Loss-of-function alterations in homologous recombination repair (HRR) genes are associated with more aggressive prostate cancer and sensitivity to poly (adenosine diphosphate–ribose) polymerase (PARP) inhibition treatment.1 PARP inhibitor interferes with DNA repair which leads to preferential cell death in the faster growing cancer cells which require more frequent DNA repair. A recent study published in the New England Journal of Medicine reported that olaparib, a PARP inhibitor, is more effective in treating patients with metastatic castration-resistant prostate cancer (mCRPC) than hormone therapy. The study compared the efficacy of olaparib to new hormone agents including enzalutamide and abiraterone.
mCRPC is a heterogeneous disease with poor outcomes that no longer completely respond to testosterone lowering treatment.1,2 Despite the lack of complete response to hormone therapy, most patients with mCRPC continued treatment with androgen deprivation therapy (ADT) as some prostate cancer cells will continue to respond to treatment.2,3 To prevent further cancer growth, additional treatments such as chemotherapy, immunotherapy, and radiotherapy are often used to control the symptoms and slow the progress of mCRPC.2
Olaparib is a PARP inhibitor involved in the base excision repair (BER) pathway. By catalyzing the poly(adenosine diphosphate–ribosyl)ation of a limited number of acceptor proteins involved in the chromatin architecture and in DNA metabolism, the detection or signaling pathway can be triggered, and the broken DNA strand can be repaired.4
In the prospective, open-label, randomized, phase 3 PROfound trial, adult male patients (≥18 years of age) with confirmed mCRPC whose disease had progressed during treatment with enzalutamide or abiraterone were randomized into two cohorts based on their qualifying gene alteration.1 Patients with at least one alteration in BRCA1, BRCA2, or ATM were assigned to cohort A (n=245), and patients with alterations in other prespecified genes with direct or indirect role in HRR were assigned to cohort B (n=142).1 Patients in each cohort were then randomly assigned in a 2:1 ratio to receive either olaparib or the prespecified physician’s choice of enzalutamide or abiraterone plus prednisone (control).1
The primary end point was imaging-based progression-free survival (PFS) in cohort A. Additional secondary end points included confirmed objective response rate, time to pain progression, overall survival (OS), a reduction of >50% in the concentration of prostate-specific antigen (PSA50 response), and the circulating-tumor-cell conversion rate.1
In cohort A, the median imaging-based PFS was significantly longer in the olaparib group when compared to the control group at 7.4 vs 3.6 months, respectively. The hazard ratio (HR) for progression or death was also significantly lower in the olaparib group (HR=0.34; 95% CI: 0.25-0.47; p<0.001).1 In addition to pain progression delay, a higher confirmed objective response rate (33% vs. 2%; p<0.001) and a longer median OS (18.5 vs. 15.1 months) were observed in the olaparib group when compared to the control group in cohort A.1 Similar significant benefits for olaparib were also demonstrated in the overall population (cohorts A and B).1 Notably, olaparib was associated with longer PFS or OS and better measures of response than enzalutamide or abiraterone, and the efficacy of olaparib was observed regardless of whether olaparib monotherapy was administered before chemotherapy or after chemotherapy.1
A higher incidence of peripheral edema, back pain and constipation was observed in the olaparib group, and these adverse events can be attributed to the duration of olaparib administration which was twice as long as the control group.1 Apart from that, the safety profile of olaparib was similar to that described in other monotherapy studies.1
Given the efficacy of olaparib in treating HRR gene-mutated mCRPC in the PROfound trial, the Food and Drug Administration (FDA) has approved olaparib for the treatment of mCRPC in patients whose diseases progressed after treatment with enzalutamide or abiraterone in May 2020.5 Together with the new FDA approval, olaparib is now indicated for mCRPC, advanced ovarian cancer, metastatic pancreatic cancer and metastatic breast cancer.4