The PROfound trial was a pivotal phase III randomized, open-label study evaluating the efficacy of olaparib in men with metastatic castration-resistant prostate cancer (mCRPC) who had disease progression despite treatment with next-generation hormonal agents such as enzalutamide or abiraterone. This biomarker-driven trial enrolled 387 men with deleterious or suspected deleterious alterations in at least one of 15 prespecified genes involved in homologous recombination repair (HRR), such as BRCA1, BRCA2, ATM, CHEK2, and PALB2, as identified using the FoundationOneCDx assay. Patients were divided into two cohorts: Cohort A included those with BRCA1, BRCA2, or ATM mutations (n=245), while Cohort B included alterations in 12 other HRR genes (n=142). Patients were randomized in a 2:1 ratio to receive olaparib (300 mg twice daily) or physician’s choice of enzalutamide or abiraterone.
In Cohort A, olaparib significantly improved imaging-based progression-free survival (iPFS) compared to control (median 7.4 vs. 3.6 months; HR, 0.34; P<0.001), with a confirmed objective response rate of 33% versus 2%, and significantly delayed time to pain progression (HR, 0.44). Interim analysis showed an improvement in median overall survival (18.5 vs. 15.1 months; HR, 0.64), despite 81% of patients in the control group crossing over to olaparib upon progression. In the overall study population (cohorts A+B), iPFS was also significantly longer with olaparib (median 5.8 vs. 3.5 months; HR, 0.49; P<0.001). Exploratory subgroup analyses indicated that patients with BRCA1/2 mutations derived the most benefit, although activity was observed across other HRR gene alterations as well.
Olaparib was generally well tolerated, though adverse events were more frequent compared to control. The most common adverse effects included anemia (46%), nausea (41%), and fatigue (37%). Grade ≥3 adverse events were reported in 51% of olaparib-treated patients, versus 38% in the control arm. Pulmonary embolism occurred in 4% of the olaparib group but was not associated with increased mortality.
The findings from the PROfound study support the use of olaparib as a targeted treatment for patients with mCRPC harboring BRCA1, BRCA2, or other HRR gene alterations, offering a significant improvement in disease control and patient-reported outcomes over current standard-of-care hormonal therapies. These results also reinforce the role of routine genomic testing in advanced prostate cancer to identify candidates for PARP inhibitor therapy.
Reference: https://www.nejm.org/doi/full/10.1056/NEJMoa1911440
