FDA Approves Olaparib for HRR Gene-Mutated mCRPC

On May 19, 2020, the FDA approved olaparib (Lynparza; AstraZeneca) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations, that progressed following prior therapy with enzalutamide or abiraterone.

In addition, the FDA approved 2 companion diagnostic devices, FoundationOne CDx (Foundation Medicine) for identifying HRR gene alterations in patients with mCRPC and BRACAnalysis CDx (Myriad Genetic Laboratories) for identifying germline BRCA1/2 alterations in patients with mCRPC.

This approval is based on efficacy results from the PROfound trial. This open-label, multicenter trial randomized patients with mCRPC in a 2:1 ratio to olaparib 300 mg twice daily (n = 256) or investigator’s choice of enzalutamide or abiraterone acetate (n = 131). All patients on the trial had received a GnRH analog or had prior bilateral orchiectomy.

Based on HRR gene mutation status, patients were split into 2 different cohorts. Patients with BRCA1/2 or ATM mutations were included in Cohort A (n = 245) and patients with any mutations among 12 other genes in the HRR pathway were included in Cohort B (n = 142).

The major efficacy outcome of the trial was radiological progressions-free survival (PFS) in Cohort A. Secondary outcomes included confirmed objective response rate (ORR) in patients with measurable disease, radiological PFS in both Cohorts A and B, and overall survival (OS) in Cohort A.

The median radiological PFS for Cohort A was 7.4 months with olaparib compared to 3.6 months with investigator’s choice (HR, 0.34; 95% CI, 0.25, 0.47; P <.0001). Median OS was 19.1 months versus 14.7 months (HR, 0.69; 95% CI, 0.50, 0.97, P = .0175), respectively. Additionally, ORR was 33% versus 2% (P <.0001), respectively.

A statistically significant improvement in rPFS was also demonstrated for olaparib in Cohorts A and B combined in comparison to investigator’s choice. The median rPFS for the combined cohorts was 5.8 months with olaparib compared to 3.5 months with investigator’s choice.

The most common adverse events (≥10% of patients) associated with olaparib were anemia, nausea, fatigue (including asthenia), decreased appetite, diarrhea, vomiting, thrombocytopenia, cough and dyspnea. Patients receiving olaparib had an increased incidence of venous thromboembolic events, including pulmonary embolism (7%) compared to those receiving enzalutamide or abiraterone (3.1%).—Janelle Bradley

Source: US Food and Drug Administration. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. May 19, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer. Accessed May 20, 2020.