On May 19, 2020, the FDA approved a new indication for olaparib (Lynparza; AstraZeneca), a PARP inhibitor, for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) and deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) mutation, as identified by an FDA-approved test, whose disease progressed after enzalutamide (Xtandi) or abiraterone acetate (Zytiga) therapy.
Olaparib is the first FDA-approved PARP inhibitor for prostate cancer. The FDA granted olaparib a priority review and a breakthrough therapy designation for this indication.
Olaparib was previously approved for several indications, including different types of ovarian cancer, breast cancer, and pancreatic cancer.
On the same day, the FDA also approved FoundationOne CDx for the identification of patients with mCRPC and HRR mutation, as well as the BRACAnalysis CDx test for the identification of patients with mCRPC and the germline BRCA1 or BRCA2 mutation as companion diagnostic devices for treatment with olaparib.
“Prostate cancer has lagged behind other solid tumors in the era of precision medicine. I am thrilled by the approval of Lynparza, which now brings a new molecular targeted treatment for this patient population,” said Maha Hussain, MD, a principal investigator of the PROfound study and Deputy Director, Robert H. Lurie Comprehensive Cancer Center, Northwestern University. “The PROfound trial was an international effort and I want to thank the patients, their families, the investigators and their teams involved in making it possible.”
The efficacy of olaparib in prostate cancer was investigated in the PROfound study, an open-label, randomized, multicenter clinical trial. The PROfound study included 387 patients who were randomized in a 2:1 ratio to olaparib 300 mg twice daily (N = 256) or to the investigator’s choice of enzalutamide or abiraterone acetate (N = 131). All patients received a gonadotropin-releasing hormone analog or had previous bilateral orchiectomy.
Patients were divided into 2 cohorts based on their HRR mutation status. Cohort A included patients with BRCA1, BRCA2, or ATM gene mutations (N = 245); group B included patients with any of the 12 HRR gene mutations (N = 142). Patients who had at least 1 mutation of cohort A and 1 mutation of cohort B were included in cohort A.
The primary efficacy outcome was radiologic progression-free survival (PFS) in cohort A. Other efficacy outcomes included objective response rate (ORR) in cohort A, combined radiologic PFS in cohorts A and B, and overall survival (OS) in cohort A.
The median radiologic PFS was significantly longer with olaparib than with the investigator’s choice—7.4 months versus 3.6 months—in cohort A (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.25-0.47; P <.0001); the median OS was 19.1 months versus 14.7 months, respectively (HR, 0.69; 95% CI, 0.50-0.97; P = .0175); and the ORR was 33% versus 2%, respectively (P <.0001). A significant improvement in radiologic PFS was reported with olaparib versus investigator’s choice in cohorts A and B, with a median of 5.8 months versus 3.5 months, respectively (HR, 0.49; 95% CI, 0.38-0.63; P <.0001).
The most common (≥10%) adverse events with olaparib in the PROfound study were anemia, nausea, fatigue, decreased appetite, diarrhea, vomiting, thrombocytopenia, cough, and dyspnea. The rate of venous thromboembolism (including pulmonary embolism) was 7% with olaparib versus 3.1% with enzalutamide or abiraterone.
The recommended dose of olaparib is 300 mg taken orally twice daily, with or without food.