Abstract 445: Genomic characteristics and response to rucaparib and enzalutamide in the phase 1b RAMP study of metastatic castration-resistant prostate cancer (mCRPC) patients
Authors: Rao Arpit , Ryan Charles J. , Morris David , Assikis Vasileios , Jha Gautam , Ablaza Adriel-John , Habeck Jenn , Loehr Andrea , Xiao Jim , Gangolli Esha A. 
Published: July 2021

Abstract
Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), is approved in the US as monotherapy for patients (pts) with BRCA1/2-mutated mCRPC after androgen receptor (AR)-directed therapy and a taxane. Synthetic lethality has been observed in studies combining AR-directed therapy (eg, enzalutamide) and a PARPi, independent of DNA-damage repair (DDR) gene defects. The RAMP study (NCT04179396) is investigating the safety and potential drug-drug interactions (DDIs) between rucaparib and enzalutamide in unselected mCRPC pts. In this exploratory analysis, we evaluated the association between treatment response and gene alterations of known clinical significance in mCRPC.
Methods: Enrolled pts were previously treated with 0-2 lines of AR-directed therapy and ≤2 lines of chemotherapy for mCRPC. A 1-week run-in of rucaparib monotherapy (600 mg BID) was followed by rucaparib (600 mg BID) + enzalutamide (160 mg QD). Primary endpoints were pharmacokinetics (PK) and safety, including dose-limiting toxicities (DLTs). Change in prostate-specific antigen (PSA) levels from baseline was a secondary endpoint. As an exploratory objective, plasma and/or tissue samples were profiled for genomic alterations using a Foundation Medicine, Inc., assay to evaluate the relationship between genomics and clinical outcome.
Results: As of Oct 1, 2020, 8 pts had received treatment; 7 were evaluable for PK and 6 for DLTs. The median age was 68.5 years and 7/8 (88%) pts had received 1 or 2 prior AR-directed therapies. The PK and overall safety profiles of rucaparib + enzalutamide were consistent with each as a single agent, and no DLTs were reported. Overall, 6/8 (75%) pts had a PSA decline, with 4/8 (50%) pts meeting criteria for a confirmed PSA response (≥50% decrease from baseline). Genomic data were available for 6/8 (75%) pts, all of whom had received prior AR-directed therapy. Of the 4/6 (66%) pts who had one or more somatic AR alterations, 3 had a PSA decline (best PSA change of -99%, -22%, and -17% from baseline) with the combination treatment. One pt had a DDR gene mutation, a subclonal (&lt;1% allele frequency) alteration of CHEK2 with no PSA decline observed; no BRCA1/2 or PALB2 alterations were identified. Mutations in TP53 and PTEN were observed in 4/6 (67%) and 2/6 (33%) pts, respectively.
Conclusions: A combination of enzalutamide and rucaparib had an acceptable safety profile and no clinically significant DDIs. In this small pt set, pts previously treated with AR-directed therapies showed responses to the combination even in the presence of AR alterations and in the absence of DDR gene alterations. These genomic and early efficacy data support further studies of rucaparib and enzalutamide at the recommended combination dose (rucaparib 600 mg BID + enzalutamide 160 mg QD), including in the phase 3 CASPAR study in biomarker-unselected mCRPC pts (NCT04455750).
Citation Format: Arpit Rao, Charles J. Ryan, David Morris, Vasileios Assikis, Gautam Jha, Adriel-John Ablaza, Jenn Habeck, Andrea Loehr, Jim Xiao, Esha A. Gangolli. Genomic characteristics and response to rucaparib and enzalutamide in the phase 1b RAMP study of metastatic castration-resistant prostate cancer (mCRPC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 445.