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FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA-Mutated Metastatic
Mitchell S Anscher1, Elaine Chang1, Xin Gao1
1Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
Abstract:
The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%-57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3-4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. IMPLICATIONS FOR PRACTICE: The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug.
Insights
Rucaparib received accelerated FDA approval for BRCA-mutated metastatic castrate-resistant prostate cancer (mCRPC) based on the TRITON2 trial. The drug showed a 44% objective response rate in patients previously treated with specific therapies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Metastatic castrate-resistant prostate cancer (mCRPC) with BRCA mutations presents a therapeutic challenge.
- Targeted therapies are emerging for specific genetic alterations in advanced cancers.
Purpose of the Study:
- To summarize the FDA's review process and supporting data for rucaparib's accelerated approval.
- To evaluate the efficacy and safety of rucaparib in patients with mCRPC and BRCA mutations.
Main Methods:
- Analysis of data from the single-arm, open-label TRITON2 trial.
- Inclusion criteria: adult patients with deleterious BRCA mutation-associated mCRPC, previously treated with specific therapies.
Main Results:
- Confirmed objective response rate (ORR) was 44% (95% CI: 31%-57%) in 62 eligible patients.
- Median duration of response was not estimable; 56% had response >6 months.
- Safety profile consistent with PARP inhibitors; 1.7% deaths due to AEs, 8% discontinued due to AEs.
Conclusions:
- Rucaparib is the first approved therapy for this specific mCRPC patient population.
- The trial demonstrated a favorable response rate and duration with an acceptable toxicity profile.
- The ongoing TRITON3 trial will further verify rucaparib's clinical benefit in mCRPC.
