The combination of rucaparib (Rubraca) and enzalutamide (Xtandi) was shown to be safe with early signs of efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 1b RAMP study presented during the 2021 American Association for Cancer Research Virtual Annual Meeting.1
The doublet of the PARP inhibitor rucaparib and the androgen receptor (AR) inhibitor enzalutamide induced a PSA decline in three-fourths of patients and a confirmed PSA response in half of patients enrolled in the small study.
“A combination of enzalutamide and rucaparib had an acceptable safety profile and no clinically significant drug-drug interactions. In this small patient set, patients previously treated with AR-directed therapies showed responses to the combination even in the presence of AR alterations and in the absence of DNA damage response and repair (DDR) gene alterations,” the investigators wrote in their poster.
The phase 1b RAMP study (NCT04179396) included 8 patients with mCRPC who had received no more than 2 lines of chemotherapy for mCRPC and 0 to 2 lines of androgen receptor–directed therapy. The median patient age was 68.5 years and 7 (88%) of the 8 patients had been treated with either 1 or 2 prior AR-directed agents.
All patients received a 1-week run-in of 600 mg of rucaparib twice daily followed by the same dose of rucaparib combined with enzalutamide at 160 mg daily. The primary end points were pharmacokinetics (PK) and safety, including dose-limiting toxicities (DLTs). A key secondary outcome measure was PSA change from baseline.
Regarding the primary end point, the investigators reported in their poster that the PK and overall safety profiles of both rucaparib and enzalutamide were comparable to results in prior research with these treatments as monotherapies. Additionally, the researchers reported that there were no DLTs.
Of the 8 patients, 75% (n = 6) had a PSA decline. Four (50%) patients had a confirmed PSA response, defined as a ≥50% decline in PSA level from baseline.
The investigators also conducted an exploratory analysis to assess the association between genomics and clinical activity. For this analysis, the researchers used a Foundation Medicine assay to profile plasma and/or tissue samples for genomic alterations.
Of the 8 patients, genomic data were available for 6. All of these patients had prior AR-directed therapy.
The combination led to a PSA decline in 3 of the 4 patients with ≥1 somatic AR alteration. The PSA declines from baseline in these 3 patients were -99%, -22%, and -17%, respectively. There was no PSA decline observed in the 1 patient with a DDR gene mutation (a subclonal alteration of CHEK2). Of note, genomic testing did not identify any alterations in BRCA1/2 or PALB2.
The researchers concluded that the early efficacy signals and genomic data support additional trials exploring the combination of rucaparib and enzalutamide in mCRPC. One such study, the CASPAR trial (NCT04455750), has already been launched.2 The phase 3 trial is exploring the combination as a frontline treatment in biomarker-unselected men with mCRPC. Of note, the ClinicalTrials.gov page for the trial describes the recruitment status as, “suspended (data from a recently completed phase 1 trial of enzalutamide and rucaparib is being reviewed to determine the need for the PK substudy).”
Rucaparib is approved by the FDA for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated metastatic mCRPC who have been treated with AR-directed therapy and a taxane-based chemotherapy. Enzalutamide has FDA-approved indications for both CRPC and castration-sensitive prostate cancer.
1. Rao A, Ryan CJ, Morris D, et al. Genomic characteristics and response to rucaparib and enzalutamide in the phase 1b RAMP study of metastatic castration-resistant prostate cancer (mCRPC) patients. Presented at: 2021 AACR Virtual Annual Meeting Week 1; April 10-15, 2021. Poster 445.
2. NIH ClinicTrials.gov. A Clinical Study Evaluating The Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant To Testosterone-Deprivation Therapy (CASPAR). Updated March 22, 2021. Accessed April 15, 2021. https://clinicaltrials.gov/ct2/show/NCT04455750.