Mutations in the DNA damage repair genes BRCA 1 and BRCA2 increase a tumor’s susceptibility to treatment with poly(ADP)ribose polymerase (PARP) inhibitors. This treatment approach is standard in breast and ovarian cancers, where these mutations commonly occur. Mutations in BRCA1/2 and the DNA damage repair gene ATM occur in as many as 30% of patients with metastatic castration-resistant prostate cancer (mCRPC), making PARP inhibitor treatment rational in this patient population. At the ESMO Congress 2019, Maha Hussain, MD (Northwestern University, Chicago, Illinois, United States), presented interim results from the randomized phase III PROfound trial, which compared the PARP inhibitor olaparib to hormonal therapy with physician’s choice of enzalutamide or abiraterone in 387 patients with previously treated mCRPC who carried mutations in BRCA1/2 or ATM (Cohort 1) or other DNA damage repair genes (Cohort 2).
Among patients in Cohort 1, the median radiographic progression-free survival (rPFS) was significantly prolonged with olaparib treatment compared to hormonal therapy (7.4 months vs 3.6 months; HR 0.34, P < .0001). A similar benefit for olaparib treatment was seen in the overall trial population (5.8 months vs 3.5 months; HR 0.49, P < .0001). The PFS benefit of olaparib was seen in all prespecified patient subgroups. The objective response rate was also significantly higher in patients receiving olaparib compared to hormonal therapy in Cohort 1 (33.3% vs 2.3%; P < .0001). While overall survival (OS) data are not yet mature, interim analysis detected a trend in favor of olaparib treatment. The median OS among patients in Cohort 1 was 18.5 months with olaparib treatment, compared to 15.1 months with hormonal therapy (HR 0.64, P = .0173). In the overall trial population, the median OS was 17.5 months and 14.3 months with olaparib and hormonal therapy, respectively (HR 0.67, P = .0063). A total of 80% of patients in the control arm crossed over to olaparib treatment.
Adverse events (AEs) occurred more frequently in patients treated with olaparib. Grade 3/4 AEs occurred in 50.8% of patients receiving olaparib and 37.7% of patients receiving hormonal therapy. The most common AE in patients receiving olaparib was anemia, which occurred in 21.5% of patients. Dose reductions and discontinuations due to AEs were more common in patients receiving olaparib.
Dr Hussain concluded that these results support the efficacy and safety of olaparib in patients with mCRPC with DNA damage mutations. Most importantly, she noted these results suggest that widespread testing for these mutations should be incorporated as a standard part of patient evaluation for men with mCRPC, similar to testing strategies in patients with breast and ovarian cancer.
Read more about this study on Medscape News.