Olaparib Leads to Longer OS for BRCA1/2- or ATM–Altered mCRPC

December 31, 2020
Hannah Slater

Treatment with olaparib versus physician’s choice of standard therapy led to a significantly longer duration of overall survival in patients with metastatic castration-resistant prostate cancer who had tumors with at least 1 alteration in BRCA1/2 or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent.

Among men with metastatic castration-resistant prostate cancer (mCRPC) who had tumors with at least 1 alteration in BRCA1/2 or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib (Lynparza) had a significantly improved survival outcomes versus those assigned to receive enzalutamide (Xtandi) or abiraterone (Zytiga) plus prednisone as the control therapy, according to the phase 3 PROfound trial (NCT02987543) results that were recently published in The New England Journal of Medicine.

The median duration of overall survival (OS) for these patients who received olaparib was 19.1 months compared with 14.7 months for those who received a control therapy (HR, 0.69; 95% CI, 0.50-0.97; P = .02). Moreover, the risk of death was 31% lower with olaparib treatment than with control therapy. Importantly, these improvements were observed despite considerable crossover from the control therapy arm to olaparib.

The median duration of treatment with olaparib among participants who crossed over was 4.8 months and the median duration of treatment in the control group was 3.9 months.

“These findings support the previously reported result of a significantly longer duration of imaging-based progression-free survival with olaparib than with control therapy in the same patient population,” wrote the study authors who were led by Maha Hussain, MD.

In this open-label trial, patients with mCRPC who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent were randomized 2:1 to receive either olaparib (n = 256) or physician’s choice of enzalutamide or abiraterone plus prednisone as the control therapy (n = 131). Cohort A consisted of 245 patients with at least 1 alteration in BRCA1, BRCA2, or ATM, and cohort B consisted of 142 patients with at least 1 alteration in any of the other 12 prespecified genes.

In cohort B, the median duration of OS was 14.1 months with olaparib and 11.5 months with control therapy (HR, 0.96; 95% CI, 0.63-1.49). In the overall study population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months (HR, 0.79; 95% CI, 0.61-1.03).

In total, 86 of 131 patients (66%) in the control group crossed over to receive olaparib, including 56 of 83 patients (67%) treated in cohort A. A sensitivity analysis that adjusted for crossover to olaparib demonstrated hazard ratios for death of 0.42 (95% CI, 0.19-0.91) in cohort A, 0.83 (95% CI, 0.11-5.98) in cohort B, and 0.55 (95% CI, 0.29-1.06) in the overall population.

Of note, this trial was not designed to test the benefit of therapy with regard to survival at the individual gene level. However, the investigators did not observe a clinical benefit for olaparib in the population of patients who had homologous recombination repair gene alterations outside of BRCA1, BRCA2, or ATM.

“These data, including the results of sensitivity analyses that excluded patients with PPP2R2A alterations, and the recent regulatory approval of olaparib for metastatic castration-resistant prostate cancer in which this gene alteration was excluded highlight that additional studies are now required to further delineate genomic indicators of response to PARP inhibition,” the authors wrote.

Regarding safety, the safety profile of olaparib in this final analysis was found to be consistent with that reported in the primary analysis, with no cumulative toxic effects observed during the extended exposure period. Among patients in the olaparib group and those who crossed over to receive olaparib, the most common adverse events (AEs) were anemia, nausea, and fatigue or asthenia. In the control group, the most commonly observed AEs were anemia, fatigue or asthenia, and decreased appetite.

Reference:

Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485.