GU Cancers 2022 | CASPAR: the addition of rucaparib to enzalutamide for the treatment of mCRPC
Arpit Rao, MD, Baylor College of Medicine, Houston, TX, outlines the randomized, placebo-controlled Phase III CASPAR (NCT04455750) study investigating rucaparib plus enzalutamide compared to enzalutamide alone for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The treatment of mCRPC with novel antiandrogen and androgen deprivation therapy (ADT) has previously demonstrated to prolong over-survival (OS) rates in this patient population, however, within the first year, approximately 40% of patients showed progression. Inhibiting androgen receptor (AR) signalling generates an increase in genomic instability and double-strand DNA breaks. Via this mechanism, novel antiandrogens plus PARP inhibitors (PARPi) have been demonstrated to instigate synthetic lethality in preclinical studies, thus providing the rationale for this clinical trial. The co-primary endpoints are radiographic progression-free survival (rPFS) and OS, with the OS analysis proceeding as a primary endpoint only if rPFS is met. Secondary endpoints includes rPFS and OS in patients with pathogenic BRCA1, BRCA2 or PALB2 mutations versus those without, as well as adverse events and quality of life (QOL). This interview took place at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium 2022 in San Francisco, CA.
Transcript (edited for clarity)
Yeah, good morning. It’s such a pleasure to talk about CASPAR. So CASPAR is a randomized placebo control Phase III study that’s sponsored by the Alliance and the NCI. So it’s a cooperative group study open in the US. And we’re looking at the value of adding rucaparib, which is a PARP inhibitor, to enzalutamide, which is an AR antagonist, as the audience recognizes. This builds on, about four years ago, Professor Clarke presented a data on abiraterone and olaparib in a randomized Phase II study...
Yeah, good morning. It’s such a pleasure to talk about CASPAR. So CASPAR is a randomized placebo control Phase III study that’s sponsored by the Alliance and the NCI. So it’s a cooperative group study open in the US. And we’re looking at the value of adding rucaparib, which is a PARP inhibitor, to enzalutamide, which is an AR antagonist, as the audience recognizes. This builds on, about four years ago, Professor Clarke presented a data on abiraterone and olaparib in a randomized Phase II study. And that was the inspiration for us because we’d been tracking the progress of this biology, of inducing synthetic lethality in cancer cells by combining androgen deprivation and PARP inhibition. So when we saw that data come out, we moved and designed this study.
Now the nice thing about CASPAS is it captures all of the changes that have been happening upstream before patients get to metastatic castration-resistant disease. So we have a pretty liberal entry criteria. We have allowances built in for docetaxel use in castration sensitive disease, allowances for abiraterone, which is the most commonly used dual therapy agent in CSPC and for any other novel anti-antigen agent in castration-sensitive or non-metastatic castration-resistant disease. So there’s that part.
And then the other thing that is very important about CASPAR is from the very beginning, our coprimary endpoint is overall-survival. So we have radiographic progression-free survival and overall-survival both built in as primary endpoints. And I think that’s going to help answer some of the questions that were generated by the PROPEL data and the MAGNITUDE data and somewhat dented their impact on our field because we don’t have the survival data yet and then there is some question about whether it applies to everybody. So hopefully CASPAR answers those questions, whether upfront combination works and makes people live longer.
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