Wassim Abida, MD, on Rucaparib and Prostate Cancer

The FDA's accelerated approval of the PARP inhibitor rucaparib (Rubraca) for patients with metastatic castration-resistant prostate cancer (mCRPC) was based on results of the TRITON2 study, recently published in the Journal of Clinical Oncology.

The FDA approval was for patients with deleterious BRCA mutations (germline and/or somatic) who were previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy. In TRITON2, the confirmed objective response rate (ORR) for these patients was 43.5%, compared with the historic rates of 8-15% in such patients treated with other therapies, Wassim Abida, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues noted.

In the following interview, Abida discussed the details and future directions of the TRITON study and rucaparib.

The FDA recently approved another PARP-inhibitor, olaparib, for gene-mutated mCRPC. How do these agents stand to impact the treatment of patients with mCRPC?

Abida: Rucaparib was the first PARP inhibitor to receive FDA approval for the treatment of men with mCRPC harboring deleterious alterations in BRCA2 and BRCA1, followed shortly thereafter by approval for olaparib in mCRPC harboring an alteration in a panel of DNA repair genes. These approvals will substantially impact the treatment of a significant fraction of men with mCRPC, who now have a targeted non-chemotherapeutic option with a favorable safety profile.

Deep and durable responses have been reported for some men who have received these agents, with many responses lasting for more than 6 months. More broadly, these approvals demonstrate that targeted therapies based on molecular selection can be effective in prostate cancer as they are in other malignancies, such as breast, ovarian, and pancreatic cancers.

What can you tell us about the safety data in TRITON2?

Abida: Rucaparib has a similar safety profile in men with mCRPC from the TRITION2 study as has been observed with the agent in patients with ovarian cancer or other solid tumor types, as well as in studies of men with mCRPC who received other PARP inhibitors, with asthenia/fatigue, GI-related adverse effects, and myelosuppression among the most commonly reported treatment-emergent adverse events.

Elevations in alanine aminotransferase, aspartate aminotransferase, and creatinine levels were also commonly reported, consistent with studies of rucaparib in patients with ovarian cancer. However, these laboratory abnormalities were not associated with liver or kidney toxicity.

The TRITON2 study included a small number of patients with hepatic metastases. What were the results and potential implications for these patients?

Abida: Hepatic metastases are known to be an indicator of poor prognosis in mCRPC. Among TRITON2 patients with mCRPC associated with a BRCA alteration, the objective response rate in patients with hepatic metastases was similar to that of patients without hepatic metastases and to the overall population.

Interestingly, the PSA response rate was higher in patients with hepatic metastases than in patients without hepatic metastases and was also higher than that of the overall population. Although the numbers in TRITON2 are small, the robust responses in this subset of patients is potentially clinically important.

Were there any other notable results in patient subgroups?

Abida: It was interesting to find that patients with somatic BRCA alterations had similar radiographic and PSA [prostate-specific antigen] response rates as patients with germline alterations. This is important given that approximately half of BRCA alterations occur somatically, unlike in ovarian and breast cancer where they occur more frequently in the germline, and stresses the importance of performing somatic as well as germline testing in patients with mCRPC.

Beyond this, patients with BRCA1 alterations appeared to have lower PSA response rates compared with patients with BRCA2 alterations, although larger numbers will be needed to confirm the difference in overall response rates. Further studies are ongoing to determine the effect of co-occurring genomic alterations on response rates.

The phase III TRITON3 study is ongoing. What will this study be examining and when do you think results will be available?

Abida: TRITON3 is an international, phase III study evaluating the clinical benefit of rucaparib in patients with mCRPC associated with a BRCA or ATM alteration who have progressed after one next-generation AR [androgen receptor]-directed therapy and who have not received taxane-based chemotherapy -- an earlier line of therapy than was evaluated in the TRITON2 study.

Patients receive rucaparib or physician's choice of docetaxel, abiraterone acetate, or enzalutamide. The primary endpoint is radiographic progression-free survival, and we anticipate data will be available in the first half of 2022, depending on enrollment and the pace of events.

Read the study here and expert commentary about the clinical implications here.