The FDA approved olaparib (Lynparza, AstraZeneca) for the treatment of adults with deleterious or suspected deleterious homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer after progression with enzalutamide (Xtandi, Astellas) or abiraterone. Patient selection is based on an FDA-approved companion diagnostic test.
“Prostate cancer has lagged behind other solid tumors in the era of precision medicine. I am thrilled by the approval of [olaparib,] which now brings a molecularly targeted treatment to men with HRR gene–mutated metastatic castration-resistant prostate cancer in the U.S.,” noted Maha Hussain, MBChB, the deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, in Chicago, and one of the principal investigators of the PROfound trial, which led to the approval.
In the open-label, multicenter, phase 3 PROfound trial (ClinicalTrials.gov Identifier: NCT02987543), patients were divided into two cohorts based on their HRR gene mutation status. Patients with mutations in the BRCA1, BRCA2 or ATM subtypes of HRR genes made up cohort A (n=245); patients with mutations among 12 other genes involved in the HRR genes were included in cohort B (n=142); those with mutations of both types were assigned to cohort A. Patients then were randomly assigned within the cohorts (2:1) to receive 300 mg of olaparib twice daily (n=256) or the investigator’s choice of enzalutamide or abiraterone (n=131). All patients received a gonadotropin-releasing hormone analog or had prior bilateral orchiectomy.
The primary end point of the trial was radiographic progression-free survival (rPFS) in men with BRCA1/2 or ATM gene mutations (cohort A). Additional efficacy outcomes included confirmed objective response rate (ORR) in patients in cohort A with measurable disease, rPFS in both cohorts, and overall survival (OS) in cohort A.
The results, published in The New England Journal of Medicine (2020;382[22]:2091-2102), showed a statistically significant improvement in rPFS among cohort A patients treated with olaparib compared with those given investigator’s choice therapy (7.4 vs. 3.6 months; hazard ratio [HR], 0.34; 95% CI, 0.25-0.47; P<0.0001). There also were statistically significant improvements in median OS (19.1 vs. 14.7 months; HR, 0.69; 95% CI, 0.50-0.97; P=0.0175) and ORR (33% vs. 2%; P<0.0001) in cohort A patients. In addition, the investigators found a statistically significant improvement in rPFS among patients in cohort A+B treated with olaparib compared with those given investigator’s choice therapy (median, 5.8 vs. 3.5 months; HR, 0.49; 95% CI, 0.38-0.63; P<0.0001).
The most common adverse events occurring in patients treated with olaparib in the PROfound trial (≥10% of patients) were anemia, nausea, fatigue (including asthenia), decreased appetite, diarrhea, vomiting, thrombocytopenia, cough and dyspnea. Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients randomly assigned to the olaparib arm compared with 3.1% of those receiving enzalutamide or abiraterone.
For more information, view the full prescribing information for olaparib.
—Clinical Oncology News Staff
Based on press releases from the FDA and AstraZeneca.