PARP inhibition is moving on from breast and ovarian cancer to the treatment of patients with prostate cancer and BRCA1/2 mutation. Olaparib (Lynparza) reduced the risk for death by 31% versus enzalutamide (Xtandi) or abiraterone (Zytiga) in men with metastatic castration-resistant prostate cancer (CRPC) and BRCA1 or BRCA2, and to a lesser extent ATM mutations, according to the final analysis of the phase 3 PROfound trial.
These results were presented by Joaquin Mateo, MD, PhD, Leader, Prostate Cancer Translational Research Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain, during the European Society for Medical Oncology (ESMO) Virtual Congress 2020 and were published online to coincide with this presentation (Hussain M, et al. N Engl J Med. 2020 Sep 20. Epub ahead of print).
“In men with metastatic CRPC progression on newer hormonal agents, olaparib improved overall survival in cohort A [BRCA or ATM mutations] versus enzalutamide or abiraterone despite crossover. Metastatic CRPC with BRCA1 and BRCA2 achieve the most benefit from olaparib. This is the first randomized trial to prospectively demonstrate improved overall survival in a molecularly defined population in mCRPC. The study results support genetic analysis of men with advanced prostate cancer,” stated Dr Mateo.
Olaparib is currently approved by the FDA for the treatment of men with metastatic CRPC after disease progression during treatment with another agent. All men enrolled in the PROfound study had disease progression during treatment with enzalutamide or abiraterone.
“Olaparib has demonstrated significant clinical benefit across key end points 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 CRPC,” said coinvestigator Johann S. de Bono, MB ChB, FRCP, PhD, Professor in Experimental Cancer Medicine, Institute of Cancer Research and Royal Marsden, London, England, in a news release from AstraZeneca.
“The PROfound trial showed 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,” Dr de Bono added.
Henrik Grönberg, MD, PhD, Professor in Cancer Epidemiology, Karolinska Institutet, Stockholm, Sweden, commented on the study, noting that the PROfound study was a practice-changing clinical trial for select patients.
“It’s clear that the effect of olaparib is superior in BRCA1 and BRCA2 cohorts, and not as robust in ATM. The effect of olaparib in cohort B—with 12 other mutations—is very small if any,” Dr Grönberg said. “Based on PROfound results, most likely I would treat my patients with BRCA1- and BRCA2-positive metastatic CRPC [with olaparib] who have received standard treatments and progressed, but I would not use this drug in patients with other genetic alterations,” Dr Grönberg added.
The PROfound Study
The PROfound study enrolled patients with metastatic CRPC and had mutations in ≥1 qualifying homologous recombination repair (HRR) genes whose disease progressed with enzalutamide or abiraterone therapy.
Cohort A (N = 245) included men with CRPC and BRCA1, BRCA2, or ATM genes. Cohort B (N = 142) included men with CRPC and other genetic HRR alterations. Dr Mateo reported the final overall survival (OS) analysis in cohort A of the study.
Patients were randomized in a 2:1 ratio to olaparib or to physician’s choice of enzalutamide or abiraterone, depending on the previous hormonal treatment. Crossover to olaparib from the physician’s choice arm was allowed at radiographic disease progression.
As of data cutoff in March 2020, the median OS with olaparib was significantly longer (19.1 months) compared with physician’s choice of enzalutamide or abiraterone (14.7 months) in cohort A (P = .0175), translating to a 31% reduction in mortality risk. The OS was significantly superior in the olaparib arm, despite a 66% rate of crossover to the olaparib arm at disease progression.
Survival End Point
Olaparib improved OS in all prespecified subgroups. In an overall prespecified survival analysis adjusted for crossover to olaparib, the results were even more robust in favor of olaparib in cohort A, with a 58% improvement in survival. In cohort B, no significant difference in survival was observed between the 2 treatment arms, with a median OS of 14.1 months for olaparib versus 11.1 months for the 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 OS results in the total study population of metastatic CRPC characterized by any of the 15 HRR genetic alterations were 17.3 months for olaparib versus 14.3 months for controls, a 21% reduction in risk for dying. When this analysis was adjusted for crossover, the risk for death was reduced by 45% with olaparib. These results were the basis for FDA approval of olaparib, Dr Mateo noted.
“Further exploratory gene-level analysis of overall survival showed that olaparib had different sensitivity for different genetic populations, with the greatest benefit seen in BRCA1 and BRCA2, and a less pronounced effect for ATM,” he stated.
The safety profile of olaparib was consistent with the original report of progression-free survival in the New England Journal of Medicine. No new safety signals were raised in the study.
Treatment discontinuation because of adverse events was reported in 20% of patients taking olaparib compared with 8% of the controls, and 23% of patients in the olaparib arm required dose reductions for an adverse event compared with 5% of controls. Deaths from adverse events were reported in 4% and 5% of patients, respectively.