib.

To see whether men with mCRPC could derive a similar benefit, the investigators enrolled patients who had experienced disease progression on abiraterone or enzalutamiude and whose tumors had one or more alterations in any qualifying gene with direct or indirect role in homologous recombinant DNA repair.

Patients were stratified by previous taxane use and measurable disease, and then two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (in BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L).

The median age in cohort A was 68, and in cohort B it was 67, with men 86 years of age at the upper end of the range.

“I think it’s remarkable that men in their late 80s and even early 90s were eligible, were able to be enter this study and be treated on it, and I think that’s an important point here,” Dr. Hussain said.

Nearly one-fourth of patients in the trial had metastatic disease at their initial diagnosis, she noted.

Patients in each cohort were randomized on a 2:1 basis to receive either open-label olaparib 300 mg twice daily, or the treating physician’s choice of abireraterone or enzalutamide, plus predisone.

Upon blinded independent central review (BICR) showing disease progression, patients were allowed to cross over to the olaparib arm, which more than 80% of patients eventually did.

Radiographic PFS in the BRCA1, BRCA2 and ATM cohort according to BICR, the primary endpoint, was a median of 7.39 months with olaparib, compared with 3.55 months with the other therapies, for a hazard ratio (HR) for progression on olaparib of 0.34 (P less than .0001).

A somewhat smaller but still significant benefit was seen for olaparib in the overall population (both cohorts), with a median rPFS of 5.82 months vs. 3.52 months, respectively (HR 0.49, P less than .0001).

Among patients in cohort A, the objective response rate was 33.3% with olaparib, compared with 2.3% for the other agents, resulting in an odds ratio for response of 20.86 (P less than .0001)

Olaparib was also associated with longer time to pain progression in patients in cohort A, with the median not reached compared with 9.92 months with the hormonal agents (HR 0.44, P = .0192).

Among patients in the physician’s choice arm who had disease progression, 80.6% in cohort A and 84.6% in cohort B were crossed over to olaparib.

At this interim analysis, median overall survival was 18.5 months with olaparib, compared with 15.11 months with the other agents, but this difference was not statistically significant. Further follow-up will be needed before a difference in overall survival becomes evident, Dr. Hussain said.

“I think this study has demonstrated that now prostate cancer can be treated with a targeted therapy approach,” said Ignacio Duran, MD, of Hospital Universitario Marques de Valdecilla in Santander, Spain. He was the invited discussant and moderator of a briefing where Dr. Hussain outlined the study details prior to presentation in a symposium.

Neil Osterweil/MDedge News

“Not all prostate cancer patients have the same tumors, and this is the first time we’ve been able to identify that we can more precisely characterize the molecular biology, the genetic background of these tumors, and that is going to determine how we treat them,” he said.

The PROfound trial made “a double hit: superiority in terms of efficacy, and it has proved a new concept that in prostate cancer has not been proved before,” he added.

“This is a truly practice-changing study, not just for our practice and our patients, but also for the study design,” said Eleni Efstathiou, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant at the symposium where Dr. Hussain presented the full trial data.

Neil Osterweil/MDedge News

She lauded the use of a validated genomic testing tissue-based assay (FoundationOne CDx next-generation sequencing test) to identify patients who might benefit from olaparib.

She said that the PARP inhibition-specific strategy of the trial appears to have paid off, with statistically significant, clinically meaningful improvement in outcomes and an acceptable safety profile.

“And when it comes to a prostate cancer therapy strategry? Well, we’re starting to enter into the targeted therapy era,” she said.

The PROfound trial was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck. Dr. Hussain disclosed travel and/or accommodation support, honoraria, consulting/advisory fees and research support from AstraZeneca and others. Dr. Duran disclosed advisory board fees from Roche and BMS, and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck. Dr. Efstathiou disclosed research support and honoraria from various companies, not including AstraZeneca or Merck.

SOURCE: Hussain M et al. ESMO 2019, Abstract LBA-12.

BARCELONA – PARP inhibitors may be able to do for men with advanced castration-resistant prostate cancer what they currently do for women with breast or ovarian cancers linked to BRCA mutations, investigators report.

Neil Osterweil/MDedge News

Among men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed on prior therapy with either abiraterone (Zytiga) or enzalutamide (Xtandi) and that bore DNA-repair mutations (BRCA1, BRCA2, or ATM), those who were randomized in the PROfound trial to receive olaparib (Lynparza) had significant improvement in radiographic progression-free survival (rPFS) compared with patients assigned to the physician’s choice of a new hormonal agent, reported Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.

“PROfound is the first positive biomarker-selected phase 3 study evaluating a molecularly-targeted therapy in men with metastatic castration-resistant prostate cancer, highlighting the importance of genomic testing in this population, and also importantly highlighting the feasibility of precision-medicine trials in this disease,” she said at the European Society for Medical Oncology (ESMO) Congress.

Approximately 25% of men with mCRPC have loss-of-function mutations or alterations in homologous recombinant repair (HRR) genes, especially BRCA1, BRCA2, and ATM. Breast and ovarian cancers bearing these mutations are known to be sensitive to PARP (poly ADP ribose polymerase) inhibitors such as olaparib.

To see whether men with mCRPC could derive a similar benefit, the investigators enrolled patients who had experienced disease progression on abiraterone or enzalutamiude and whose tumors had one or more alterations in any qualifying gene with direct or indirect role in homologous recombinant DNA repair.

Patients were stratified by previous taxane use and measurable disease, and then two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (in BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L).

The median age in cohort A was 68, and in cohort B it was 67, with men 86 years of age at the upper end of the range.

“I think it’s remarkable that men in their late 80s and even early 90s were eligible, were able to be enter this study and be treated on it, and I think that’s an important point here,” Dr. Hussain said.

Nearly one-fourth of patients in the trial had metastatic disease at their initial diagnosis, she noted.

Patients in each cohort were randomized on a 2:1 basis to receive either open-label olaparib 300 mg twice daily, or the treating physician’s choice of abireraterone or enzalutamide, plus predisone.

Upon blinded independent central review (BICR) showing disease progression, patients were allowed to cross over to the olaparib arm, which more than 80% of patients eventually did.

Radiographic PFS in the BRCA1, BRCA2 and ATM cohort according to BICR, the primary endpoint, was a median of 7.39 months with olaparib, compared with 3.55 months with the other therapies, for a hazard ratio (HR) for progression on olaparib of 0.34 (P less than .0001).

A somewhat smaller but still significant benefit was seen for olaparib in the overall population (both cohorts), with a median rPFS of 5.82 months vs. 3.52 months, respectively (HR 0.49, P less than .0001).

Among patients in cohort A, the objective response rate was 33.3% with olaparib, compared with 2.3% for the other agents, resulting in an odds ratio for response of 20.86 (P less than .0001)

Olaparib was also associated with longer time to pain progression in patients in cohort A, with the median not reached compared with 9.92 months with the hormonal agents (HR 0.44, P = .0192).

Among patients in the physician’s choice arm who had disease progression, 80.6% in cohort A and 84.6% in cohort B were crossed over to olaparib.

At this interim analysis, median overall survival was 18.5 months with olaparib, compared with 15.11 months with the other agents, but this difference was not statistically significant. Further follow-up will be needed before a difference in overall survival becomes evident, Dr. Hussain said.

“I think this study has demonstrated that now prostate cancer can be treated with a targeted therapy approach,” said Ignacio Duran, MD, of Hospital Universitario Marques de Valdecilla in Santander, Spain. He was the invited discussant and moderator of a briefing where Dr. Hussain outlined the study details prior to presentation in a symposium.

Neil Osterweil/MDedge News

“Not all prostate cancer patients have the same tumors, and this is the first time we’ve been able to identify that we can more precisely characterize the molecular biology, the genetic background of these tumors, and that is going to determine how we treat them,” he said.

The PROfound trial made “a double hit: superiority in terms of efficacy, and it has proved a new concept that in prostate cancer has not been proved before,” he added.

“This is a truly practice-changing study, not just for our practice and our patients, but also for the study design,” said Eleni Efstathiou, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, who was the invited discussant at the symposium where Dr. Hussain presented the full trial data.

Neil Osterweil/MDedge News

She lauded the use of a validated genomic testing tissue-based assay (FoundationOne CDx next-generation sequencing test) to identify patients who might benefit from olaparib.

She said that the PARP inhibition-specific strategy of the trial appears to have paid off, with statistically significant, clinically meaningful improvement in outcomes and an acceptable safety profile.

“And when it comes to a prostate cancer therapy strategry? Well, we’re starting to enter into the targeted therapy era,” she said.

The PROfound trial was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck. Dr. Hussain disclosed travel and/or accommodation support, honoraria, consulting/advisory fees and research support from AstraZeneca and others. Dr. Duran disclosed advisory board fees from Roche and BMS, and speaker honoraria from Roche, Bristol-Myers Squibb, and Merck. Dr. Efstathiou disclosed research support and honoraria from various companies, not including AstraZeneca or Merck.

SOURCE: Hussain M et al. ESMO 2019, Abstract LBA-12.

BARCELONA – Men who undergo radical prostatectomy can be spared from adjuvant radiotherapy and its associated side effects unless or until they have disease recurrence, results of a large randomized trial and separate meta-analysis indicate.

Among nearly 1,400 men with postoperative prostate-specific antigen (PSA) levels below 0.2 ng/mL and one or more risk factors, followed for a median of 5 years, there were no significant differences in any of the secondary outcomes between men randomized to radiotherapy and observation alone, reported Chris Parker, MD, from the Royal Marsden Hospital in London.

“In comparison with a policy of early salvage radiotherapy, adjuvant radiotherapy did not improve biochemical progression-free survival and did not delay the further use of hormone therapy,” he said at the European Society for Medical Oncology Congress, on behalf of colleagues in the RADICALS-RT trial.

Results of the RADICAL-RT trial were also pooled with results from two other large trials in a collaborative series of meta-analyses of long-term prostate cancer outcomes – dubbed ARTISTIC – which found no significant differences in event-free survival (EFS) for men randomized to either adjuvant or salvage radiotherapy.

“We don’t see any evidence from the ARTISTIC results that adjuvant radiotherapy improves event-free survival, compared to early salvage radiotherapy, and our best estimate is of a small, 1% difference in event-free survival at 5 years,” said Claire Vale, PhD, a research fellow at University College, London.

RADICALS RT details

Dr. Parker presented results from an early analysis of the secondary endpoint of biochemical progression-free survival (PFS), conducted in cooperation with the ARTISTIC investigators.

In RADICALS RT, investigators in the United Kingdom, Denmark, Canada, and Ireland enrolled 1,369 men following radical prostatectomy and after stratification by Gleason score, margin status, treatment center, and radiotherapy schedule (52.5 Gy delivered in 20 fractions, or 66 Gy delivered), randomly assigned them to either postoperative radiotherapy or observation with radiotherapy.

The patients enrolled had postoperative PSAs less than 2 ng/mL and one or more risk factors, either pathologic stage 3/4, Gleason score 7-10, positive surgical margins, or preoperative PSA of 10 ng/mL or greater.

The trigger for radiotherapy in men assigned to observation was PSA failure, defined as a PSA level of at least 0.1 ng/mL or 3 consecutive PSA rises.

At the median 5-year follow-up, PFS rates were 85% for patients assigned to adjuvant radiotherapy, and 88% for those assigned to observation, translating to a hazard ratio of 1.10, which was not statistically significant.

However, there were significant differences between the groups in both self-reported urinary incontinence (5.3% of patients in the radiotherapy group vs. 2.7% in the observation group, P = .008) and grade 3 or 4 urethral stricture at any time (8% vs. 5%, respectively, P = .03).

Results of the primary outcome, freedom from distant metastases will require longer follow-up, Dr. Parker said.

ARTISTIC meta-analysis

Dr. Vale presented results of the ARTISTIC collaborative meta-analysis, which included data from three randomized trials, including RADICALS, GETUG-AFU 17, and RAVES.

The meta-analysis was designed to include a consistent definition of PSA-driven EFS, prior to the unblinding of trial results.

The definition of EFS used in the trial was time from randomization until the first evidence of either PSA of 0.4 ng/mL or greater and rising after completion of radiotherapy, clinical/radiological progression, initiation on nontrial treatment, death from prostate cancer following completion of radiotherapy, or PSA level of 2.0 ng/mL or greater any time after randomization.

They analyzed data on a total of 1,074 men assigned to adjuvant radiotherapy and 1,077 assigned to salvage radiotherapy.

In each of the three trials included in the meta-analysis, there was a nonsignificant trend toward better PSA-driven EFS with salvage radiotherapy vs. adjuvant radiotherapy. The overall hazard ratio was 1.12, with the 95% confidence interval crossing 1, indicating a nonsignificant result.

Dr. Vale noted that early salvage radiotherapy spares many men from potentially unnecessary radiation and its negative consequences. Of the men included in the trials, more than 60% of those randomized to observation with salvage radiotherapy have yet to start radiotherapy.

She noted that investigators still need to assess long-term definitive outcomes such as metastases and survival, and whether some patients may derive benefit from adjuvant radiotherapy.

Invited discussant Gert De Meerleer, MD, PhD, a radiation oncologist at University Hospitals Leuven in Belgium, acknowledged that he agreed with most of the findings of the RADICALS-RT and ARTISTIC investigators.

An important take-home message, he said, is that “cure is the aim, and radiotherapy the keystone. If you have PSA relapse after prostatectomy, you can say, ‘I don’t treat the patient’ – fair enough. But if you treat the patient, only giving systemic therapy is the wrong way to go, you have to add radiotherapy,” he said.

He also agreed that “salvage is probably the modality of choice, and it is also in a lot of European countries, provided it is early.”

The RADICALS-RT trial is supported by Cancer Research UK and the Medical Research Council UK. Dr. Parker said he had no disclosures relevant to the trial. ARTISTIC is funded by the Medical Research Council. Dr. Vale reported having no disclosures. Dr. De Meerleer reported speaker fees, advisory board activities, and scientific grants not related to the studies.

SOURCE: Parker C et al. and Vale C et al. ESMO 2019. Abstracts LBA49_PR and LBA48_PR.

BARCELONA – Men who undergo radical prostatectomy can be spared from adjuvant radiotherapy and its associated side effects unless or until they have disease recurrence, results of a large randomized trial and separate meta-analysis indicate.

Among nearly 1,400 men with postoperative prostate-specific antigen (PSA) levels below 0.2 ng/mL and one or more risk factors, followed for a median of 5 years, there were no significant differences in any of the secondary outcomes between men randomized to radiotherapy and observation alone, reported Chris Parker, MD, from the Royal Marsden Hospital in London.

“In comparison with a policy of early salvage radiotherapy, adjuvant radiotherapy did not improve biochemical progression-free survival and did not delay the further use of hormone therapy,” he said at the European Society for Medical Oncology Congress, on behalf of colleagues in the RADICALS-RT trial.

Results of the RADICAL-RT trial were also pooled with results from two other large trials in a collaborative series of meta-analyses of long-term prostate cancer outcomes – dubbed ARTISTIC – which found no significant differences in event-free survival (EFS) for men randomized to either adjuvant or salvage radiotherapy.

“We don’t see any evidence from the ARTISTIC results that adjuvant radiotherapy improves event-free survival, compared to early salvage radiotherapy, and our best estimate is of a small, 1% difference in event-free survival at 5 years,” said Claire Vale, PhD, a research fellow at University College, London.

RADICALS RT details

Dr. Parker presented results from an early analysis of the secondary endpoint of biochemical progression-free survival (PFS), conducted in cooperation with the ARTISTIC investigators.

In RADICALS RT, investigators in the United Kingdom, Denmark, Canada, and Ireland enrolled 1,369 men following radical prostatectomy and after stratification by Gleason score, margin status, treatment center, and radiotherapy schedule (52.5 Gy delivered in 20 fractions, or 66 Gy delivered), randomly assigned them to either postoperative radiotherapy or observation with radiotherapy.

The patients enrolled had postoperative PSAs less than 2 ng/mL and one or more risk factors, either pathologic stage 3/4, Gleason score 7-10, positive surgical margins, or preoperative PSA of 10 ng/mL or greater.

The trigger for radiotherapy in men assigned to observation was PSA failure, defined as a PSA level of at least 0.1 ng/mL or 3 consecutive PSA rises.

At the median 5-year follow-up, PFS rates were 85% for patients assigned to adjuvant radiotherapy, and 88% for those assigned to observation, translating to a hazard ratio of 1.10, which was not statistically significant.

However, there were significant differences between the groups in both self-reported urinary incontinence (5.3% of patients in the radiotherapy group vs. 2.7% in the observation group, P = .008) and grade 3 or 4 urethral stricture at any time (8% vs. 5%, respectively, P = .03).

Results of the primary outcome, freedom from distant metastases will require longer follow-up, Dr. Parker said.

ARTISTIC meta-analysis

Dr. Vale presented results of the ARTISTIC collaborative meta-analysis, which included data from three randomized trials, including RADICALS, GETUG-AFU 17, and RAVES.

The meta-analysis was designed to include a consistent definition of PSA-driven EFS, prior to the unblinding of trial results.

The definition of EFS used in the trial was time from randomization until the first evidence of either PSA of 0.4 ng/mL or greater and rising after completion of radiotherapy, clinical/radiological progression, initiation on nontrial treatment, death from prostate cancer following completion of radiotherapy, or PSA level of 2.0 ng/mL or greater any time after randomization.

They analyzed data on a total of 1,074 men assigned to adjuvant radiotherapy and 1,077 assigned to salvage radiotherapy.

In each of the three trials included in the meta-analysis, there was a nonsignificant trend toward better PSA-driven EFS with salvage radiotherapy vs. adjuvant radiotherapy. The overall hazard ratio was 1.12, with the 95% confidence interval crossing 1, indicating a nonsignificant result.

Dr. Vale noted that early salvage radiotherapy spares many men from potentially unnecessary radiation and its negative consequences. Of the men included in the trials, more than 60% of those randomized to observation with salvage radiotherapy have yet to start radiotherapy.

She noted that investigators still need to assess long-term definitive outcomes such as metastases and survival, and whether some patients may derive benefit from adjuvant radiotherapy.

Invited discussant Gert De Meerleer, MD, PhD, a radiation oncologist at University Hospitals Leuven in Belgium, acknowledged that he agreed with most of the findings of the RADICALS-RT and ARTISTIC investigators.

An important take-home message, he said, is that “cure is the aim, and radiotherapy the keystone. If you have PSA relapse after prostatectomy, you can say, ‘I don’t treat the patient’ – fair enough. But if you treat the patient, only giving systemic therapy is the wrong way to go, you have to add radiotherapy,” he said.

He also agreed that “salvage is probably the modality of choice, and it is also in a lot of European countries, provided it is early.”

The RADICALS-RT trial is supported by Cancer Research UK and the Medical Research Council UK. Dr. Parker said he had no disclosures relevant to the trial. ARTISTIC is funded by the Medical Research Council. Dr. Vale reported having no disclosures. Dr. De Meerleer reported speaker fees, advisory board activities, and scientific grants not related to the studies.

SOURCE: Parker C et al. and Vale C et al. ESMO 2019. Abstracts LBA49_PR and LBA48_PR.

BARCELONA – Men who undergo radical prostatectomy can be spared from adjuvant radiotherapy and its associated side effects unless or until they have disease recurrence, results of a large randomized trial and separate meta-analysis indicate.

Among nearly 1,400 men with postoperative prostate-specific antigen (PSA) levels below 0.2 ng/mL and one or more risk factors, followed for a median of 5 years, there were no significant differences in any of the secondary outcomes between men randomized to radiotherapy and observation alone, reported Chris Parker, MD, from the Royal Marsden Hospital in London.

“In comparison with a policy of early salvage radiotherapy, adjuvant radiotherapy did not improve biochemical progression-free survival and did not delay the further use of hormone therapy,” he said at the European Society for Medical Oncology Congress, on behalf of colleagues in the RADICALS-RT trial.

Results of the RADICAL-RT trial were also pooled with results from two other large trials in a collaborative series of meta-analyses of long-term prostate cancer outcomes – dubbed ARTISTIC – which found no significant differences in event-free survival (EFS) for men randomized to either adjuvant or salvage radiotherapy.

“We don’t see any evidence from the ARTISTIC results that adjuvant radiotherapy improves event-free survival, compared to early salvage radiotherapy, and our best estimate is of a small, 1% difference in event-free survival at 5 years,” said Claire Vale, PhD, a research fellow at University College, London.

RADICALS RT details

Dr. Parker presented results from an early analysis of the secondary endpoint of biochemical progression-free survival (PFS), conducted in cooperation with the ARTISTIC investigators.

In RADICALS RT, investigators in the United Kingdom, Denmark, Canada, and Ireland enrolled 1,369 men following radical prostatectomy and after stratification by Gleason score, margin status, treatment center, and radiotherapy schedule (52.5 Gy delivered in 20 fractions, or 66 Gy delivered), randomly assigned them to either postoperative radiotherapy or observation with radiotherapy.

The patients enrolled had postoperative PSAs less than 2 ng/mL and one or more risk factors, either pathologic stage 3/4, Gleason score 7-10, positive surgical margins, or preoperative PSA of 10 ng/mL or greater.

The trigger for radiotherapy in men assigned to observation was PSA failure, defined as a PSA level of at least 0.1 ng/mL or 3 consecutive PSA rises.

At the median 5-year follow-up, PFS rates were 85% for patients assigned to adjuvant radiotherapy, and 88% for those assigned to observation, translating to a hazard ratio of 1.10, which was not statistically significant.

However, there were significant differences between the groups in both self-reported urinary incontinence (5.3% of patients in the radiotherapy group vs. 2.7% in the observation group, P = .008) and grade 3 or 4 urethral stricture at any time (8% vs. 5%, respectively, P = .03).

Results of the primary outcome, freedom from distant metastases will require longer follow-up, Dr. Parker said.

ARTISTIC meta-analysis

Dr. Vale presented results of the ARTISTIC collaborative meta-analysis, which included data from three randomized trials, including RADICALS, GETUG-AFU 17, and RAVES.

The meta-analysis was designed to include a consistent definition of PSA-driven EFS, prior to the unblinding of trial results.

The definition of EFS used in the trial was time from randomization until the first evidence of either PSA of 0.4 ng/mL or greater and rising after completion of radiotherapy, clinical/radiological progression, initiation on nontrial treatment, death from prostate cancer following completion of radiotherapy, or PSA level of 2.0 ng/mL or greater any time after randomization.

They analyzed data on a total of 1,074 men assigned to adjuvant radiotherapy and 1,077 assigned to salvage radiotherapy.

In each of the three trials included in the meta-analysis, there was a nonsignificant trend toward better PSA-driven EFS with salvage radiotherapy vs. adjuvant radiotherapy. The overall hazard ratio was 1.12, with the 95% confidence interval crossing 1, indicating a nonsignificant result.

Dr. Vale noted that early salvage radiotherapy spares many men from potentially unnecessary radiation and its negative consequences. Of the men included in the trials, more than 60% of those randomized to observation with salvage radiotherapy have yet to start radiotherapy.

She noted that investigators still need to assess long-term definitive outcomes such as metastases and survival, and whether some patients may derive benefit from adjuvant radiotherapy.

Invited discussant Gert De Meerleer, MD, PhD, a radiation oncologist at University Hospitals Leuven in Belgium, acknowledged that he agreed with most of the findings of the RADICALS-RT and ARTISTIC investigators.

An important take-home message, he said, is that “cure is the aim, and radiotherapy the keystone. If you have PSA relapse after prostatectomy, you can say, ‘I don’t treat the patient’ – fair enough. But if you treat the patient, only giving systemic therapy is the wrong way to go, you have to add radiotherapy,” he said.

He also agreed that “salvage is probably the modality of choice, and it is also in a lot of European countries, provided it is early.”

The RADICALS-RT trial is supported by Cancer Research UK and the Medical Research Council UK. Dr. Parker said he had no disclosures relevant to the trial. ARTISTIC is funded by the Medical Research Council. Dr. Vale reported having no disclosures. Dr. De Meerleer reported speaker fees, advisory board activities, and scientific grants not related to the studies.

SOURCE: Parker C et al. and Vale C et al. ESMO 2019. Abstracts LBA49_PR and LBA48_PR.

For men with prostate cancer who have a low prostate-specific antigen (PSA) level prior to salvage radiation therapy (SRT), adding an antiandrogen may increase the risk of other-cause mortality by twofold or more, according to investigators.

This finding was drawn from a secondary analysis of the NRG Oncology/RTOG 9601 phase 3 trial, a practice-changing study that showed that 2 years of antiandrogen therapy with bicalutamide improved overall survival when added to SRT, compared with that of SRT alone.

Results from the present analysis paint a more complex picture, revealing that patients with low PSA levels who received hormone therapy had a higher rate of other-cause mortality, primarily because of high-grade cardiac and neurologic events, reported lead author Daniel Spratt, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor, who presented findings at the annual meeting of the American Society for Radiation Oncology.

Dr. Spratt described how treatment paradigms have changed since RTOG 9601 began in 1998, which prompted a revisitation of the trial. “Almost half of the men [in the trial] had a persistently elevated PSA after they underwent their initial surgery,” Dr. Spratt said. “This is uncommonly seen today. Additionally, about 60% of patients received what we call late salvage radiation therapy, where PSA was monitored and continued to rise beyond 0.5 [ng/mL]; again, this is not what is recommended to be used today.”

In the present analysis, the investigators stratified patients by PSA level. Of the 760 men involved, 85% had a PSA of 0.2-1.5 ng/mL. Patients were further subgrouped by those with a PSA of 0.2-0.6 ng/mL and those with a very low PSA, of 0.2-0.3 ng/mL. Multiple endpoints were assessed, including overall survival, other-cause mortality, distant metastasis, and rates of grade 3-5 cardiac or neurologic events.

The analysis showed that men with a PSA greater than 1.5 ng/mL had improved survival (hazard ratio, 0.45; 95% confidence interval, 0.25-0.81) when treated with bicalutamide, but those with PSA of 1.5 ng/mL or less did not (HR, 0.87; 95% CI, 0.66-1.16). Looking more closely at patients with a PSA of 1.5 ng/mL or less, those with a PSA of 0.2-0.6 ng/mL had a twofold increased rate of other-cause mortality (subdistribution HR, 1.94; P = .009). The picture became even more concerning for patients with a PSA of 0.2-0.3 ng/mL who were treated with bicalutamide: They had a fourfold increased risk of other cause mortality (sHR, 4.14). Among the cases with elevated other-cause mortality, grade 3-4 cardiac and neurologic events were likely to be blamed.

“What is likely driving this, and of concern, is that for [patients with a] PSA of less than 1.5 [ng/mL] … there was a three- to four-and-a-half-fold increased risk of high grade cardiac events,” Dr. Spratt said.

“The current guidelines recommend that all men be offered hormone therapy when receiving salvage radiation therapy, but our data demonstrate that men with lower PSA’s are probably more harmed than helped by long-term hormone therapy,” Dr. Spratt concluded. “We now have three randomized trials with over 2,400 men in total, [none of which showed that] short- or long-term hormone therapy improves overall survival in men [with a low PSA level who receive] early salvage radiotherapy. Thus, PSA prior to salvage radiation actually is not only prognostic, it predicts who will benefit most from hormone therapy, and guidelines should now be updated to reflect this finding.”

The session moderator, Anthony Zietman, MD, of Massachusetts General Hospital, Boston, helped put the findings in perspective: “This really suggests that we’ve got to hold back a little,” Dr. Zietman said. “There are some people who really benefit [from hormone therapy], some who don’t benefit, and some who just might be harmed, so I think we can be much more thoughtful and cautious in the future. … Thirty thousand men a year are in this situation who could be receiving this treatment. You could fill Fenway Park with that many people. So there are some big downstream implications. From here on out, I’m going to be a lot more cautious with my patients.”

The study was primarily funded by AstraZeneca with additional support from the Korea Institute of Radiological and Medical Sciences. The investigators disclosed relationships with Novartis, Roche, Amgen, and others.

SOURCE: Spratt et al. ASTRO 2019, Abstract LBA1.

For men with prostate cancer who have a low prostate-specific antigen (PSA) level prior to salvage radiation therapy (SRT), adding an antiandrogen may increase the risk of other-cause mortality by twofold or more, according to investigators.

This finding was drawn from a secondary analysis of the NRG Oncology/RTOG 9601 phase 3 trial, a practice-changing study that showed that 2 years of antiandrogen therapy with bicalutamide improved overall survival when added to SRT, compared with that of SRT alone.

Results from the present analysis paint a more complex picture, revealing that patients with low PSA levels who received hormone therapy had a higher rate of other-cause mortality, primarily because of high-grade cardiac and neurologic events, reported lead author Daniel Spratt, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor, who presented findings at the annual meeting of the American Society for Radiation Oncology.

Dr. Spratt described how treatment paradigms have changed since RTOG 9601 began in 1998, which prompted a revisitation of the trial. “Almost half of the men [in the trial] had a persistently elevated PSA after they underwent their initial surgery,” Dr. Spratt said. “This is uncommonly seen today. Additionally, about 60% of patients received what we call late salvage radiation therapy, where PSA was monitored and continued to rise beyond 0.5 [ng/mL]; again, this is not what is recommended to be used today.”

In the present analysis, the investigators stratified patients by PSA level. Of the 760 men involved, 85% had a PSA of 0.2-1.5 ng/mL. Patients were further subgrouped by those with a PSA of 0.2-0.6 ng/mL and those with a very low PSA, of 0.2-0.3 ng/mL. Multiple endpoints were assessed, including overall survival, other-cause mortality, distant metastasis, and rates of grade 3-5 cardiac or neurologic events.

The analysis showed that men with a PSA greater than 1.5 ng/mL had improved survival (hazard ratio, 0.45; 95% confidence interval, 0.25-0.81) when treated with bicalutamide, but those with PSA of 1.5 ng/mL or less did not (HR, 0.87; 95% CI, 0.66-1.16). Looking more closely at patients with a PSA of 1.5 ng/mL or less, those with a PSA of 0.2-0.6 ng/mL had a twofold increased rate of other-cause mortality (subdistribution HR, 1.94; P = .009). The picture became even more concerning for patients with a PSA of 0.2-0.3 ng/mL who were treated with bicalutamide: They had a fourfold increased risk of other cause mortality (sHR, 4.14). Among the cases with elevated other-cause mortality, grade 3-4 cardiac and neurologic events were likely to be blamed.

“What is likely driving this, and of concern, is that for [patients with a] PSA of less than 1.5 [ng/mL] … there was a three- to four-and-a-half-fold increased risk of high grade cardiac events,” Dr. Spratt said.

“The current guidelines recommend that all men be offered hormone therapy when receiving salvage radiation therapy, but our data demonstrate that men with lower PSA’s are probably more harmed than helped by long-term hormone therapy,” Dr. Spratt concluded. “We now have three randomized trials with over 2,400 men in total, [none of which showed that] short- or long-term hormone therapy improves overall survival in men [with a low PSA level who receive] early salvage radiotherapy. Thus, PSA prior to salvage radiation actually is not only prognostic, it predicts who will benefit most from hormone therapy, and guidelines should now be updated to reflect this finding.”

The session moderator, Anthony Zietman, MD, of Massachusetts General Hospital, Boston, helped put the findings in perspective: “This really suggests that we’ve got to hold back a little,” Dr. Zietman said. “There are some people who really benefit [from hormone therapy], some who don’t benefit, and some who just might be harmed, so I think we can be much more thoughtful and cautious in the future. … Thirty thousand men a year are in this situation who could be receiving this treatment. You could fill Fenway Park with that many people. So there are some big downstream implications. From here on out, I’m going to be a lot more cautious with my patients.”

The study was primarily funded by AstraZeneca with additional support from the Korea Institute of Radiological and Medical Sciences. The investigators disclosed relationships with Novartis, Roche, Amgen, and others.

SOURCE: Spratt et al. ASTRO 2019, Abstract LBA1.

For men with prostate cancer who have a low prostate-specific antigen (PSA) level prior to salvage radiation therapy (SRT), adding an antiandrogen may increase the risk of other-cause mortality by twofold or more, according to investigators.

This finding was drawn from a secondary analysis of the NRG Oncology/RTOG 9601 phase 3 trial, a practice-changing study that showed that 2 years of antiandrogen therapy with bicalutamide improved overall survival when added to SRT, compared with that of SRT alone.

Results from the present analysis paint a more complex picture, revealing that patients with low PSA levels who received hormone therapy had a higher rate of other-cause mortality, primarily because of high-grade cardiac and neurologic events, reported lead author Daniel Spratt, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor, who presented findings at the annual meeting of the American Society for Radiation Oncology.

Dr. Spratt described how treatment paradigms have changed since RTOG 9601 began in 1998, which prompted a revisitation of the trial. “Almost half of the men [in the trial] had a persistently elevated PSA after they underwent their initial surgery,” Dr. Spratt said. “This is uncommonly seen today. Additionally, about 60% of patients received what we call late salvage radiation therapy, where PSA was monitored and continued to rise beyond 0.5 [ng/mL]; again, this is not what is recommended to be used today.”

In the present analysis, the investigators stratified patients by PSA level. Of the 760 men involved, 85% had a PSA of 0.2-1.5 ng/mL. Patients were further subgrouped by those with a PSA of 0.2-0.6 ng/mL and those with a very low PSA, of 0.2-0.3 ng/mL. Multiple endpoints were assessed, including overall survival, other-cause mortality, distant metastasis, and rates of grade 3-5 cardiac or neurologic events.

The analysis showed that men with a PSA greater than 1.5 ng/mL had improved survival (hazard ratio, 0.45; 95% confidence interval, 0.25-0.81) when treated with bicalutamide, but those with PSA of 1.5 ng/mL or less did not (HR, 0.87; 95% CI, 0.66-1.16). Looking more closely at patients with a PSA of 1.5 ng/mL or less, those with a PSA of 0.2-0.6 ng/mL had a twofold increased rate of other-cause mortality (subdistribution HR, 1.94; P = .009). The picture became even more concerning for patients with a PSA of 0.2-0.3 ng/mL who were treated with bicalutamide: They had a fourfold increased risk of other cause mortality (sHR, 4.14). Among the cases with elevated other-cause mortality, grade 3-4 cardiac and neurologic events were likely to be blamed.

“What is likely driving this, and of concern, is that for [patients with a] PSA of less than 1.5 [ng/mL] … there was a three- to four-and-a-half-fold increased risk of high grade cardiac events,” Dr. Spratt said.

“The current guidelines recommend that all men be offered hormone therapy when receiving salvage radiation therapy, but our data demonstrate that men with lower PSA’s are probably more harmed than helped by long-term hormone therapy,” Dr. Spratt concluded. “We now have three randomized trials with over 2,400 men in total, [none of which showed that] short- or long-term hormone therapy improves overall survival in men [with a low PSA level who receive] early salvage radiotherapy. Thus, PSA prior to salvage radiation actually is not only prognostic, it predicts who will benefit most from hormone therapy, and guidelines should now be updated to reflect this finding.”

The session moderator, Anthony Zietman, MD, of Massachusetts General Hospital, Boston, helped put the findings in perspective: “This really suggests that we’ve got to hold back a little,” Dr. Zietman said. “There are some people who really benefit [from hormone therapy], some who don’t benefit, and some who just might be harmed, so I think we can be much more thoughtful and cautious in the future. … Thirty thousand men a year are in this situation who could be receiving this treatment. You could fill Fenway Park with that many people. So there are some big downstream implications. From here on out, I’m going to be a lot more cautious with my patients.”

The study was primarily funded by AstraZeneca with additional support from the Korea Institute of Radiological and Medical Sciences. The investigators disclosed relationships with Novartis, Roche, Amgen, and others.

SOURCE: Spratt et al. ASTRO 2019, Abstract LBA1.

Stereotactic ablative radiation therapy (SABR) may be able to extend progression-free survival (PFS) among patients with oligometastatic prostate cancer, based on results from the phase 2 ORIOLE trial.

Will Pass/MDedge News

SABR appeared to control disease, in part, by triggering a systemic immune response, reported lead author Ryan Phillips, MD, PhD, chief resident of radiation oncology at Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, at the annual meeting of the American Society for Radiation Oncology. This is a particularly noteworthy finding, since prostate cancer is generally considered to be immunologically cold, Dr. Phillips explained.

The ORIOLE trial also demonstrated how prostate-specific membrane antigen (PSMA)–based PET/CT scans can be used to more accurately predict metastasis by detecting lesions that would otherwise be missed by standard imaging.

“There’s a hypothesis that these first few sites of spread pave the way for additional widespread metastasis down the road,” Dr. Phillips said, “and that if we can treat all detectable disease early enough, we may be able to provide long-term control or in the best-case scenario, be able to cure these patients of early metastatic disease.”

The trial involved 54 men with recurrent, hormone-sensitive prostate cancer who had been previously treated with radiation therapy or surgery. Additional eligibility requirements included one to three lesions that were 5 cm or smaller, detectable by MRI, CT, or bone scan; a prostate-specific antigen (PSA) doubling time of less than 15 months; and an Eastern Cooperative Oncology Group performance status of 2 or less.

Patients were randomized in a 2:1 ratio to receive either SABR or observation, with follow-up every 3 months including physical exam and PSA measurement, and at 6 months, CT and bone scan. The primary endpoint was disease progression at 6 months.

In addition to this protocol, biomarker correlative analyses were performed, including PSMA-based PET/CT, T-cell clonality testing, and circulating tumor DNA (ctDNA) assessment.

Results showed that significantly fewer men treated with SABR had disease progression at 6 months (19% vs. 61%; P = .005). This benefit extended beyond the primary endpoint, as median PFS among patients treated with SABR was not yet reached after more than a year of follow-up, while those in the observation group had a median PFS of 5.8 months (P = .0023).

“Clinically, this is promising,” Dr. Phillips said, “but we also were really interested in learning more about oligometastatic prostate cancer, and something that sets ORIOLE apart are the correlative studies.”

The first of these studies involved PSMA-based PET/CT, which can identify lesions that may be missed or underappreciated with conventional imaging. Within the SABR group, 35 of 36 men had PSMA-based PET/CT performed at baseline and 6 months later. Of these, 19 had all PSMA-based PET/CT–detectable lesions treated with SABR (total consolidation), while 16 had subtotal consolidation. This difference was predictive of outcome, as only 16% of patients with total consolidation developed new lesions 6 months later, compared with 63% of those who had subtotal consolidation (P = .006).

“Not only are we treating the disease we’re detecting, but it seems to be preventing the development of new metastases outside the areas that we treated,” Dr. Phillips said. “This also held when we looked at points beyond 6 months,” he added.

Further testing showed that SABR triggered a systemic adaptive immune response involving expansion of T-cell clones. “There’s a lot more activity and changes within the immune system that were only seen within the SABR arm,” Dr. Phillips said, noting that these changes were “similar in scope to what we see after a vaccination.”

Finally, the investigators assessed ctDNA, which showed that men with at least one high-risk mutation had similar outcomes regardless of treatment group; in contrast, those without any high-risk mutations had significantly better PFS when treated with SABR.

“These are low sample size, hypothesis-generating experiments,” Dr. Phillips said, “but it is promising that there may be measurable baseline factors that will help us decide which patients are likely to benefit from this approach, and which would really be better served with an alternate treatment strategy.”

Will Pass/MDedge News

Session moderator Anthony Zietman, MD, of Massachusetts General Hospital, Boston, suggested that the ORIOLE trial could have a big future. “This is a small study, but it’s a prospective study, and the findings are really provocative,” Dr. Zietman said. “Just imagine, if there was a patient with just two or three metastatic lesions, and by irradiating those, you could liberate proteins from the destroyed metastases, generate an immune response, and suppress the development of new metastases, that will be something extraordinary. So this trial will be followed very closely as it seems to be hinting at something that’s a bit of a Holy Grail in oncology.”

The investigators disclosed relationships with RefleXion Medical, Pfizer, Genentech, and others.

SOURCE: Phillips R et al. ASTRO 2019. Abstract LBA3.

Stereotactic ablative radiation therapy (SABR) may be able to extend progression-free survival (PFS) among patients with oligometastatic prostate cancer, based on results from the phase 2 ORIOLE trial.

Will Pass/MDedge News

SABR appeared to control disease, in part, by triggering a systemic immune response, reported lead author Ryan Phillips, MD, PhD, chief resident of radiation oncology at Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, at the annual meeting of the American Society for Radiation Oncology. This is a particularly noteworthy finding, since prostate cancer is generally considered to be immunologically cold, Dr. Phillips explained.

The ORIOLE trial also demonstrated how prostate-specific membrane antigen (PSMA)–based PET/CT scans can be used to more accurately predict metastasis by detecting lesions that would otherwise be missed by standard imaging.

“There’s a hypothesis that these first few sites of spread pave the way for additional widespread metastasis down the road,” Dr. Phillips said, “and that if we can treat all detectable disease early enough, we may be able to provide long-term control or in the best-case scenario, be able to cure these patients of early metastatic disease.”

The trial involved 54 men with recurrent, hormone-sensitive prostate cancer who had been previously treated with radiation therapy or surgery. Additional eligibility requirements included one to three lesions that were 5 cm or smaller, detectable by MRI, CT, or bone scan; a prostate-specific antigen (PSA) doubling time of less than 15 months; and an Eastern Cooperative Oncology Group performance status of 2 or less.

Patients were randomized in a 2:1 ratio to receive either SABR or observation, with follow-up every 3 months including physical exam and PSA measurement, and at 6 months, CT and bone scan. The primary endpoint was disease progression at 6 months.

In addition to this protocol, biomarker correlative analyses were performed, including PSMA-based PET/CT, T-cell clonality testing, and circulating tumor DNA (ctDNA) assessment.

Results showed that significantly fewer men treated with SABR had disease progression at 6 months (19% vs. 61%; P = .005). This benefit extended beyond the primary endpoint, as median PFS among patients treated with SABR was not yet reached after more than a year of follow-up, while those in the observation group had a median PFS of 5.8 months (P = .0023).

“Clinically, this is promising,” Dr. Phillips said, “but we also were really interested in learning more about oligometastatic prostate cancer, and something that sets ORIOLE apart are the correlative studies.”

The first of these studies involved PSMA-based PET/CT, which can identify lesions that may be missed or underappreciated with conventional imaging. Within the SABR group, 35 of 36 men had PSMA-based PET/CT performed at baseline and 6 months later. Of these, 19 had all PSMA-based PET/CT–detectable lesions treated with SABR (total consolidation), while 16 had subtotal consolidation. This difference was predictive of outcome, as only 16% of patients with total consolidation developed new lesions 6 months later, compared with 63% of those who had subtotal consolidation (P = .006).

“Not only are we treating the disease we’re detecting, but it seems to be preventing the development of new metastases outside the areas that we treated,” Dr. Phillips said. “This also held when we looked at points beyond 6 months,” he added.

Further testing showed that SABR triggered a systemic adaptive immune response involving expansion of T-cell clones. “There’s a lot more activity and changes within the immune system that were only seen within the SABR arm,” Dr. Phillips said, noting that these changes were “similar in scope to what we see after a vaccination.”

Finally, the investigators assessed ctDNA, which showed that men with at least one high-risk mutation had similar outcomes regardless of treatment group; in contrast, those without any high-risk mutations had significantly better PFS when treated with SABR.

“These are low sample size, hypothesis-generating experiments,” Dr. Phillips said, “but it is promising that there may be measurable baseline factors that will help us decide which patients are likely to benefit from this approach, and which would really be better served with an alternate treatment strategy.”

Will Pass/MDedge News

Session moderator Anthony Zietman, MD, of Massachusetts General Hospital, Boston, suggested that the ORIOLE trial could have a big future. “This is a small study, but it’s a prospective study, and the findings are really provocative,” Dr. Zietman said. “Just imagine, if there was a patient with just two or three metastatic lesions, and by irradiating those, you could liberate proteins from the destroyed metastases, generate an immune response, and suppress the development of new metastases, that will be something extraordinary. So this trial will be followed very closely as it seems to be hinting at something that’s a bit of a Holy Grail in oncology.”

The investigators disclosed relationships with RefleXion Medical, Pfizer, Genentech, and others.

SOURCE: Phillips R et al. ASTRO 2019. Abstract LBA3.

Stereotactic ablative radiation therapy (SABR) may be able to extend progression-free survival (PFS) among patients with oligometastatic prostate cancer, based on results from the phase 2 ORIOLE trial.

Will Pass/MDedge News

SABR appeared to control disease, in part, by triggering a systemic immune response, reported lead author Ryan Phillips, MD, PhD, chief resident of radiation oncology at Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, at the annual meeting of the American Society for Radiation Oncology. This is a particularly noteworthy finding, since prostate cancer is generally considered to be immunologically cold, Dr. Phillips explained.

The ORIOLE trial also demonstrated how prostate-specific membrane antigen (PSMA)–based PET/CT scans can be used to more accurately predict metastasis by detecting lesions that would otherwise be missed by standard imaging.

“There’s a hypothesis that these first few sites of spread pave the way for additional widespread metastasis down the road,” Dr. Phillips said, “and that if we can treat all detectable disease early enough, we may be able to provide long-term control or in the best-case scenario, be able to cure these patients of early metastatic disease.”

The trial involved 54 men with recurrent, hormone-sensitive prostate cancer who had been previously treated with radiation therapy or surgery. Additional eligibility requirements included one to three lesions that were 5 cm or smaller, detectable by MRI, CT, or bone scan; a prostate-specific antigen (PSA) doubling time of less than 15 months; and an Eastern Cooperative Oncology Group performance status of 2 or less.

Patients were randomized in a 2:1 ratio to receive either SABR or observation, with follow-up every 3 months including physical exam and PSA measurement, and at 6 months, CT and bone scan. The primary endpoint was disease progression at 6 months.

In addition to this protocol, biomarker correlative analyses were performed, including PSMA-based PET/CT, T-cell clonality testing, and circulating tumor DNA (ctDNA) assessment.

Results showed that significantly fewer men treated with SABR had disease progression at 6 months (19% vs. 61%; P = .005). This benefit extended beyond the primary endpoint, as median PFS among patients treated with SABR was not yet reached after more than a year of follow-up, while those in the observation group had a median PFS of 5.8 months (P = .0023).

“Clinically, this is promising,” Dr. Phillips said, “but we also were really interested in learning more about oligometastatic prostate cancer, and something that sets ORIOLE apart are the correlative studies.”

The first of these studies involved PSMA-based PET/CT, which can identify lesions that may be missed or underappreciated with conventional imaging. Within the SABR group, 35 of 36 men had PSMA-based PET/CT performed at baseline and 6 months later. Of these, 19 had all PSMA-based PET/CT–detectable lesions treated with SABR (total consolidation), while 16 had subtotal consolidation. This difference was predictive of outcome, as only 16% of patients with total consolidation developed new lesions 6 months later, compared with 63% of those who had subtotal consolidation (P = .006).

“Not only are we treating the disease we’re detecting, but it seems to be preventing the development of new metastases outside the areas that we treated,” Dr. Phillips said. “This also held when we looked at points beyond 6 months,” he added.

Further testing showed that SABR triggered a systemic adaptive immune response involving expansion of T-cell clones. “There’s a lot more activity and changes within the immune system that were only seen within the SABR arm,” Dr. Phillips said, noting that these changes were “similar in scope to what we see after a vaccination.”

Finally, the investigators assessed ctDNA, which showed that men with at least one high-risk mutation had similar outcomes regardless of treatment group; in contrast, those without any high-risk mutations had significantly better PFS when treated with SABR.

“These are low sample size, hypothesis-generating experiments,” Dr. Phillips said, “but it is promising that there may be measurable baseline factors that will help us decide which patients are likely to benefit from this approach, and which would really be better served with an alternate treatment strategy.”

Will Pass/MDedge News

Session moderator Anthony Zietman, MD, of Massachusetts General Hospital, Boston, suggested that the ORIOLE trial could have a big future. “This is a small study, but it’s a prospective study, and the findings are really provocative,” Dr. Zietman said. “Just imagine, if there was a patient with just two or three metastatic lesions, and by irradiating those, you could liberate proteins from the destroyed metastases, generate an immune response, and suppress the development of new metastases, that will be something extraordinary. So this trial will be followed very closely as it seems to be hinting at something that’s a bit of a Holy Grail in oncology.”

The investigators disclosed relationships with RefleXion Medical, Pfizer, Genentech, and others.

SOURCE: Phillips R et al. ASTRO 2019. Abstract LBA3.

Loss-of-function mutations in the PBRM1 gene are more common among patients with metastatic clear cell renal cell carcinoma (ccRCC) who have clinical responses to immune checkpoint inhibitors (ICIs), but the mutations fall a little short of serving as clinical biomarkers, investigators say.

Among patients with metastatic ccRCC enrolled in a randomized, phase 3 clinical trial comparing nivolumab (Opdivo) with everolimus (Afinitor) in patients who had previously received antiangiogenic therapy, patients with responses to nivolumab were more than twice as likely as nonresponders to have a truncating loss-of-function mutation in PBRM1, reported Toni K. Choueiri, MD, and colleagues from the Dana-Farber Cancer Institute in Boston.

Patients with PBRM1 mutations were also more likely to have a clinical benefit (complete/partial response, or stable disease with tumor shrinkage and progression-free survival [PFS] of at least 6 months) as well as better PFS and overall survival than patients without mutations.

“The association of PBRM1 truncating mutations with response to anti–[programmed death-1] therapy was confirmed in an independent ccRCC cohort. However, key limitations restrict use of PBRM1 mutations as a clinical biomarker,” they wrote in a research letter to JAMA Oncology.

Those limitations include an only modest effect of mutations on response and survival, a lack of evidence for a PBRM1 mutation effect in the first-line setting, and a possible association between mutations and benefit from prior antiangiogenic therapies, they acknowledged.

Dr. Choueiri was a coauthor of a previous study of genomic correlates of response to ICIs in ccRCC, which found that PBRM1 loss may influence response to checkpoint inhibitors by altering global tumor-cell expression.

In the current study, he and his colleagues looked at archival tumor tissue from an independent cohort of 382 patients who were part of a larger phase 3 trial. Of this group, 189 were treated with nivolumab, and 193 were treated with everolimus. PBRM1 mutations were identified in 55 of the nivolumab-treated patients (29%) and in 45 of the everolimus-treated patients (23%).

When they looked at clinical responses, they found that 15 of 38 patients with response to nivolumab (39%) had truncating PBRM1 mutations, compared with 16 of 74 nonresponding patients (22%), which translated into an odds ratio for response of 2.34 (P = .04).

Similarly, PBRM1 mutations among nivolumab-treated patients were significantly associated with clinical benefit (OR, 2.14; P = .0497), PFS (hazard ratio for progression, 0.67; P = .03), and overall survival (HR, 0.65; P = .03).

In contrast, there were no significant associations in everolimus-treated patients between PBRM1 mutations and either response, PFS, or overall survival.

“The concomitant presence of other cellular or molecular features may further influence the findings described herein. Nonetheless, this validated association between PBRM1 alterations and ICI response in a large randomized study represents a further step toward the development of genomic predictors for immunotherapies in advanced RCC,” the investigators concluded.

The study was supported by Department of Defense Congressionally Directed Medical Research Programs and Bristol-Myers Squibb. Dr. Choueiri disclosed personal fees from Bristol-Myers Squibb and fees and grants from other companies. One coauthor is a Bristol-Myers Squibb employee and shareholder.

SOURCE: Choueiri TK et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.3158.

Loss-of-function mutations in the PBRM1 gene are more common among patients with metastatic clear cell renal cell carcinoma (ccRCC) who have clinical responses to immune checkpoint inhibitors (ICIs), but the mutations fall a little short of serving as clinical biomarkers, investigators say.

Among patients with metastatic ccRCC enrolled in a randomized, phase 3 clinical trial comparing nivolumab (Opdivo) with everolimus (Afinitor) in patients who had previously received antiangiogenic therapy, patients with responses to nivolumab were more than twice as likely as nonresponders to have a truncating loss-of-function mutation in PBRM1, reported Toni K. Choueiri, MD, and colleagues from the Dana-Farber Cancer Institute in Boston.

Patients with PBRM1 mutations were also more likely to have a clinical benefit (complete/partial response, or stable disease with tumor shrinkage and progression-free survival [PFS] of at least 6 months) as well as better PFS and overall survival than patients without mutations.

“The association of PBRM1 truncating mutations with response to anti–[programmed death-1] therapy was confirmed in an independent ccRCC cohort. However, key limitations restrict use of PBRM1 mutations as a clinical biomarker,” they wrote in a research letter to JAMA Oncology.

Those limitations include an only modest effect of mutations on response and survival, a lack of evidence for a PBRM1 mutation effect in the first-line setting, and a possible association between mutations and benefit from prior antiangiogenic therapies, they acknowledged.

Dr. Choueiri was a coauthor of a previous study of genomic correlates of response to ICIs in ccRCC, which found that PBRM1 loss may influence response to checkpoint inhibitors by altering global tumor-cell expression.

In the current study, he and his colleagues looked at archival tumor tissue from an independent cohort of 382 patients who were part of a larger phase 3 trial. Of this group, 189 were treated with nivolumab, and 193 were treated with everolimus. PBRM1 mutations were identified in 55 of the nivolumab-treated patients (29%) and in 45 of the everolimus-treated patients (23%).

When they looked at clinical responses, they found that 15 of 38 patients with response to nivolumab (39%) had truncating PBRM1 mutations, compared with 16 of 74 nonresponding patients (22%), which translated into an odds ratio for response of 2.34 (P = .04).

Similarly, PBRM1 mutations among nivolumab-treated patients were significantly associated with clinical benefit (OR, 2.14; P = .0497), PFS (hazard ratio for progression, 0.67; P = .03), and overall survival (HR, 0.65; P = .03).

In contrast, there were no significant associations in everolimus-treated patients between PBRM1 mutations and either response, PFS, or overall survival.

“The concomitant presence of other cellular or molecular features may further influence the findings described herein. Nonetheless, this validated association between PBRM1 alterations and ICI response in a large randomized study represents a further step toward the development of genomic predictors for immunotherapies in advanced RCC,” the investigators concluded.

The study was supported by Department of Defense Congressionally Directed Medical Research Programs and Bristol-Myers Squibb. Dr. Choueiri disclosed personal fees from Bristol-Myers Squibb and fees and grants from other companies. One coauthor is a Bristol-Myers Squibb employee and shareholder.

SOURCE: Choueiri TK et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.3158.

Loss-of-function mutations in the PBRM1 gene are more common among patients with metastatic clear cell renal cell carcinoma (ccRCC) who have clinical responses to immune checkpoint inhibitors (ICIs), but the mutations fall a little short of serving as clinical biomarkers, investigators say.

Among patients with metastatic ccRCC enrolled in a randomized, phase 3 clinical trial comparing nivolumab (Opdivo) with everolimus (Afinitor) in patients who had previously received antiangiogenic therapy, patients with responses to nivolumab were more than twice as likely as nonresponders to have a truncating loss-of-function mutation in PBRM1, reported Toni K. Choueiri, MD, and colleagues from the Dana-Farber Cancer Institute in Boston.

Patients with PBRM1 mutations were also more likely to have a clinical benefit (complete/partial response, or stable disease with tumor shrinkage and progression-free survival [PFS] of at least 6 months) as well as better PFS and overall survival than patients without mutations.

“The association of PBRM1 truncating mutations with response to anti–[programmed death-1] therapy was confirmed in an independent ccRCC cohort. However, key limitations restrict use of PBRM1 mutations as a clinical biomarker,” they wrote in a research letter to JAMA Oncology.

Those limitations include an only modest effect of mutations on response and survival, a lack of evidence for a PBRM1 mutation effect in the first-line setting, and a possible association between mutations and benefit from prior antiangiogenic therapies, they acknowledged.

Dr. Choueiri was a coauthor of a previous study of genomic correlates of response to ICIs in ccRCC, which found that PBRM1 loss may influence response to checkpoint inhibitors by altering global tumor-cell expression.

In the current study, he and his colleagues looked at archival tumor tissue from an independent cohort of 382 patients who were part of a larger phase 3 trial. Of this group, 189 were treated with nivolumab, and 193 were treated with everolimus. PBRM1 mutations were identified in 55 of the nivolumab-treated patients (29%) and in 45 of the everolimus-treated patients (23%).

When they looked at clinical responses, they found that 15 of 38 patients with response to nivolumab (39%) had truncating PBRM1 mutations, compared with 16 of 74 nonresponding patients (22%), which translated into an odds ratio for response of 2.34 (P = .04).

Similarly, PBRM1 mutations among nivolumab-treated patients were significantly associated with clinical benefit (OR, 2.14; P = .0497), PFS (hazard ratio for progression, 0.67; P = .03), and overall survival (HR, 0.65; P = .03).

In contrast, there were no significant associations in everolimus-treated patients between PBRM1 mutations and either response, PFS, or overall survival.

“The concomitant presence of other cellular or molecular features may further influence the findings described herein. Nonetheless, this validated association between PBRM1 alterations and ICI response in a large randomized study represents a further step toward the development of genomic predictors for immunotherapies in advanced RCC,” the investigators concluded.

The study was supported by Department of Defense Congressionally Directed Medical Research Programs and Bristol-Myers Squibb. Dr. Choueiri disclosed personal fees from Bristol-Myers Squibb and fees and grants from other companies. One coauthor is a Bristol-Myers Squibb employee and shareholder.

SOURCE: Choueiri TK et al. JAMA Oncol. 2019 Sep 5. doi: 10.1001/jamaoncol.2019.3158.

For patients with localized renal cell carcinoma (RCC), stereotactic ablative body radiotherapy (SABR) may be an effective alternative to surgery, according to findings from a retrospective study.

Patients with smaller tumors and nonmetastatic disease achieved the best outcomes with SABR, reported lead author Rodney E. Wegner, MD, of Allegheny Health Network Cancer Institute, Pittsburgh, and colleagues.

“Radiation therapy is often overlooked in [RCC] as historic preclinical data reported RCC as being relatively radioresistant to external beam radiation at conventional doses,” the investigators wrote in Advances in Radiation Oncology. However, SABR may be able to overcome this resistance by delivering “highly conformal dose escalated radiation,” the investigators noted, citing two recent reports from the International Radiosurgery Oncology Consortium for Kidney (IROCK) that showed promising results (J Urol. 2019 Jun;201[6]:1097-104 and Cancer. 2018 Mar 1;124[5]:934-42).

The present study included 347 patients with RCC from the National Cancer Database who were treated with SABR and not surgery. Most patients (94%) did not have systemic therapy. Similar proportions lacked lymph node involvement (97%) or distant metastasis (93%). About three-quarters of patients (76%) had T1 disease. The median SABR dose was 45 Gy, ranging from 35 to 54 Gy, most frequently given in three fractions.

After a median follow-up of 36 months, ranging from 1 to 156 months, median overall survival across all patients was 58 months. SABR was most effective for patients with nonmetastatic disease who had smaller tumors.

An inverse correlation between tumor size and overall survival was apparent given that patients with tumors 2.5 cm or smaller had the longest median overall survival, at 92 months, with decrements in survival as tumors got larger. Survival dropped to 88 months for tumors 2.6-3.5 cm, 44 months for tumors 3.5-5.0 cm, and finally to 26 months for tumors larger than 5.0 cm. In addition to tumor size and metastatic disease, age was a risk factor for shorter survival.

“The results presented demonstrate excellent post-SABR outcomes, with median overall survival in the range of 7-8 years for smaller lesions,” the investigators wrote. “This is particularly impressive considering that many of these patients were likely medically inoperable.”

The researchers noted that most of kidney SABR is done at academic centers, which highlights the importance of appropriate technology and training for delivering this treatment.

“Further prospective research is needed to verify its safety and efficacy,” the investigators concluded.

No external funding was provided for the project and the investigators reported no conflicts of interest.

SOURCE: Wegner RE et al. Adv Rad Onc. 2019 Aug 8. doi: 10.1016/j.adro.2019.07.018.
 

For patients with localized renal cell carcinoma (RCC), stereotactic ablative body radiotherapy (SABR) may be an effective alternative to surgery, according to findings from a retrospective study.

Patients with smaller tumors and nonmetastatic disease achieved the best outcomes with SABR, reported lead author Rodney E. Wegner, MD, of Allegheny Health Network Cancer Institute, Pittsburgh, and colleagues.

“Radiation therapy is often overlooked in [RCC] as historic preclinical data reported RCC as being relatively radioresistant to external beam radiation at conventional doses,” the investigators wrote in Advances in Radiation Oncology. However, SABR may be able to overcome this resistance by delivering “highly conformal dose escalated radiation,” the investigators noted, citing two recent reports from the International Radiosurgery Oncology Consortium for Kidney (IROCK) that showed promising results (J Urol. 2019 Jun;201[6]:1097-104 and Cancer. 2018 Mar 1;124[5]:934-42).

The present study included 347 patients with RCC from the National Cancer Database who were treated with SABR and not surgery. Most patients (94%) did not have systemic therapy. Similar proportions lacked lymph node involvement (97%) or distant metastasis (93%). About three-quarters of patients (76%) had T1 disease. The median SABR dose was 45 Gy, ranging from 35 to 54 Gy, most frequently given in three fractions.

After a median follow-up of 36 months, ranging from 1 to 156 months, median overall survival across all patients was 58 months. SABR was most effective for patients with nonmetastatic disease who had smaller tumors.

An inverse correlation between tumor size and overall survival was apparent given that patients with tumors 2.5 cm or smaller had the longest median overall survival, at 92 months, with decrements in survival as tumors got larger. Survival dropped to 88 months for tumors 2.6-3.5 cm, 44 months for tumors 3.5-5.0 cm, and finally to 26 months for tumors larger than 5.0 cm. In addition to tumor size and metastatic disease, age was a risk factor for shorter survival.

“The results presented demonstrate excellent post-SABR outcomes, with median overall survival in the range of 7-8 years for smaller lesions,” the investigators wrote. “This is particularly impressive considering that many of these patients were likely medically inoperable.”

The researchers noted that most of kidney SABR is done at academic centers, which highlights the importance of appropriate technology and training for delivering this treatment.

“Further prospective research is needed to verify its safety and efficacy,” the investigators concluded.

No external funding was provided for the project and the investigators reported no conflicts of interest.

SOURCE: Wegner RE et al. Adv Rad Onc. 2019 Aug 8. doi: 10.1016/j.adro.2019.07.018.
 

For patients with localized renal cell carcinoma (RCC), stereotactic ablative body radiotherapy (SABR) may be an effective alternative to surgery, according to findings from a retrospective study.

Patients with smaller tumors and nonmetastatic disease achieved the best outcomes with SABR, reported lead author Rodney E. Wegner, MD, of Allegheny Health Network Cancer Institute, Pittsburgh, and colleagues.

“Radiation therapy is often overlooked in [RCC] as historic preclinical data reported RCC as being relatively radioresistant to external beam radiation at conventional doses,” the investigators wrote in Advances in Radiation Oncology. However, SABR may be able to overcome this resistance by delivering “highly conformal dose escalated radiation,” the investigators noted, citing two recent reports from the International Radiosurgery Oncology Consortium for Kidney (IROCK) that showed promising results (J Urol. 2019 Jun;201[6]:1097-104 and Cancer. 2018 Mar 1;124[5]:934-42).

The present study included 347 patients with RCC from the National Cancer Database who were treated with SABR and not surgery. Most patients (94%) did not have systemic therapy. Similar proportions lacked lymph node involvement (97%) or distant metastasis (93%). About three-quarters of patients (76%) had T1 disease. The median SABR dose was 45 Gy, ranging from 35 to 54 Gy, most frequently given in three fractions.

After a median follow-up of 36 months, ranging from 1 to 156 months, median overall survival across all patients was 58 months. SABR was most effective for patients with nonmetastatic disease who had smaller tumors.

An inverse correlation between tumor size and overall survival was apparent given that patients with tumors 2.5 cm or smaller had the longest median overall survival, at 92 months, with decrements in survival as tumors got larger. Survival dropped to 88 months for tumors 2.6-3.5 cm, 44 months for tumors 3.5-5.0 cm, and finally to 26 months for tumors larger than 5.0 cm. In addition to tumor size and metastatic disease, age was a risk factor for shorter survival.

“The results presented demonstrate excellent post-SABR outcomes, with median overall survival in the range of 7-8 years for smaller lesions,” the investigators wrote. “This is particularly impressive considering that many of these patients were likely medically inoperable.”

The researchers noted that most of kidney SABR is done at academic centers, which highlights the importance of appropriate technology and training for delivering this treatment.

“Further prospective research is needed to verify its safety and efficacy,” the investigators concluded.

No external funding was provided for the project and the investigators reported no conflicts of interest.

SOURCE: Wegner RE et al. Adv Rad Onc. 2019 Aug 8. doi: 10.1016/j.adro.2019.07.018.
 

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.

 

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.

 

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.