The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for olaparib for approval as a monotherapy for metastatic castration-resistant prostate cancer and BRCA1/2 mutations who have progressed after previous therapy with a new hormonal agent.
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for olaparib (Lynparza) for approval as a monotherapy in the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2 mutations who have progressed after previous therapy with a new hormonal agent, according to an announcement from AstraZeneca and Merck.1
“Patients diagnosed with mCRPC unfortunately have few treatment options and a historically poor prognosis,” José Baselga, MD, PhD, executive vice president of oncology R&D, at AstraZeneca, stated in a press release. “This recommendation for [olaparib] brings us closer to making it the only PARP inhibitor to improve overall survival (OS) in this setting available to men in the European Union (EU). BRCA testing should now become a critical step for the diagnosis and determination of treatment options for men with advanced prostate cancer in the EU.”
The opinion was based on data from a subgroup analysis of patients with BRCA1/2 mutations who were included in the pivotal phase 3 PROfound trial (NCT02987543). Data previously published in the New England Journal of Medicine showed that olaparib led to a 66% reduction in the risk of disease progression or death versus abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in patients with BRCA1/2 or ATM-mutated mCRPC (hazard ratio [HR], 0.34; 95% CI, 0.25-0.47; P <.001).2
Moreover, in the entire population of patients with homologous recombination repair (HRR)–mutant mCRPC with mutations in genes for BRCA1/2, ATM, CDK12, or 11 other HRR-mutated genes, olaparib reduced the risk of disease progression or death by 51% compared with either of the antiandrogen agents (HR, 0.49; 95% CI, 0.38-0.63; P <.001).
In the prospective, multicenter, randomized, open-label phase 3 PROfound trial, investigators set out to examine the safety and efficacy of olaparib compared with abiraterone or enzalutamide in patients with mCRPC who had progressed on previous treatment with new hormonal anticancer drugs, and who also had a qualifying mutation in 1 of the 15 genes involved in the HRR pathway, including BRCA1/2, ATM, and CDK12.
The trial included 2 cohorts. Cohort A was comprised of patients with alterations in BRCA1/2 or ATM (n = 245), while cohort B (n = 142) consisted of those with an alteration in BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, or RAD54L. Within each cohort, participants were randomized 2:1 to receive either olaparib or physician’s choice of abiraterone plus prednisone or enzalutamide.
Of those in cohort A, 162 received olaparib, while 83 were administered abiraterone plus prednisone or enzalutamide. Of those in cohort B, 94 received olaparib and 48 received physician’s choice of abiraterone plus prednisone or enzalutamide. Beyond each cohort, a combined assessment of patients was also done (n = 387). Across the cohorts, participants received olaparib at a dose of 300 mg twice daily, abiraterone at 1000 mg daily with prednisone given at a dose of 5 mg twice daily, and enzalutamide at a dose of 160 mg daily.
Patient characteristics at baseline were noted to be well-balanced between the treatment arms in each cohort. In cohort A, those in the investigative arm were a median age of 68 years and 23.5% of them had metastatic disease at the time of their initial diagnosis. Moreover, the median prostate-specific antigen (PSA) level in this cohort was 62.2 ug/L. Across the arms in this cohort, 42.0% to 48.2% of participants had received previous treatment with enzalutamide and 38.3% to 34.9% had prior abiraterone. Moreover, 16.9% to 19.8% of participants had received both treatments previously. Two-thirds of participants had received previous treatment with a taxane before the start of the study.
In cohort A, the confirmed objective response rate (ORR) with olaparib was 33.3% versus just 2.3% with the hormonal therapies (odds ratio [OR], 20.86; 95% CI, 4.18-379.18; P <.0001). The median time to pain progression had not yet been reached with olaparib versus 9.92 months with hormonal agents; this translated to a 56% reduction in the risk of pain progression (HR, 0.44; 95% CI, 0.22-0.91; P = .0192). Moreover, the median radiographic progression-free survival (PFS) was 7.4 months with olaparib versus 3.6 months with hormonal therapy.
Updated results from PROfound presented during the 2020 ESMO Virtual Congress showed that olaparib also led to a significantly longer duration of overall survival (OS) versus enzalutamide or abiraterone plus prednisone in this patient population.3,4 Specifically, the risk of death was 31% lower with olaparib versus the control treatment, despite significant crossover from the control arm to the investigative arm.
In cohort A, the median OS with olaparib was 19.1 months versus 14.7 months with the hormonal agents (HR, 0.69; 95% CI, 0.50-0.97; P =.02). In cohort B, the median OS in the investigative and control arms were 14.1 months versus 11.5 months, respectively (HR, 0.96; 95% CI, 0.63-1.49).
Additionally, a sensitivity analysis that adjusted for crossover to olaparib demonstrated a HR for death of 0.42 (95% CI, 0.19-0.91) in cohort A and 0.83 (95% CI, 0.11-5.98) in cohort B. In the overall population, the HR was 0.55 (95% CI, 0.29-1.06).
With regard to safety, the toxicity profile of olaparib proved to be consistent with what has previously been reported, with the most common adverse effects consisting of anemia (39%), nausea (36%), and fatigue or asthenia (32%). Seven percent of patients discontinued treatment with olaparib due to anemia. One percent of patients each discontinued due to neutropenia, thrombocytopenia, nausea, vomiting, or fatigue or asthenia.
“In the PROfound trial, [olaparib] provided a significant clinical benefit to men with BRCA1/2-mutated mCRPC,” Roy Baynes, MD, senior vice president and head of global clinical development, as well as chief medical officer of Merck Research Laboratories, added in the release. “If approved, [olaparib] could be transformative in the treatment paradigm, bringing an additional option to certain [patients with] prostate cancer in the EU.”
In May 2020, olaparib was approved by the FDA for use in adult patients with deleterious or suspected deleterious germline or somatic HRR gene–mutated mCRPC who have progressed following previous treatment with enzalutamide or abiraterone based on data from PROfound.