The PARP inhibitor olaparib reduced the risk of death by 31% compared with a second hormonal treatment (enzalutamide or abiraterone) in men with metastatic castration-resistant prostate cancer characterized by BRCA1, BRCA2, or ATM mutations, in the final analysis of the phase III PROfound trial presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1 All men enrolled in the trial had experienced disease progression after either enzalutamide or abiraterone. Results of the PROfound trial were published in The New England Journal of Medicine to coincide with this presentation at ESMO 2020.2
“In men with metastatic castration-resistant prostate cancer progressing on newer hormonal agents [enzalutamide or abiraterone], olaparib improved overall survival in cohort A [BRCA1, BRCA2, or ATM mutations] vs enzalutamide or abiraterone, despite crossover. Patients who had metastatic castration-resistant prostate cancer with BRCA1 and BRCA2 gene alterations achieved the most benefit from olaparib. This is the first randomized trial to prospectively demonstrate improved overall survival in a molecularly defined population in metastatic castration-resistant prostate cancer. The study results support genomic analysis of men with advanced prostate cancer,” stated Joaquin Mateo, MD, PhD, of Vall d’Hebron Institute of Oncology and University Hospital, Barcelona.
“This is the first randomized trial to prospectively demonstrate improved overall survival in a molecularly defined population in metastatic castration-resistant prostate cancer.”— Joaquin Mateo, MD, PhD
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Olaparib is currently approved by the FDA for treatment of metastatic castration-resistant prostate cancer after disease progression on hormonal agent for patients with certain gene alterations.
Approximately 20% to 30% of men with metastatic castration-resistant prostate cancer harbor deleterious alterations in DNA damage repair genes, primarily in those with direct or indirect roles in homologous recombination repair (HRR). BRCA1, BRCA2, and ATM mutations are a subgroup of HRR genes.
Johann de Bono, MD, PhD
According to a press release, senior study author, Johann de Bono, MD, PhD, of the Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, commented: “Olaparib has demonstrated significant clinical benefit across key endpoints in PROfound, and the final overall survival results for men with BRCA1/2 or ATM mutations reinforce its potential to change the standard of care for men with metastatic castration-resistant prostate cancer. The PROfound trial shows that olaparib can play an important role in this new era of precision medicine in prostate cancer, bringing targeted therapy at a molecular level to patients with a historically poor prognosis and few treatment options.”
PROfound enrolled patients with metastatic castration-resistant prostate cancer who experienced disease progression on prior enzalutamide or abiraterone and had mutations in at least one qualifying HRR gene. Patients were divided into two cohorts: cohort A (n = 245) included men with cancer harboring BRCA 1, BRCA 2, or ATM genes; cohort B (n = 142) included men with other genetic alterations in HRR. At ESMO 2020, Dr. Mateo reported the final overall survival analysis of the trial.
Patients enrolled in the trial were randomly assigned 2:1 to olaparib or physician’s choice of enzalutamide or abiraterone, depending on previous treatment. Crossover to olaparib was allowed at radiographic disease progression, which may have muddied the overall survival results.
Survival Endpoint Met
As of the data cutoff in March 2020, median overall survival with olaparib was significantly longer than with physician’s choice of enzalutamide or abiraterone in cohort A: 19.1 months vs 14.7 months (P = .0175), representing a 31% reduction in the risk of death. These results were achieved despite a 66% rate of crossover to olaparib at disease progression.
“Olaparib met the study’s survival endpoint,” Dr. Mateo stated. The survival benefit of olaparib was evident across all prespecified subgroups, even though some of them were small with wide confidence intervals, he added.
In an overall prespecified survival analysis adjusted for crossover to olaparib, results were even more robust favoring olaparib in cohort A, with a 58% improvement in survival. In cohort B, no significant difference in survival was observed between the two treatment arms; median overall survival was 14.1 months with olaparib vs 11.1 months for controls.
“The prespecified survival analyses adjusted for crossover suggest that the treatment effect of olaparib is likely to be greater than what has been observed in PROfound,” Dr. Mateo told listeners.
The overall survival results in the total study population of metastatic castration-resistant prostate cancer characterized by any of the 15 HRR genetic alterations were 17.3 months for olaparib vs 14.3 months for controls—a 21% reduction in the risk of death. When this analysis was adjusted for crossover, the risk of death was reduced by 45% with olaparib. These results were the basis for the U.S. Food and Drug Administration approval of olaparib, Dr. Mateo noted.
“Further exploratory gene-level analysis of overall survival showed that olaparib had a different sensitivity for different genetic populations, with the greatest benefit seen in patients with BRCA1 and BRCA2 alterations and a less pronounced effect for the ATM altered subgroup,” he stated.
Consistent Safety Profile
The safety profile of olaparib was consistent with the original report of progression-free survival in TheNew England Journal of Medicine.3 Treatment discontinuation due to adverse events was reported in 20% of patients taking olaparib compared with 8% of controls, and 23% in the olaparib group required dose reductions for an adverse event compared with 5% of controls. Death due to adverse events was reported in 4% and 5% of patients, respectively.
The most common adverse events occurring in 15% or more of patients included anemia (50%), nausea (43%), fatigue/asthenia (42%), decreased appetite (31%), diarrhea (21%), vomiting (20%), and constipation (19%). The incidence of grade 3 or higher adverse events in patients treated with olaparib was as follows: anemia (23%), fatigue or asthenia (3%), nausea (2%), decreased appetite (2%), and diarrhea (1%).
During the question-and-answer session following Dr. de Bono’s presentation, Dr. Mateo noted that prior phase II trials “clearly showed antitumor activity for ATM altered metastatic castration-resistant prostate cancer. In this study we see a benefit in the BRCA group, and we don’t see it in the ATM population. We need to figure out why this occurred.”
“Cohort B is an exploratory exercise,” Dr. Mateo continued. “Patients with many different genetic alterations may have a different biological explanation. It is difficult to interpret cohort B as a whole. It will be key to scrutinize data from prospective registries on these subsets. By restricting olaparib to patients with BRCA1/2 mutations, you will leave underrepresented patients behind.”
Dr. de Bono weighed in on the discussion of genetic selection: “As a patient advocate, I am concerned that some men with non-BRCA alterations may be sensitive to PARP inhibitors. There are undoubtedly men with other genetic alterations who will respond to these drugs. We must not fail these men who have limited options.”
DISCLOSURE: Dr. Mateo has served as a consultant or advisor to Amgen, AstraZeneca, Clovis Oncology, Janssen, MSD Oncology, and Roche; has participated in a speakers bureau for Astellas Pharma, AstraZeneca, Pfizer, and Sanofi; has received research funding from Pfizer and AstraZeneca; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Ipsen, and Sanofi. Dr. de Bono has received honoraria from Astellas Pharma, AstraZeneca, BioXCel, Daiichi Sankyo, Genentech/Roche, Janssen Oncology, Menarini Silicon Biosystems, Pfizer, Sanofi, and Sierra Oncology; has served as a consultant or advisor to Astellas Pharma, AstraZeneca, Bayer, BioXCel Therapeutics, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genentech/Roche, Genmab, GlaxoSmithKline, Janssen Oncology, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma GmbH, Pfizer, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; has received institutional research funding from Astex Pharmaceuticals, AstraZeneca, Bayer, Celgene, CellCentric, Daiichi Sankyo, Genentech, GlaxoSmithKline, MedImmune, Medivation, Merck Serono, Merck Sharp & Dohme, Orion Pharma GmbH, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; and has been reimbursed for travel, accommodations, or other expenses by Astellas Pharma, AstraZeneca, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Sanofi, Taiho Pharmaceutical, Qiagen, and Vertex.
1. de Bono JS, Mateo J, Fizazi K, et al: Final overall survival analysis of PROfound: Olaparib vs physician’s choice of enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alteration. ESMO Virtual Congress 2020. Abstract 610O. Presented September 20, 2020.
2. de Bono J, Mateo J, Fizazi K, et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382:2091-2102, 2020.
Henrik Grönberg, MD
Formal discussant of the PROfound trial, Henrik Grönberg, MD, of the Karolinska Institute, Stockholm, agreed that this was a practice-changing trial for select patients.
“The patient population is representative, but the problem is the control group, which included...