As reported in The New England Journal of Medicine and during the ESMO Virtual Congress 2020 (Abstract 610O) by Maha Hussain, MD, FACP, FASCO, and colleagues, an overall survival analysis from the phase III PROfound trial has shown a significant benefit with olaparib vs physician’s choice of enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer and alterations in the BRCA1, BRCA2, or ATM genes.
In the previously reported primary analysis of PROfound, olaparib significantly prolonged imaging-based progression-free survival. The trial supported the May 2020 U.S. Food and Drug Administration approval of olaparib for treatment of adults with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer whose disease progressed following treatment with enzalutamide or abiraterone.
Maha Hussain, MD, FACP, FASCO
Study Details
In the open-label trial, 387 patients with disease progression on previous treatment with enzalutamide or abiraterone were randomly assigned 2:1 to receive olaparib at 300 mg twice daily (n = 256) or physician’s choice of either enzalutamide at 160 mg once daily or abiraterone at 1,000 mg once daily plus prednisone at 5 mg twice daily (n = 131). Patients were assigned to two cohorts: Cohort A included 245 patients (162 in the olaparib group and 83 in the control group) with at least one alteration in BRCA1, BRCA2, or ATM, and cohort B included 142 patients (94 in the olaparib group and 48 in the control group) with at least one alteration in any of the other 12 prespecified genes in the HRR pathway. Crossover from the control group to olaparib was allowed after imaging-based disease progression (for patients who met prespecified criteria). Overall survival in cohort A was a key secondary endpoint, with analysis performed at a data maturity of approximately 60%.
Key Findings
A total of 86 of 131 patients (66%) in the control group crossed over to receive olaparib, including 56 of 83 (67%) control group patients in cohort A and 30 of 48 (63%) control group patients in cohort B.
In cohort A, 79 of 162 patients (49%) in the olaparib group and 64 of 83 patients (77%) in the control group received a subsequent anticancer therapy, including crossover olaparib. In the overall population, 50% of the olaparib group and 73% of the control group received subsequent anticancer therapy.
“Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM, and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib.”— Maha Hussain, MD, FACP, FASCO, and colleagues
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In cohort A, median overall survival was 19.1 months in the olaparib group vs 14.7 months in the control group (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.50–0.97, P = 0.02). In a sensitivity analysis adjusting for crossover to olaparib, the hazard ratio was 0.42 (95% CI = 0.19–0.91).
In cohort B, median overall survival was 14.1 months vs 11.5 months (HR = 0.96, 95% CI = 0.63–1.49). In a sensitivity analysis adjusting for crossover to olaparib, the hazard ratio was 0.83 (95% CI = 0.11–5.98).
In the overall population, median overall survival was 17.3 months vs 14.0 months (HR = 0.79, 95% CI = 0.61–1.03). After adjustment for crossover, the hazard ratio was 0.55 (95% CI = 0.29–1.06).
Investigator-assessed median time to second disease progression or death was 15.5 months vs 10.6 months (HR = 0.64, 95% CI = 0.45–0.93) in cohort A, 9.9 months vs 7.9 months (HR = 0.77, 95% CI = 0.50–1.21) in cohort B, and 13.4 months vs 9.7 months (HR = 0.68, 95% CI = 0.51–0.90) in the overall population.
The investigators concluded: “Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2, or ATM, and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib.”
Disclosure: The study was funded by AstraZeneca and Merck Sharp & Dohme. For full disclosures of the study authors, visit nejm.org or oncologypro.esmo.org.
