A multicenter, randomized, phase 2, investigator-initiated ETCTN trial of olaparib + radium-223 vs. radium-223 in men with castration-resistant prostate cancer (CRPC) with bone metastases (BM) (COMRADE): Initial efficacy and biomarker analysis.

Abstract

5007 Background: Radium-223 is an α-emitting radioisotope which has improved overall survival (OS) in men with CRPC with BM. PARP inhibitors demonstrate synergy with radiation. Our phase 1 trial established olaparib 200 mg twice daily + radium-223 (55 kBq/kg IV q4weeks x 6) as the recommended phase 2 dose. Here, we report the phase 2 results (NCT03317392). Methods: Patients were randomized 1:1 to olaparib + radium-223 (Arm A) vs. radium-223 (Arm B), stratified by prior docetaxel and BM extent (≤20/>20). Crossover was permitted in Arm B. Eligibility included any line of prior therapy, ≥2 BM by CT/MRI or bone scan, and at least 1 BM without prior radiation. Visceral metastases or lymphadenopathy > 4 cm were excluded. Bone protecting agents (BPA) were required unless contraindicated. Homologous recombination repair gene (HRR) mutation status was determined using FoundationOne Monitor with algorithmic clonal hematopoiesis determination from baseline plasma (reported here) and Oncopanel assay from baseline biopsy or archival tissue. The primary endpoint was radiographic progression-free survival (rPFS). With 120 patients, the study was designed to have 88% power to detect an improvement in rPFS from 6.0 to 10.5 months (1-sided α=0.10). Results: 120 patients enrolled across 9 centers (Arm A=61, B=59). 96% received prior ARPI, 53% prior docetaxel, 32% with nodal disease, 46% had > 20 BM, and 90% with concurrent BPA. Of the 103 evaluable patients, 18.5% in Arm A and 26.5% in Arm B had an HRR gene alteration by ctDNA, with 7.4% and 10.2% with BRCA1/2 mutations, respectively. Olaparib + radium-223 had a significant improvement in rPFS vs. radium-223 (median 8.6 vs. 4.0 months, HR 0.51, 80% CI 0.37-0.70, 2-sided p=0.005). Secondary endpoints are in Table 1. The addition of olaparib improved rPFS regardless of HRR status (HRR+: HR 0.52, 80% CI 0.26-1.04; HRR-: HR 0.54, 80% CI 0.38-0.77). 56% of patients in Arm A and 35% of patients in Arm B had grade ≥3 treatment-related adverse events, the most common on Arm A/Arm B being: anemia (22.0%/18.0%), lymphocyte decrease (30.5%/9.1%), platelet decrease (6.8%/3.6%), and neutrophil decrease (5.1%/7.3%). Conclusions: In this phase 2, multicenter trial, olaparib + radium-223 demonstrated superior rPFS to radium-223, in both HRR+ and HRR- groups, with manageable side effect profile in CRPC patients with BM. Tissue and serial ctDNA analyses are underway and will be presented. Clinical trial information: NCT03317392 . Arm A median (months)/% Arm Bmedian (months)/% rPFS 8.6 4.0 rPFS (HRR+) 5.5 3.8 rPFS (HRR-) 8.8 4.5 PSA response (confirmed) 13.1% 13.6% Alkaline phosphatase response (confirmed) 49.2% 50.8% Time to PSA progression 3.6 3.3 Time to Alkaline phosphatase progression 7.9 7.4 Time to next treatment 12.0 7.7 1-year symptomatic skeletal event 11.0% 22.1% 12-month OS 74% 71%