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Combo delivers ‘impressive’ survival results in first-line RCC setting
Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.
Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.
The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.
The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.
Treatment-related adverse events were more common with both combinations but manageable with dose modifications.
“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.
Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.
“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.
The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.
“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
Trial details
The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.
The primary analysis was conducted at a median follow-up of 27 months.
The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).
Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.
An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.
In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.
“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.
The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.
Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.
The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).
“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
Which combination, which sequence?
“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.
CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.
“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”
The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.
“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”
The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.
Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.
Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.
The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.
The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.
Treatment-related adverse events were more common with both combinations but manageable with dose modifications.
“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.
Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.
“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.
The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.
“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
Trial details
The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.
The primary analysis was conducted at a median follow-up of 27 months.
The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).
Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.
An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.
In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.
“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.
The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.
Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.
The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).
“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
Which combination, which sequence?
“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.
CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.
“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”
The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.
“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”
The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.
Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.
Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.
The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.
The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.
Treatment-related adverse events were more common with both combinations but manageable with dose modifications.
“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.
Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.
“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.
The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.
“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
Trial details
The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.
The primary analysis was conducted at a median follow-up of 27 months.
The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).
Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.
An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.
In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.
“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.
The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.
Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.
The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).
“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
Which combination, which sequence?
“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.
CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.
“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”
The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.
“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”
The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.
FROM GUCS 2021
Cabozantinib could be new standard for papillary RCC
Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.
“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.
Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.
The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.
Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.
“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.
Dr. Pal noted that current evidence supports only monotherapy in papillary disease.
“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.
Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
SWOG 1500 details
The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.
Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.
The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.
For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.
The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.
The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.
The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.
The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.
There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
MET alterations may be key
“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.
Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.
“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”
SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.
Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.
“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.
Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.
The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.
Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.
“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.
Dr. Pal noted that current evidence supports only monotherapy in papillary disease.
“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.
Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
SWOG 1500 details
The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.
Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.
The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.
For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.
The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.
The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.
The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.
The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.
There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
MET alterations may be key
“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.
Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.
“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”
SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.
Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.
“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.
Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.
The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.
Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.
“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.
Dr. Pal noted that current evidence supports only monotherapy in papillary disease.
“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.
Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
SWOG 1500 details
The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.
Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.
The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.
For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.
The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.
The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.
The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.
The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.
There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
MET alterations may be key
“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.
Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.
“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”
SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.
FROM GUCS 2021
RPLND deemed ‘attractive’ option for early metastatic seminoma
The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.
“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.
“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.
He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
Practice-changing?
Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.
Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.
“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.
Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
Trial details
The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.
The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.
Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.
The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.
All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.
“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.
Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.
The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.
The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.
“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.
“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.
He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
Practice-changing?
Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.
Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.
“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.
Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
Trial details
The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.
The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.
Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.
The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.
All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.
“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.
Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.
The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.
The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.
“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.
“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.
He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
Practice-changing?
Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.
Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.
“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.
Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
Trial details
The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.
The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.
Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.
The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.
All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.
“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.
Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.
The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.
FROM GUCS 2021
Adjuvant nivolumab: A new standard of care in high-risk MIUC?
The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.
“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.
“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
Trial details
The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.
By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).
The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.
At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).
In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.
The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).
Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.
Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.
The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
Awaited findings
Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.
“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.
“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.
“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.
Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.
Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”
The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.
The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.
“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.
“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
Trial details
The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.
By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).
The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.
At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).
In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.
The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).
Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.
Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.
The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
Awaited findings
Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.
“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.
“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.
“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.
Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.
Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”
The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.
The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.
“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.
“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
Trial details
The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.
By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).
The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.
At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).
In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.
The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).
Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.
Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.
The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
Awaited findings
Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.
“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.
“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.
“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.
Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.
Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”
The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.
FROM GUCS 2021
TITAN: Final results confirm apalutamide benefit in mCSPC
At a median follow-up of 44 months, the median overall survival (OS) was not reached in patients who received apalutamide plus standard androgen deprivation therapy (ADT), but the median OS was 52.2 months in patients who received placebo plus ADT.
“In the final analysis, the risk of death with apalutamide was reduced by 35%, with a hazard ratio of 0.65 and P value of less than .0001. This was similar to the hazard ratio of 0.67 in the primary analysis of TITAN, despite an almost 40% crossover rate from the placebo group to the apalutamide,” said Kim N. Chi, MD, a medical oncologist at BC Cancer Vancouver Prostate Centre.
Dr. Chi reported these results at the 2021 Genitourinary Cancer Symposium (Abstract 11).
Study details
The international, double-blind TITAN trial compared apalutamide (240 mg daily) with placebo, both added to standard ADT, in 1,052 patients with metastatic castration-sensitive prostate cancer, including those with high- and low-volume disease, prior docetaxel use, prior treatment for localized disease, and prior ADT for no more than 6 months.
At the primary analysis, reported in the New England Journal of Medicine in 2019, the dual primary endpoints of radiographic progression-free survival and OS met statistical significance at a median follow up of 22.7 months.
At the final analysis, the median treatment duration was 39.3 months for the apalutamide arm, 20.2 months for the placebo arm, and 15.4 months for patients who crossed over from placebo to apalutamide.
After adjusting for crossover, the effect of apalutamide on OS increased (HR, 0.52), indicating a reduction in the risk of death by 48% versus placebo, Dr. Chi said. He noted that the treatment effect on OS favored apalutamide in both high- and low-volume disease.
“Treatment with apalutamide also significantly prolonged second progression-free survival on next subsequent therapy and delayed development of castration resistance,” Dr. Chi said.
The median second progression-free survival was 44.0 months in the placebo arm and was not reached in the apalutamide arm. The median time to castration resistance was 11.4 months in the placebo arm and was not reached in the apalutamide arm.
Health-related quality of life was also maintained in the apalutamide group throughout the study and did not differ from the placebo group. Safety was consistent with previous reports.
“Importantly, the cumulative incidence of treatment-related falls, fracture, and fatigue was similar between groups, as was the cumulative incidence of treatment-related adverse events and serious adverse events,” Dr. Chi said.
An increased incidence of any-grade rash that was seen in the apalutamide group was expected but plateaued after about 6 months.
“These results confirm the favorable risk-benefit profile of apalutamide,” Dr. Chi concluded.
Implications for practice
The study results raise questions about how to best incorporate the findings into practice, including how to use docetaxel or other androgen receptor inhibitors in treatment strategies for this patient population and if they should be used in high-volume patients, said Elisabeth Heath, MD, session cochair and associate director of translational science at Wayne State University in Detroit.
Dr. Chi said a number of studies over the past 5 years have demonstrated OS benefit when combining ADT with additional therapy.
“Really, this should be considered the standard of care,” he said. “However, real-world studies ... suggest that only a minority of patients are actually receiving this additional therapy.”
Although there are challenges with comparing outcomes across studies to determine which treatments to use, the TITAN data reinforce apalutamide plus ADT as a good option, including in high-volume patients, Dr. Chi said.
Funding for TITAN was provided by Janssen Research & Development. Dr. Chi and Dr. Heath disclosed relationships with Janssen and many other companies. [email protected]
At a median follow-up of 44 months, the median overall survival (OS) was not reached in patients who received apalutamide plus standard androgen deprivation therapy (ADT), but the median OS was 52.2 months in patients who received placebo plus ADT.
“In the final analysis, the risk of death with apalutamide was reduced by 35%, with a hazard ratio of 0.65 and P value of less than .0001. This was similar to the hazard ratio of 0.67 in the primary analysis of TITAN, despite an almost 40% crossover rate from the placebo group to the apalutamide,” said Kim N. Chi, MD, a medical oncologist at BC Cancer Vancouver Prostate Centre.
Dr. Chi reported these results at the 2021 Genitourinary Cancer Symposium (Abstract 11).
Study details
The international, double-blind TITAN trial compared apalutamide (240 mg daily) with placebo, both added to standard ADT, in 1,052 patients with metastatic castration-sensitive prostate cancer, including those with high- and low-volume disease, prior docetaxel use, prior treatment for localized disease, and prior ADT for no more than 6 months.
At the primary analysis, reported in the New England Journal of Medicine in 2019, the dual primary endpoints of radiographic progression-free survival and OS met statistical significance at a median follow up of 22.7 months.
At the final analysis, the median treatment duration was 39.3 months for the apalutamide arm, 20.2 months for the placebo arm, and 15.4 months for patients who crossed over from placebo to apalutamide.
After adjusting for crossover, the effect of apalutamide on OS increased (HR, 0.52), indicating a reduction in the risk of death by 48% versus placebo, Dr. Chi said. He noted that the treatment effect on OS favored apalutamide in both high- and low-volume disease.
“Treatment with apalutamide also significantly prolonged second progression-free survival on next subsequent therapy and delayed development of castration resistance,” Dr. Chi said.
The median second progression-free survival was 44.0 months in the placebo arm and was not reached in the apalutamide arm. The median time to castration resistance was 11.4 months in the placebo arm and was not reached in the apalutamide arm.
Health-related quality of life was also maintained in the apalutamide group throughout the study and did not differ from the placebo group. Safety was consistent with previous reports.
“Importantly, the cumulative incidence of treatment-related falls, fracture, and fatigue was similar between groups, as was the cumulative incidence of treatment-related adverse events and serious adverse events,” Dr. Chi said.
An increased incidence of any-grade rash that was seen in the apalutamide group was expected but plateaued after about 6 months.
“These results confirm the favorable risk-benefit profile of apalutamide,” Dr. Chi concluded.
Implications for practice
The study results raise questions about how to best incorporate the findings into practice, including how to use docetaxel or other androgen receptor inhibitors in treatment strategies for this patient population and if they should be used in high-volume patients, said Elisabeth Heath, MD, session cochair and associate director of translational science at Wayne State University in Detroit.
Dr. Chi said a number of studies over the past 5 years have demonstrated OS benefit when combining ADT with additional therapy.
“Really, this should be considered the standard of care,” he said. “However, real-world studies ... suggest that only a minority of patients are actually receiving this additional therapy.”
Although there are challenges with comparing outcomes across studies to determine which treatments to use, the TITAN data reinforce apalutamide plus ADT as a good option, including in high-volume patients, Dr. Chi said.
Funding for TITAN was provided by Janssen Research & Development. Dr. Chi and Dr. Heath disclosed relationships with Janssen and many other companies. [email protected]
At a median follow-up of 44 months, the median overall survival (OS) was not reached in patients who received apalutamide plus standard androgen deprivation therapy (ADT), but the median OS was 52.2 months in patients who received placebo plus ADT.
“In the final analysis, the risk of death with apalutamide was reduced by 35%, with a hazard ratio of 0.65 and P value of less than .0001. This was similar to the hazard ratio of 0.67 in the primary analysis of TITAN, despite an almost 40% crossover rate from the placebo group to the apalutamide,” said Kim N. Chi, MD, a medical oncologist at BC Cancer Vancouver Prostate Centre.
Dr. Chi reported these results at the 2021 Genitourinary Cancer Symposium (Abstract 11).
Study details
The international, double-blind TITAN trial compared apalutamide (240 mg daily) with placebo, both added to standard ADT, in 1,052 patients with metastatic castration-sensitive prostate cancer, including those with high- and low-volume disease, prior docetaxel use, prior treatment for localized disease, and prior ADT for no more than 6 months.
At the primary analysis, reported in the New England Journal of Medicine in 2019, the dual primary endpoints of radiographic progression-free survival and OS met statistical significance at a median follow up of 22.7 months.
At the final analysis, the median treatment duration was 39.3 months for the apalutamide arm, 20.2 months for the placebo arm, and 15.4 months for patients who crossed over from placebo to apalutamide.
After adjusting for crossover, the effect of apalutamide on OS increased (HR, 0.52), indicating a reduction in the risk of death by 48% versus placebo, Dr. Chi said. He noted that the treatment effect on OS favored apalutamide in both high- and low-volume disease.
“Treatment with apalutamide also significantly prolonged second progression-free survival on next subsequent therapy and delayed development of castration resistance,” Dr. Chi said.
The median second progression-free survival was 44.0 months in the placebo arm and was not reached in the apalutamide arm. The median time to castration resistance was 11.4 months in the placebo arm and was not reached in the apalutamide arm.
Health-related quality of life was also maintained in the apalutamide group throughout the study and did not differ from the placebo group. Safety was consistent with previous reports.
“Importantly, the cumulative incidence of treatment-related falls, fracture, and fatigue was similar between groups, as was the cumulative incidence of treatment-related adverse events and serious adverse events,” Dr. Chi said.
An increased incidence of any-grade rash that was seen in the apalutamide group was expected but plateaued after about 6 months.
“These results confirm the favorable risk-benefit profile of apalutamide,” Dr. Chi concluded.
Implications for practice
The study results raise questions about how to best incorporate the findings into practice, including how to use docetaxel or other androgen receptor inhibitors in treatment strategies for this patient population and if they should be used in high-volume patients, said Elisabeth Heath, MD, session cochair and associate director of translational science at Wayne State University in Detroit.
Dr. Chi said a number of studies over the past 5 years have demonstrated OS benefit when combining ADT with additional therapy.
“Really, this should be considered the standard of care,” he said. “However, real-world studies ... suggest that only a minority of patients are actually receiving this additional therapy.”
Although there are challenges with comparing outcomes across studies to determine which treatments to use, the TITAN data reinforce apalutamide plus ADT as a good option, including in high-volume patients, Dr. Chi said.
Funding for TITAN was provided by Janssen Research & Development. Dr. Chi and Dr. Heath disclosed relationships with Janssen and many other companies. [email protected]
FROM GUCS 2021
CCR score can guide treatment decisions after radiation in prostate cancer
The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.
His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.
“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.
He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.
This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
Value of CCR
The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.
“Each patient has in their own mind what that risk reduction is that works for them,” he added.
For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.
The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.
The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
‘Uncomfortable’ findings, barriers to acceptance
“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.
“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.
The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.
In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.
All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.
Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.
CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.
Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.
“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”
The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.
The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.
His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.
“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.
He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.
This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
Value of CCR
The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.
“Each patient has in their own mind what that risk reduction is that works for them,” he added.
For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.
The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.
The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
‘Uncomfortable’ findings, barriers to acceptance
“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.
“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.
The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.
In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.
All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.
Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.
CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.
Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.
“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”
The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.
The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.
His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.
“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.
He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.
This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
Value of CCR
The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.
“Each patient has in their own mind what that risk reduction is that works for them,” he added.
For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.
The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.
The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
‘Uncomfortable’ findings, barriers to acceptance
“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.
“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.
The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.
In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.
All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.
Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.
CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.
Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.
“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”
The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.
FROM GUCS 2021
Liquid vs. tissue biopsy in advanced prostate cancer: Why not both?
The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.
Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.
“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.
“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”
Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.
ctDNA profiling proves feasible, comparable
CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.
The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.
Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.
“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.
“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.
ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).
“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.
When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.
However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.
Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.
Rare and novel AR alterations
“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.
She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.
Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.
“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.
The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.
“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.
BRCA1/2: High concordance
To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.
The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.
There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.
The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.
Implications for practice
This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.
“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.
“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.
“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”
Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).
The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.
Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.
“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.
“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”
Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.
ctDNA profiling proves feasible, comparable
CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.
The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.
Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.
“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.
“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.
ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).
“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.
When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.
However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.
Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.
Rare and novel AR alterations
“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.
She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.
Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.
“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.
The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.
“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.
BRCA1/2: High concordance
To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.
The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.
There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.
The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.
Implications for practice
This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.
“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.
“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.
“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”
Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).
The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.
Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.
“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.
“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”
Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.
ctDNA profiling proves feasible, comparable
CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.
The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.
Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.
“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.
“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.
ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).
“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.
When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.
However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.
Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.
Rare and novel AR alterations
“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.
She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.
Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.
“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.
The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.
“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.
BRCA1/2: High concordance
To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.
The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.
There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.
The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.
Implications for practice
This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.
“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.
“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.
“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”
Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).
FROM GUCS 2021
Androgen annihilation strategy prolongs rPFS in mCRPC
Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.
These findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 9).
“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.
Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.
With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.
Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.
Study outcomes
The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).
Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.
For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.
The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).
Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.
Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.
“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.
“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
Practice changing?
To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.
However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.
Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.
“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”
The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.
Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.
These findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 9).
“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.
Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.
With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.
Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.
Study outcomes
The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).
Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.
For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.
The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).
Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.
Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.
“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.
“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
Practice changing?
To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.
However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.
Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.
“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”
The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.
Adding the androgen receptor antagonist to standard care – abiraterone acetate and prednisone – prolonged radiographic progression-free survival (rPFS) by 6.0 months at the trial’s primary analysis and by 7.4 months at the trial’s final analysis. Adverse events were consistent with the drug’s known safety profile.
These findings were reported at the 2021 Genitourinary Cancers Symposium (Abstract 9).
“mCRPC is frequently driven by activated androgen receptors and elevated intratumoral androgens,” said investigator Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center, New York.
Therefore, androgen annihilation using agents with distinct mechanisms that target both pathways is attractive.
With this in mind, investigators conducted the ACIS trial. They enrolled 982 patients who had mCRPC that had progressed on androgen deprivation therapy but who had not received chemotherapy or androgen-signaling inhibitors for castration-resistant disease.
Patients were randomized evenly to apalutamide or placebo, each given with abiraterone plus prednisone. All patients continued their ongoing androgen deprivation therapy.
Study outcomes
The trial met its primary endpoint, Dr. Rathkopf reported. In the primary analysis, conducted at a median follow-up of 25.7 months, the median investigator-assessed rPFS was 22.6 months with apalutamide and 16.6 months with placebo (hazard ratio, 0.69; P < .0001).
Results held up at the final analysis, conducted at a median follow-up of 54.8 months. At that time, the median investigator-assessed rPFS was 24.0 months with apalutamide and 16.6 months with placebo (HR, 0.70; 95% confidence interval, 0.60-0.83). The median overall survival was 36.2 months and 33.7 months, respectively, a nonsignificant difference.
For both rPFS and overall survival, there were trends toward benefit in two clinical subgroups typically having poorer prognosis – men with visceral metastases and men aged 75 years and older. In analyses of biomarkers, benefit was greater in men whose tumors were luminal subtype and in patients who had average or high androgen receptor activity.
The apalutamide and placebo groups did not differ significantly on time to second PFS, initiation of cytotoxic chemotherapy, chronic opioid use, and pain progression. However, apalutamide therapy increased the percentage of men who achieved a confirmed decline of at least 50% in prostate-specific antigen (PSA) level (79.5% vs. 72.9%) and an undetectable PSA level at any time during treatment (24.6% vs. 19.2%).
Apalutamide was associated with a higher rate of grade 3/4 treatment-emergent adverse events (63.3% vs. 56.2%), including fatigue, hypertension, rash, cardiac disorders, and fracture/osteoporosis.
Health-related quality of life declined over time in both treatment groups, although not to a clinically meaningful extent.
“Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone and prednisone in mCRPC,” Dr. Rathkopf said, noting that she currently looks at the whole picture when deciding whether to use the combination.
“It’s not just luminal subtype or Gleason grade or age. You have to look at all of these variables together. There are definitely patients that are more suited to a more aggressive approach early on,” she elaborated. “And some patients want to be more aggressive. A progression-free survival gain of 6 or 7 months up front is meaningful to them. A longer time to progression and a more profound decline in PSA will allow them to possibly enjoy their life more during this treatment period, balanced against whatever toxicities we may see with the combination.”
Practice changing?
To its merit, the ACIS trial was large; used an active, standard-of-care comparator; and had a blinded design, said invited discussant Joshi J. Alumkal, MD, of the Rogel Cancer Center at the University of Michigan, Ann Arbor.
However, “because of the increase in toxicity, cost, similar radiographic progression-free survival 2, and the lack of overall survival benefit at this time, and in light of the clinical insights from other studies with combined or sequential ARSI [androgen receptor signaling inhibitor] treatment, I do not believe results from ACIS change practice at this time,” he said.
Additional research into the varied molecular pathways driving this disease will be essential for tailoring therapy to improve clinical outcomes for various patient subsets, Dr. Alumkal maintained.
“To move the needle in CRPC, it is important to understand the biology in those patients who derive the least benefit from ARSI treatment,” he elaborated. “Understanding the key drivers in these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors that appear to do quite poorly, even with ARSI escalation as done in SPARTAN or ACIS.”
The ACIS study was funded by Janssen Research and Development. Dr. Rathkopf disclosed relationships with AstraZeneca, Bayer, Janssen, Celgene, Ferring, Genentech/Roche, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda, and TRACON Pharma. Dr. Alumkal disclosed relationships with Dendreon, Merck Sharpe & Dohme, Aragon Pharmaceuticals, Astellas Pharma, Gilead Sciences, and Zenith Epigenetics.
FROM GUCS 2021
Declines in PSA screening may account for rise in metastatic prostate cancers
Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).
A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.
The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”
Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”
Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.
“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.
PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.
Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”
The task force recommended against PSA screening in men older than 70 years.
The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.
Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.
Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).
A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.
The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”
Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”
Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.
“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.
PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.
Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”
The task force recommended against PSA screening in men older than 70 years.
The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.
Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.
Between 2008 and 2016, the mean incidence of prostate cancers that were metastatic at diagnosis increased from 6.4 to 9.0 per 100,000 men. During the same period, the mean percentage of men undergoing PSA screening decreased from 61.8% to 50.5%, Vidit Sharma, MD, reported in a poster session at the 2021 Genitourinary Cancers Symposium (Abstract 228).
A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were indeed associated with increased age-adjusted incidence of metastatic prostate cancer, said Dr. Sharma, the lead author of the study and a health services fellow in urologic oncology at the University of California, Los Angeles.
The regression coefficient per 100,000 men was 14.9, confirming that states with greater declines in screening had greater increases in prostate cancers that were metastatic at diagnosis, he added, noting that, “overall, variation in PSA screening explained 27% of the longitudinal variation in metastatic disease at diagnosis.”
Dr. Sharma and colleagues had reviewed North American Association of Central Cancer Registries data from 2002 to 2016 for each state and extracted survey-weighted PSA screening estimates from the Centers for Disease Control and Prevention’s Behavioral Risk Factor Surveillance System. The researchers noted wide variations in screening across states, but they said across-the-board declines were evident beginning in 2010, marking a “worrisome consequence that needs attention.”
Robert Dreicer, MD, deputy director of the University of Virginia Cancer Center, Charlottesville, agreed, noting in a press statement that the findings suggest reduced PSA screening may come at the cost of more men presenting with metastatic disease.
“Patients should discuss the risks and benefits associated with PSA screening with their doctor to identify the best approach for them,” Dr. Dreicer said.
PSA screening has been shown to reduce prostate cancer metastasis and mortality, but screening has also been linked to overdiagnosis and overtreatment of prostate cancer. As a result, the U.S. Preventive Services Task Force (USPSTF) “found insufficient evidence to recommend PSA screening in 2008 and later recommended against PSA screening in 2012,” Dr. Sharma said.
Several studies subsequently showed a rise in metastatic prostate cancer diagnosis, but the role of PSA screening reductions in those findings was unclear. In 2018, the USPSTF updated its recommendations, stating that men aged 55-69 years should make “an individual decision about whether to be screened after a conversation with their clinician about the potential benefits and harms.”
The task force recommended against PSA screening in men older than 70 years.
The current study “strengthens the epidemiological evidence that reductions in PSA screening may be responsible for at least some of the increase in metastatic prostate cancer diagnoses,” Dr. Sharma said. He added that he and his coauthors support shared decision-making policies to optimize PSA screening approaches to reduce the incidence of metastatic prostate cancer, such as those recommended in the 2018 USPSTF update.
Dr. Sharma disclosed research funding from the Veterans Affairs Health Services Research & Development Fellowship. He and his colleagues had no other disclosures.
FROM GUCS 2021
Combo disappoints in metastatic, castration-resistant prostate cancer
In a phase 1/2 study, adding saracatinib to docetaxel increased toxicity without improving progression-free or overall survival.
“Although we could safely combine the Src kinase inhibitor saracatinib with docetaxel, it did not show any improvement in outcomes, when compared with docetaxel plus placebo. We therefore do not recommend proceeding to a phase 3 trial,” said investigator Robert J. Jones, MD, PhD, of the Institute of Cancer Sciences at the University of Glasgow, Scotland.
Dr. Jones presented the phase 1/2 trial results at the 2021 Genitourinary Cancers Symposium (Abstract 107).
He explained that saracatinib targets Src family members, and Src activity is increased during the acquisition of castration resistance and during taxane resistance. Dr. Jones and colleagues therefore theorized that saracatinib could be beneficial for patients with mCRPC.
The team tested their theory with the phase 1/2 trial, enrolling patients with mCRPC who had not previously received taxanes or radionucleotides. Dr. Jones reported results for 10 patients in the phase 1 portion of the trial and 140 patients in the phase 2 portion.
In phase 1, patients received saracatinib at 50 mg, 125 mg, or 175 mg daily plus docetaxel at 75 mg/m2.
There were no dose-limiting toxicities or pharmacokinetic interactions in these patients, so the phase 2 dose of saracatinib was 175 mg daily.
In phase 2, patients were randomized to receive saracatinib plus docetaxel or placebo plus docetaxel.
Results: Safety and efficacy
“In terms of efficacy, the trial failed to meet its primary endpoint of demonstrating an improvement in progression-free survival. Indeed, there was a trend toward an improvement in progression-free survival for patients receiving placebo,” Dr. Jones said. “Similarly, in this key secondary endpoint of overall survival, there was no benefit from the addition of saracatinib. And again, there was a trend toward an improved survival in patients receiving placebo.”
The median progression-free survival was 19 weeks with saracatinib and 29 weeks with placebo (adjusted hazard ratio, 1.348).
The median overall survival was 62 weeks with saracatinib and 83 weeks with placebo (adjusted HR, 1.422).
Furthermore, there were no significant differences between the treatment arms for two other efficacy endpoints – maximum absolute change in prostate-specific antigen levels and absolute change in circulating tumor cell count from baseline to cycle three.
However, grade 3 or higher adverse events were more common in the saracatinib arm than in the placebo arm – 59% (41/69) and 41% (29/71), respectively.
The most common grade 3 or higher adverse events (in the saracatinib and placebo arms, respectively) were neutropenia (25% vs. 8%), diarrhea (12% vs. 4%), and fatigue (6% vs. 4%).
This research was funded by the UK National Health Service and Cancer Research UK. Dr. Jones disclosed relationships with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, and a number of other companies.
In a phase 1/2 study, adding saracatinib to docetaxel increased toxicity without improving progression-free or overall survival.
“Although we could safely combine the Src kinase inhibitor saracatinib with docetaxel, it did not show any improvement in outcomes, when compared with docetaxel plus placebo. We therefore do not recommend proceeding to a phase 3 trial,” said investigator Robert J. Jones, MD, PhD, of the Institute of Cancer Sciences at the University of Glasgow, Scotland.
Dr. Jones presented the phase 1/2 trial results at the 2021 Genitourinary Cancers Symposium (Abstract 107).
He explained that saracatinib targets Src family members, and Src activity is increased during the acquisition of castration resistance and during taxane resistance. Dr. Jones and colleagues therefore theorized that saracatinib could be beneficial for patients with mCRPC.
The team tested their theory with the phase 1/2 trial, enrolling patients with mCRPC who had not previously received taxanes or radionucleotides. Dr. Jones reported results for 10 patients in the phase 1 portion of the trial and 140 patients in the phase 2 portion.
In phase 1, patients received saracatinib at 50 mg, 125 mg, or 175 mg daily plus docetaxel at 75 mg/m2.
There were no dose-limiting toxicities or pharmacokinetic interactions in these patients, so the phase 2 dose of saracatinib was 175 mg daily.
In phase 2, patients were randomized to receive saracatinib plus docetaxel or placebo plus docetaxel.
Results: Safety and efficacy
“In terms of efficacy, the trial failed to meet its primary endpoint of demonstrating an improvement in progression-free survival. Indeed, there was a trend toward an improvement in progression-free survival for patients receiving placebo,” Dr. Jones said. “Similarly, in this key secondary endpoint of overall survival, there was no benefit from the addition of saracatinib. And again, there was a trend toward an improved survival in patients receiving placebo.”
The median progression-free survival was 19 weeks with saracatinib and 29 weeks with placebo (adjusted hazard ratio, 1.348).
The median overall survival was 62 weeks with saracatinib and 83 weeks with placebo (adjusted HR, 1.422).
Furthermore, there were no significant differences between the treatment arms for two other efficacy endpoints – maximum absolute change in prostate-specific antigen levels and absolute change in circulating tumor cell count from baseline to cycle three.
However, grade 3 or higher adverse events were more common in the saracatinib arm than in the placebo arm – 59% (41/69) and 41% (29/71), respectively.
The most common grade 3 or higher adverse events (in the saracatinib and placebo arms, respectively) were neutropenia (25% vs. 8%), diarrhea (12% vs. 4%), and fatigue (6% vs. 4%).
This research was funded by the UK National Health Service and Cancer Research UK. Dr. Jones disclosed relationships with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, and a number of other companies.
In a phase 1/2 study, adding saracatinib to docetaxel increased toxicity without improving progression-free or overall survival.
“Although we could safely combine the Src kinase inhibitor saracatinib with docetaxel, it did not show any improvement in outcomes, when compared with docetaxel plus placebo. We therefore do not recommend proceeding to a phase 3 trial,” said investigator Robert J. Jones, MD, PhD, of the Institute of Cancer Sciences at the University of Glasgow, Scotland.
Dr. Jones presented the phase 1/2 trial results at the 2021 Genitourinary Cancers Symposium (Abstract 107).
He explained that saracatinib targets Src family members, and Src activity is increased during the acquisition of castration resistance and during taxane resistance. Dr. Jones and colleagues therefore theorized that saracatinib could be beneficial for patients with mCRPC.
The team tested their theory with the phase 1/2 trial, enrolling patients with mCRPC who had not previously received taxanes or radionucleotides. Dr. Jones reported results for 10 patients in the phase 1 portion of the trial and 140 patients in the phase 2 portion.
In phase 1, patients received saracatinib at 50 mg, 125 mg, or 175 mg daily plus docetaxel at 75 mg/m2.
There were no dose-limiting toxicities or pharmacokinetic interactions in these patients, so the phase 2 dose of saracatinib was 175 mg daily.
In phase 2, patients were randomized to receive saracatinib plus docetaxel or placebo plus docetaxel.
Results: Safety and efficacy
“In terms of efficacy, the trial failed to meet its primary endpoint of demonstrating an improvement in progression-free survival. Indeed, there was a trend toward an improvement in progression-free survival for patients receiving placebo,” Dr. Jones said. “Similarly, in this key secondary endpoint of overall survival, there was no benefit from the addition of saracatinib. And again, there was a trend toward an improved survival in patients receiving placebo.”
The median progression-free survival was 19 weeks with saracatinib and 29 weeks with placebo (adjusted hazard ratio, 1.348).
The median overall survival was 62 weeks with saracatinib and 83 weeks with placebo (adjusted HR, 1.422).
Furthermore, there were no significant differences between the treatment arms for two other efficacy endpoints – maximum absolute change in prostate-specific antigen levels and absolute change in circulating tumor cell count from baseline to cycle three.
However, grade 3 or higher adverse events were more common in the saracatinib arm than in the placebo arm – 59% (41/69) and 41% (29/71), respectively.
The most common grade 3 or higher adverse events (in the saracatinib and placebo arms, respectively) were neutropenia (25% vs. 8%), diarrhea (12% vs. 4%), and fatigue (6% vs. 4%).
This research was funded by the UK National Health Service and Cancer Research UK. Dr. Jones disclosed relationships with Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, and a number of other companies.
FROM GUCS 2021