The European Union has approved olaparib for use in patients with metastatic castration-resistant prostate cancer who harbor BRCA1/2 mutations.
The European Union (EU) has approved olaparib (Lynparza) for use in patients with metastatic castration-resistant prostate cancer (mCRPC) who harbor BRCA1/2 mutations, according to an announcement from AstraZeneca and Merck.1
The regulatory decision was based on findings from a subgroup analysis of the phase 3 PROfound trial, which demonstrated that olaparib significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) compared with enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in patients with BRCA1/2-mutated mCRPC.
Results from the subgroup analysis showed that olaparib led to a 78% reduction in the risk of disease progression or death compared with enzalutamide or abiraterone (hazard ratio [HR], 0.22; 95% CI, 0.15-0.32; P <.0001) in patients with mCRPC and BRCA1/2 mutations. Moreover, the median rPFS with the PARP inhibitor was 9.8 months versus just 3.0 months with either of the antiandrogens. Olaparib also resulted in a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.42-0.95); the median OS was 20.1 months with olaparib versus 14.4 months with enzalutamide or abiraterone.
In patients with mCRPC and BRCA1/2 or ATM mutations, olaparib led to a 66% reduction in the risk of disease progression or death versus the control (HR, 0.34; 95% CI, 0.25-0.47; P <.0001).2,3 In the entire population of patients with homologous recombination repair (HRR)–mutated disease, the PARP inhibitor reduced the risk of disease progression or death by 51% versus the either of the antiandrogens (HR, 0. 49; 95% CI, 0.38-0.63; P <.0001).
“This approval in the EU is a landmark moment that begins a new era of precision medicine in prostate cancer,” Johann de Bono, a principal investigator on PROfound and head of drug development at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, stated in a press release. “[Olaparib] now provides a targeted treatment option at a molecular level to patients with advanced prostate cancer who have historically poor prognosis and few treatment options.”
In the prospective, multicenter, open-label phase 3 trial, the safety and efficacy of olaparib was examined in comparison with abiraterone or enzalutamide in patients with mCRPC who had progressed on prior treatment with new hormonal anticancer agents and also had a qualifying mutation in 1 of the 15 genes involved in the HRR pathway; these aberrations included BRCA1/2, ATM, and CDK12.4
The study comprised 2 cohorts. Cohort A enrolled 245 patients with BRCA1/2 or ATM alterations, while cohort B included 142 patients with an alteration in BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, or RAD54L. Participants in each cohort underwent a 2:1 randomization to either olaparib or physician’s choice of abiraterone plus prednisone or enzalutamide.
Among those in cohort A, 162 patients were given olaparib, while 83 received abiraterone plus prednisone or enzalutamide. In cohort B, 94 were administered the PARP inhibitor, while 48 received physician’s choice of abiraterone plus prednisone or enzalutamide. Beyond these cohorts, a combined assessment was performed on all patients (n = 387).
Across all cohorts examined in the trial, the PARP inhibitor was given at a dose of 300 mg twice daily, abiraterone was given at a daily dose of 1000 mg with 5 mg of prednisone twice daily, and enzalutamide was administered at a daily dose of 160 mg. Patient characteristics were found to be well balanced between the arms in each cohort.
Additional results showed that the confirmed objective response rate (ORR) in cohort A was 33.3% with the PARP inhibitor versus 2.3% with the antiandrogens (odds ratio [OR], 20.86; 95% CI, 4.18-379.18; P <.0001). The median time to pain progression with olaparib versus the control had not yet been reached versus 9.92 months, respectively; this translated to a 56% reduction in the risk of pain progression (HR, 0.44; 95% CI, 0.22-0.91; P =.0192). The median rPFS in cohort A with olaparib versus the control was 7.4 months and 3.6 months, respectively. In cohort B, the HR for rPFS was 0.88 (95% CI, 0.58-1.36).
In both cohorts combined, the median rPFS was 5.8 months with olaparib versus 3.5 months with the antiandrogen agents. Moreover, the confirmed ORR was 21.7% with olaparib versus 4.5% with abiraterone/prednisone or enzalutamide, respectively (OR, 5.93; 95% CI, 2.01-25.40; P =.0006). Here, the median OS reported in the investigational and control arms was 17.5 months versus 14.3 months, respectively (HR, 0.67; 95% CI, 0.49-0.93; P =.0063).
Updated results from PROfound were presented during the 2020 ESMO Virtual Congress and demonstrated that olaparib resulted in a significant improvement in OS compared with abiraterone/prednisone or enzalutamide in this patient population.5,6 The risk of death with olaparib was 31% lower compared with what had been seen with the antiandrogen agents, despite significant crossover from the control arm to the experimental arm.
The median OS in cohort A was 19.1 months with olaparib compared with 14.7 months with the hormonal agents (HR, 0.69; 95% CI, 0.50-0.97; P =.02). In cohort B, the median OS was 14.1 months with the PARP inhibitor versus 11.5 months with the antiandrogen agents (HR, 0.96; 95% CI, 0.63-1.49).
A sensitivity analysis that adjusted for crossover to the PARP inhibitor showed a HR for death of 0.42 (95% CI, 0.19-0.91) in cohort A; the HR was 0.83 (95% CI, 0.11-5.98) in cohort B. In both cohorts combined, the HR was 0.55 (95% CI, 0.29-1.06).
Regarding safety, the toxicity profile of olaparib proved to be consistent with what had previously been observed with the agent in other trials. The most common toxicities included anemia (39%), nausea (36%), and fatigue or asthenia (32%). Moreover, 7% of patients discontinued treatment with the PARP inhibitor because of anemia; 1% of participants discontinued because of neutropenia, thrombocytopenia, nausea, vomiting, or fatigue or asthenia.
“[Olaparib] more than tripled rPFS and is the only PARP inhibitor to show an OS benefit versus certain new hormonal agents for men with BRCA-mutated mCRPC,” Dave Fredrickson, executive vice president of the Oncology Business Unit, at AstraZeneca, added in the release. “This approval means BRCA testing should now become a critical step in the diagnosis and determination of treatment for men with advanced prostate cancer in the EU.”
In May 2020, the FDA approved olaparib for use in adult patients with deleterious or suspected deleterious germline or somatic HRR gene–mutated mCRPC who have progressed on previous treatment with enzalutamide or abiraterone acetate based on data from PROfound.