Updated biomarker results from a phase 1/2 study of olaparib and radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE)

Autor: Rana R. McKay, Wanling Xie, Archana Ajmera, Biren Saraiya, Mamta Parikh, Edmund Folefac, Adam C. Olson, Elisabeth I. Heath, Rahul Atul Parikh, S. Percy Ivy, Eliezer Mendel Van Allen, Neal Ian Lindeman, Geoffrey Shapiro
Rok vydání: 2022
Předmět:
Zdroj: Journal of Clinical Oncology. 40:119-119
ISSN: 1527-7755
0732-183X
Popis: 119 Background: Radium-223 is an α-emitting radioisotope that induces DNA double-strand breaks leading to cell death. In preclinical models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the safety and efficacy of radium-223 + olaparib. Tissue based studies investigated homologous recombination repair (HRR) gene status. Methods: This was an open-label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of radium-223 + olaparib. Eligible patients (pts) had mCRPC with ≥2 bone metastases without visceral metastases or lymphadenopathy > 4 cm. There was no limit on prior therapy. All pts had a baseline biopsy and archival tissue was collected when available. The phase 1 used a 3+3 dose escalation design with fixed dose radium-223 (55 kBq/kg IV every 4 weeks x 6). Dose level 1 (DL1) was olaparib 200 mg PO BID; DL2 was olaparib 300 mg PO BID. The primary objective was to determine the recommended phase 2 dose (RP2D). Secondary objectives included radiographic progression-free survival (rPFS) (PCWG3 criteria), PSA response (50% decline from baseline), and alkaline phosphatase response (30% decline from baseline). HRR gene status was determined using Oncopanel tissue profiling. Results: 12 pts were enrolled on the phase 1. Median age was 68 (range 59-81) years. Median prior lines of CRPC therapies was 2 (1-5), including 3 (25%) who had received prior chemotherapy and 12 (100%) a prior novel hormone therapy. The RP2D of olaparib was 200 mg BID when combined with radium-223. Overall, PSA response and alkaline phosphatase response were 16.7% (n=2) and 67% (n=8), respectively. Median follow-up was 6.5 (range 2.8, 11.8) months, and 6-month rPFS was 57% (95% CI: 25%, 80%). 9 patients had available tissue for Oncopanel testing (7 from baseline metastasis biopsy; 2 from archival prostate tissue). Two patients were identified to have pathogenic HRR gene alterations: 1 patient with a BRCA2 mutation with rPFS of 11.63 months, 1 patient with CDK12 mutation with rPFS 2.60 months (Table). Conclusions: We demonstrate that olaparib can be safety combined with radium-223 with RP2D of 200 mg BID. Though limited by sample size, we demonstrate prolonged disease control in a pt with a BRCA2 mutation receiving radium-223 + olaparib. Additional profiling from the currently accruing phase 2 study of radium-223 +/- olaparib will further elucidate biomarkers of response. Clinical trial information: NCT03317392. [Table: see text]
Databáze: OpenAIRE
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