A completely new approach to the treatment of prostate cancer is now available to clinicians through the approval of the first PARP inhibitor for use in certain patients with this disease.
Rucaparib (Rubraca, Clovis Oncology) is the first PARP inhibitor approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) that harbors deleterious BRCA mutations (germline and/or somatic). The drug is indicated for use in patients who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.
The drug is already marketed for use in ovarian cancer.
The new prostate cancer indication was granted an accelerated approval by the US Food and Drug Administration (FDA) on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial. A confirmatory phase 3 trial, TRITON3, is currently underway.
“Standard treatment options for men with mCRPC have been limited to androgen receptor–targeting therapies, taxane chemotherapy, radium-223, and sipuleucel-T,” said Wassim Abida, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, in a statement.
“Rucaparib is the first in a class of drugs to become newly available to patients with mCRPC who harbor a deleterious BRCA mutation,” said Abida, who is also the principal investigator of the TRITON2 study. “Given the level and duration of responses observed with rucaparib in men with mCRPC and these mutations, it represents an important and timely new treatment option for this patient population.”
Other indications, another PARP inhibitor
Rucaparib is alreadyfor the treatment of women with advanced BRCA mutation–positive ovarian cancer who have received two or more prior chemotherapies. It is also approved as for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who demonstrate a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.
Another PARP inhibitor, olaparib (Lynparza, AstraZeneca), is awaiting approval for use in prostate cancer in men with BRCA mutations. That pending approval is based on results from the phase 3 PROfound trial, which was hailed as a “” when it was presented last year. The results showed a significant improved in disease-free progression. The company that there was also a significant improvement in overall survival.
Olaparib is already approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status and as first-line maintenance treatment in BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved for germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy and for the maintenance treatment of germline BRCA-mutated advanced pancreatic cancer following first-line platinum-based chemotherapy.
Details of the TRITON2 study
The accelerated approval for use of rucaparib in BRCA prostate cancer was based on efficacy data from the multicenter, single-arm TRITON2 clinical trial. The cohort included 62 patients with a BRCA (germline and/or somatic) mutation and measurable disease; 115 patients with a BRCA (germline and/or somatic) mutation and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency (HRD)–positive mCRPC.
The major efficacy outcomes were objective response rate (ORR) and duration of response. Confirmed PSA response rate was also a prespecified endpoint. Data were assessed by independent radiologic review.
For the patients with measurable disease and a BRCA mutation, the ORR was 44%. The ORR was similar for patients with a germline BRCA mutation.
Median duration of response was not evaluable at data cutoff but ranged from 1.7 to 24+ months. Of the 27 patients with a confirmed objective response, 15 (56%) patients showed a response that lasted 6 months or longer.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%.
The safety evaluation was based on an analysis of the 209 patients with HRD-positive mCRPC and included 115 with deleterious BRCA mutations. The most common adverse events (≥20%; grade 1-4) in the patients with BRCA mutations were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).
Rucaparib has been associated with hematologic toxicity, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, MDS/AML was not observed in the TRITON2 study, regardless of HRD mutation.
Confirmation with TRITON3
A phase 3, randomized, open-label study, TRITON3, is currently underway and is expected to serve as the confirmatory study for the accelerated approval in mCRPC. TRITON3 is comparing rucaparib with physician’s choice of therapy in patients with mCRPC who have specific gene alterations, including BRCA and ATM alterations, and who have experienced disease progression after androgen receptor–directed therapy but have not yet received chemotherapy. The primary endpoint for TRITON3 is radiographic progression-free survival.
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