FDA Approves Olaparib for HRR Gene–Mutated Metastatic Castration-Resistant Prostate Cancer

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) has been approved for the treatment of men with somatic homologous recombination repair (HRR) gene—mutated metastatic castration-resistant prostate cancer (mCRPC). Prostate cancer is the second most common cancer in men, and PARP inhibitors kill cancer cells by blocking enzymes that let the cells repair DNA.

AstraZeneca and Merck said Wednesday the therapy is for patients with deleterious or suspected deleterious germline HRR gene—mutated cancer or for those whose cancer has progressed after prior treatment with enzalutamide or abiraterone.

Approximately 20% to 30% of men with mCRPC have an HRR gene mutation. The companies said patients will be selected for therapy based on an FDA-approved companion diagnostic.

The FDA approval was based on results from the phase 3 PROfound trial, which had a primary endpoint of radiographic progression-free survival (rPFS) in men with BRCA1/2 or ATM gene mutations, a subpopulation of HRR gene mutations. Results showed olaparib reduced the risk of disease progression or death by 66% (HR, 0.34; P < .0001) and improved rPFS to a median of 7.4 months versus 3.6 months with enzalutamide or abiraterone.

Olaparib also showed an rPFS benefit in the overall HRR gene—mutated trial population, a key secondary endpoint, and reduced the risk of disease progression or death by 51% (HR, 0.49; P < .0001) and improved rPFS to a median of 5.8 months versus 3.5 months with enzalutamide or abiraterone.

Additional results released last month demonstrated a statistically significant and clinically meaningful improvement in the key secondary endpoint of overall survival (OS) with olaparib versus abiraterone or enzalutamide in men with mCRPC and BRCA1/2 or ATM gene mutations. Results showed olaparib reduced the risk of death by 31% (HR, 0.69; P = .0175) and improved OS to a median of 19.1 months versus 14.7 months with enzalutamide or abiraterone.

Fatal adverse reactions occurred in 4% of patients, including pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%), intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari Syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%). Serious adverse reactions occurred in 36% of patients.

The most common adverse reactions occurring in at least 10% of the study arm (n = 256) were anemia (46%), nausea (41%), fatigue including asthenia (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%) and dyspnea (10%).

In addition, venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with mCRPC who received olaparib plus androgen deprivation therapy (ADT) compared with 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving olaparib and ADT had a 6% incidence of pulmonary embolism compared with 0.8% of patients treated with ADT plus either enzalutamide or abiraterone.

Last year, the FDA approved olaparib for BRCA-mutated pancreatic cancers.