FDA Approves First PARP Inhibitor Rucaparib for Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) - Charles Ryan

May 15, 2020

Alicia Morgans and Charles Ryan highlight the breaking news that the Food and Drug Administration (FDA) approved the first PARP Inhibitor for men with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious BRCA mutation. Rubraca® (rucaparib) tablets for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. The FDA approved this indication under accelerated approval based on objective response rate (ORR) and duration of response (DOR) data from the multi-center, single-arm TRITON2 clinical trial.

Biographies:

Charles J. Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology, and Transplantation.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


Read the Full Video Transcript

Alicia Morgans: Hi, this is Alicia Morgans, Associate Professor of Medicine and GU medical oncologist at Northwestern University in Chicago in the United States. I am so excited to have here with me today, Dr. Charles Ryan, who's a Professor of Medicine and the Director of Hematology and Oncology at the University of Minnesota. Thank you so much for joining me today.

Charles Ryan: It's my pleasure.

Alicia Morgans: Wonderful. So I wanted to talk with you about incredibly late-breaking information. We just learned that moments ago, rucaparib was approved as the first PARP inhibitor for men with prostate cancer. Can you talk a little bit about which patients may be eligible for treatment with rucaparib?

Charles Ryan: I certainly can. And by way of disclosure, I should also say that I am an investigator on the studies that are mentioned here. But the exciting news today is that rucaparib was approved as the first PARP inhibitor approved for the treatment of prostate cancer. The FDA label that's coming out is for men with BRCA1 or 2, mutant metastatic castration-resistant prostate cancer, and specifically, those who have been treated with androgen receptor-targeted therapy and taxane-based chemotherapy.

Now, this approval comes on the basis of a study known as TRITON2. TRITON2 was a study that looked at patients who had already received docetaxel chemotherapy, and as I stated before, had already received one AR-directed therapy such as abiraterone or enzalutamide. The other interesting thing about this recent approval is that it is based on the response rate of 44% of patients on this clinical trial. So that's 44% of patients who had measurable disease, experienced a significant reduction in their tumor volumes during the course of therapy. This is also associated with 55% of the patients experiencing a 50% decline in their PSA.

This approval is significant for a few reasons. One is that to date, we do not have any approvals specifically for patients with BRCA1 and BRCA2 gene alterations. The other feature is that for patients with metastatic castration-resistant prostate cancer, there are four classes of drugs that are approved, demonstrating survival benefits. Those include AR targeted drugs, taxane-based chemotherapies, radium-223, as well as sipuleucel-T. But the majority of patients who have progressed after an AR targeted drug and taxane chemotherapy have few, if any, survival inducing treatments available to them.

Now, we're going to have to wait and see what the survival benefits are of rucaparib, and that will come on the basis of the TRITON3 study that is currently underway. And it is expected that that will serve as a confirmatory study. And that study looks at the use of rucaparib in the BRCA1 and BRCA2 population in patients who have not received prior chemotherapy. And that is a randomized trial, which allows crossover, and that study continues to enroll patients around the world.

Alicia Morgans: So just to make sure that that's really clear, this was a Phase II single-arm trial, TRITON2. And so it's actually very common for the FDA to then require a confirmatory study and that's what the TRITON3 study will be. But as clinicians are thinking about using this drug and they're thinking about how do I identify these patients, the BRCA1 or BRCA2 mutation patients who may be eligible can get germline or somatic testing, or actually should get both, but that mutation could be in the germline or somatic tissue, right?

Charles Ryan: Yeah, that's correct. And that's a really important point. Now, there are a few PARP inhibitors that are in development, and various different approaches are being taken for how to select patients. In some cases, there are requirements that, for example, the tumor show biallelic loss of BRCA2, but this label does not go into that level of detail. The label for this indication of rucaparib suggests that patients need to have a deleterious BRCA mutation that can be either germline and or somatic. And so it's a little bit open in that regard, but it is limited to the BRCA1 and BRCA2 population.

Alicia Morgans: Great. So for all of these patients, by NCCN guidelines at this point, any patient with metastatic disease should be getting germline genetic testing. That can be done either with a genetic counselor or by many practices it can be done independently as long as they feel they have adequate resources for followup, including things like chat boxes and other ways to ensure that patients understand the implications of germline genetic mutations for their families. And then the NCCN also now strongly recommends that tissue from the prostate, the primary prostate or from a metastatic site, if that is available, can undergo or should undergo somatic testing to also look for genetic aberrations and mutations in BRCA1 and BRCA2 in that setting. And so any of those patients with a mutation in either setting could be eligible for treatment with rucaparib.

So, thank you so much for talking this through. One more thing before we wrap up, I just want to ensure that everyone has a balanced view and understanding of the safety profile. In your hands and in the TRITON2 study, what were the safety adverse events that we should be most aware of?

Charles Ryan: Right. So the most common adverse events that occur in rucaparib treated patients include fatigue, some nausea can occur, anemia is relatively common. There is some bone marrow toxicity that can manifest as either anemia or thrombocytopenia. Liver functions do need to be monitored. There can be elevations of the ALT and the AST, and some patients did report vomiting and diarrhea. But the most common laboratory abnormalities are increases in ALT as well as the decreases in the blood counts associated with mild myelosuppression.

Alicia Morgans: Great. Well, thank you so much for talking with me today about this really important step for men with metastatic castration-resistant prostate cancer. Rucaparib is now approved after progression on androgen receptor directed therapy and taxane-based chemotherapy for mCRPC. Thank you.