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.
, 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.
OncLive: What was the rationale to conduct this trial?
: 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.
Could you highlight the design of the trials and the efficacy data thus far?
TRITON2 has 3 cohorts: one cohort with patients with BRCA1
, 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 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 does the safety profile of rucaparib look like 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.
How common are germline DNA-repair mutations in patients with mCRPC?
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.
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