Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), is approved in the US as monotherapy for BRCA1/2 mutated mCRPC that has been treated with androgen receptor (AR)-directed therapy and a taxane. In previous studies, synthetic lethality was observed with a combination of AR-directed therapy (eg, enzalutamide) and a PARPi, independent of DNA-damage repair gene defects. The potential for drug-drug interaction between rucaparib and enzalutamide was recognized as enzalutamide is a strong clinical inducer of CYP3A4, a mediator of the formation of rucaparib metabolite M324. RAMP (NCT04179396) is investigating the combination of rucaparib and enzalutamide in unselected pts with mCRPC to assess PK and safety and inform subsequent studies. Methods: Eligible pts had 0–2 lines of AR-directed therapy and ≤2 lines of chemotherapy for mCRPC. Prior PARPi treatment was not allowed. A 1-week run-in of rucaparib monotherapy (600 mg BID) was followed by rucaparib (600 mg BID) + enzalutamide (160 mg QD) in continuous 28-day cycles. Trough PK was evaluated for rucaparib and enzalutamide and their metabolites (M324 and N-desmethyl enzalutamide). Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles. Primary endpoints were PK and safety for the combination. Secondary endpoints were change from baseline in prostate-specific antigen (PSA) levels and objective response rate (per modified RECIST/PCWG3). 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 6/8 (75%) pts had ≥2 prior mCRPC therapies. Rucaparib and M324 reached apparent steady-state PK at the end of the run-in period. Concomitant treatment with enzalutamide had no significant effect on the PK of either rucaparib or M324. The PK of enzalutamide and N-desmethyl enzalutamide in the combination were also consistent with monotherapy enzalutamide PK data. No DLTs were reported. The most common grade ≥3 TEAEs among all 8 pts were anemia (n = 5) and fatigue (n = 4). Seven of 8 (87.5%) pts required a dose modification (treatment interruption or dose reduction). Four of 8 (50%) pts had a confirmed PSA response (reduction ≥50% from baseline); 1/1 (100%) pt with measurable disease achieved a confirmed complete radiographic response. At the time of data cutoff, 1/8 (12.5%) pts was on study for > 6 cycles. Conclusions: A combination of enzalutamide and rucaparib was not associated with a clinically significant effect on PK profiles of either drug. No DLTs were observed. The overall safety profile of rucaparib 600 mg BID + enzalutamide 160 mg QD was consistent with that observed in monotherapy. These PK, safety, and early efficacy data support further studies of rucaparib and enzalutamide at the recommended combination dose, including in the phase 3 CASPAR study in pts with mCRPC (NCT04455750). Clinical trial information: NCT04179396