Rucaparib Shows Encouraging Responses in BRCA+ mCRPC

Josep Piulats, MD

The overall and prostate-specific antigen (PSA) response rates observed with the PARP inhibitor rucaparib (Rubraca) could be a game-changer for the metastatic castration-resistant prostate cancer (mCRPC) patient population, explained Josep Piulats, MD.

“The important thing is that we have a really active drug in an important group of patients, even though they are not the majority of patients with prostate cancer,” said Piulats. “[In] exploring the clinical characteristics of these patients, this is a special population with a really bad prognosis.”

Preliminary data from the ongoing, single-arm, phase II TRITON2 trial, which were presented at the 2018 ESMO Congress, demonstrated a 44% confirmed objective response rate by investigator assessment among evaluable patients with BRCA1/2-mutated mCRPC who received rucaparib. Additionally, there was a 51% confirmed PSA response in those who received the PARP inhibitor. The study, which is being conducted at 106 locations, is enrolling approximately 160 men with mCRPC who have germline or somatic BRCA1/2 mutations and evidence of a homologous recombination gene deficiency.

In October 2018, the FDA granted rucaparib a breakthrough therapy designation in this setting based on the TRITON2 findings.

OncLive: What was the rationale to conduct this trial?

Could you highlight the design of the trials and the efficacy data thus far?

In an interview with OncLive, Piulats, a member of the Medical Oncology Unit at the Catalan Cancer Institute in Barcelona, Spain, and an investigator on the TRITON clinical trial program, discussed the TRITON2 data and how rucaparib could shift treatment for these biomarker-specific patients with mCRPC.Piulats: We have known that DNA repair defects are present in a high number of patients with prostate cancer. We know that other diseases have [this deficiency] as well, and we know that PARP inhibitors work in that population. Why they work there is because of the principles of what we call synthetic lethality. These are tumors that carry DNA repair mutations, so they are not repairing the DNA. That is giving them an advantage as a tumor, but [our] advantage is that they still need to repair the DNA and they are depending on specific pathways. We can block these specific pathways, so if the cell cannot repair the DNA, then it just dies. That is the principle. What we do with PARP inhibitors is block these deficient pathways through BRCA1/2 or other mutations that are dependent.TRITON2 has 3 cohorts: one cohort with patients with BRCA1, BRCA2, and ATM mutations with measurable disease, one with [these mutations] and without measurable disease, and one testing [rucaparib] in [patients with] different DNA defects in which we still don’t know if they will respond to PARP inhibition. [This third cohort] is to test the hypothesis that if there are other DNA defects in the pathway, [then perhaps those patients] can benefit from the treatment.

What does the safety profile of rucaparib look like in this patient population?

How common are germline DNA-repair mutations in patients with mCRPC?

What we see is an amazing response by RECIST and by PSA. It is close to a 50% rate [for RECIST] and a little over 50% rate in PSA response. I would also like to make people remember that the drugs that we have approved for [patients with] prostate cancer in that indication have never shown these results. They are drugs that we consider to be active and are used in this patient population.What we see from the safety results is that they are similar to what we have observed with other PARP inhibitors in other indications. With rucaparib, especially in ovarian cancer, it is very similar. It may be a little better tolerated in men than in women, but we don’t know if that [is related to the gender or another factor]. One of the things that we conclude is that we are not observing any major finding in toxicity and safety.Two years ago, there was a paper in the New England Journal of Medicine of a population of patients from the United States and the United Kingdom. [Investigators] found that there were 12% of patients with these mutations in the germline level. In Spain, we have made an effort to collect almost 500 samples [to see how common it is]. These results show, more or less, exactly the same frequency and are similar with other populations.

Do you predict rucaparib and other PARP inhibitors will be explored in other prostate cancer indications?

With the TRITON2 and TRITON3 trials, we are observing an even higher population of patients who carry somatic mutations, which are mutations that appear in the tissue and they can be drivers [of the disease]. What was shown in the poster session [at the 2018 ESMO Congress], was that of all the patients with BRCA1/2 mutations, two-thirds are somatic mutations and one-third are germline mutations. Therefore, with these results, we can say that we are potentially talking about 12% of the patients with germline mutations could benefit from the drug. Perhaps these numbers will go higher, to 25% or 30%, when the study is finished.That is a really interesting question. What we are just seeing now is the tip of the iceberg. We are showing high response rates in a biomarker-specific population and in patients who previously received 2 or 3 lines of therapy. We know, with our experience in oncology, that [with] active drugs we move forward to more initial stages of the disease. The TRITON3 trial is, in fact, trying to answer this question. It is a randomized study in patients who already had 1 line of treatment with an androgen receptor inhibitor.

What are you hoping to see with longer follow-up from TRITON2?

[Regarding combination studies], we know there are other drugs that are active in prostate cancer. Or, perhaps we don’t know that they are active, but they showed high synergy in combination with PARP inhibitors in preclinical studies. That is going to be the second wave of studies. We are really interested to try and expand the benefits of treating patients with PARP inhibitors to other patients with prostate cancer.For the BRCA1/2-mutant patients who received rucaparib, you see responses that are kind of narrow; the tip of the arrow means patients are still on treatment. What you can see is there is a small group of patients who are progressing, but the patients who respond tend to respond fast. Also, of all the patients who responded, there are only 2 patients who have already progressed. Therefore, all of the other responders still [are on] the tip of the arrow and are still on treatment. We hope to see a lot of responses in this patient population.

Particularly, in my practice, I have 1 patient on this trial who has one of these unknown mutations—we don’t know if he’s going to respond or not. This is a patient who was primarily resistant to hormone therapy, chemotherapy, and to abiraterone acetate (Zytiga). It has been already 8 months in the clinical trial, and he is still responding.

Abida W, Bryce AH, Vogelzang NJ, et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract PD793.