The FDA has granted a priority review designation to a supplemental new drug application for rucaparib for the treatment of adult patients with BRCA1/2-mutant recurrent, metastatic castration-resistant prostate cancer.
Patrick J. Mahaffy
The FDA has granted a priority review designation to a supplemental new drug application (sNDA) for rucaparib (Rubraca) for the treatment of adult patients with BRCA1/2-mutant recurrent, metastatic castration-resistant prostate cancer (mCRPC).1
The application is based on findings from the ongoing phase II TRITON2 trial (NCT02952534), in which the PARP inhibitor induced a 43.9% confirmed objective response rate (ORR) by investigator assessment in 57 RECIST—evaluable patients with BRCA1/2-mutant mCRPC.2
“Recently presented data suggests that Rubraca may play a meaningful role in the treatment of patients with BRCA1/2-mutant recurrent, metastatic castrate-resistant prostate cancer, and this filing represents an important milestone for Clovis as it brings us one step closer to potentially making this valuable therapy available,” Patrick J. Mahaffy, president and CEO of Clovis Oncology, the developer of the PARP inhibitor, stated in a press release. “We are encouraged by the FDA’s decision to grant priority review to the Rubraca application, which focuses on eligible patients with advanced prostate cancer, for whom new treatment options are very much needed.”
Under the Prescription Drug User Fee Act, the FDA will make a decision on the application by May 15, 2020.
In October 2018, the FDA granted rucaparib a breakthrough therapy designation for single-agent use in adult patients with BRCA1/2-positive mCRPC following ≥1 androgen receptor (AR)—directed therapy and taxane-based chemotherapy, based on the preliminary TRITON2 findings.
In the international, multicenter, open-label TRITON2 study, investigators enrolled male patients with mCRPC associated with 1 of 13 homologous recombination repair (HRR) gene alterations. Patients had disease progression on AR-directed therapy and 1 prior taxane-based chemotherapy. Additionally, they had an ECOG performance status of 0 or 1 and could not have received prior PARP inhibitor, mitoxantrone, cyclophosphamide, or platinum-based chemotherapy.
Patients were treated with rucaparib at 600 mg twice daily until radiographic progression or treatment discontinuation. Tumors were radiographically assessed every 8 weeks for 24 weeks, and then every 12 weeks. Prostate-specific antigen (PSA) assessments were performed every 4 weeks.
The primary endpoints of the trial include confirmed ORR per RECIST/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease at baseline and PSA response in patients with no measurable disease at baseline.
The evaluable population for PSA response included 45 patients with BRCA1/2 mutations, and the population evaluable for radiographic response included 25 patients with BRCA1/2 mutations.
The median age of the evaluable 45 patients with BRCA1/2 mutations was 71 years (range, 50-88); most (62.2%) had an ECOG performance status of 1. Prior therapies included abiraterone acetate (Zytiga; 55.6%), enzalutamide (Xtandi; 73.3%), both abiraterone and enzalutamide (31.1%), docetaxel (95.6%), cabazitaxel (Jevtana; 8.9%), sipuleucel-T (Provenge; 13.3%), and radium-223 dichloride (Xofigo; 11.1%).
A total of 88.9% of patients with BRCA1/2 mutations had bone metastases, 62.2% had nodal metastases, and 42.2% of patients had visceral metastases. Additionally, 33.3% of patients had a germline BRCA1/2 mutation and 66.7% had a somatic BRCA1/2 mutation.
The preliminary results included data from 85 patients enrolled through June 29, 2018, which had a median follow-up of 5.7 months (range, 2.6-16.4). These data showed that rucaparib demonstrated a 44% confirmed ORR (95% CI, 24.4%-65.1%) by investigator assessment among evaluable men with BRCA1/2-mutated mCRPC. Among those with BRCA1/2 alterations, 51.1% had a confirmed PSA response to rucaparib.
All 11 investigator-assessed radiographic responses in the patients with BRCA-mutated tumors were partial responses (PRs); 9 patients (36.0%) had stable disease. The median duration of response had not been reached.
Updated findings were presented at the 2019 ESMO Congress, with a median follow-up of 13.1 months (range, 4.1-28.5).3 Results showed that rucaparib elicited a 43.9% confirmed ORR and a confirmed PSA response of 52.0% in patients with mCRPC and a BRCA1/2 mutation. Responses were durable, with 60% of responses lasting ≥24 weeks.
Regarding safety, the most common any-grade treatment-emergent adverse events occurring in >20% of patients were asthenia/fatigue (55.3%), nausea (49.5%), anemia/decreased hemoglobin (37.9%), decreased appetite (27.9%), transient increased aspartate transaminase/alanine aminotransferase (24.7%), constipation (24.7%), vomiting (22.1%), and diarrhea (21.1%).
Additionally, the multicenter, randomized phase III TRITON3 trial (NCT02975934) is comparing single-agent rucaparib with physician’s choice of abiraterone acetate, enzalutamide, or docetaxel in men with mCRPC and homologous recombination deficiency whose disease has progressed on prior treatment.
Rubraca is currently approved as monotherapy for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to platinum-based chemotherapy. It is also approved for the treatment of patients with deleterious BRCA mutations—germline and/or somatic—associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with ≥2 chemotherapies and selected for therapy based on an FDA-approved companion diagnostic.