Multicenter, Randomized, Phase II Trial of Olaparib Plus Radium-223 Versus Radium-223 in Men With Castration-Resistant Prostate Cancer With Bone Metastases (COMRADE)
Mené sur 120 patients atteints d'un cancer de la prostate résistant à la castration et présentant des métastases osseuses, cet essai multicentrique de phase II évalue l'efficacité, du point de vue de la survie sans progression mesurée par radiographie, et la toxicité de l'ajout d'olaparib à du radium-223 dispensé en intraveineuse
Purpose: Radium-223 is an
α-emitting radiopharmaceutical that improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhibition and radiation. After phase I dose-finding, we conducted a randomized phase II trial to assess efficacy and safety of this combination versus radium-223.
Patients and Methods
:
Men with mCRPC and
≥2 bone metastases (BM) were randomly assigned 1:1 to olaparib (200 mg twice daily) plus radium-223 (55 kBq/kg intravenous once every 4 weeks × 6 doses) or radium-223. Crossover was allowed at progression. The primary end point was investigator-assessed radiographic progression-free survival (rPFS).
Results: A total of 120 patients were randomly assigned. Most had prior androgen receptor pathway inhibitor exposure (96%), 52% had received docetaxel, 47% had >20 BM, and 90% received bone-protecting agents. The combination significantly improved rPFS (median 8.9 v 4.7 months; hazard ratio [HR], 0.50 [one-sided 90% CI, 0.35 to 0.70]; one-sided P = .0042). The benefit was most pronounced in patients without prior docetaxel (13.7 v 5.7 months; HR, 0.24 [90% CI, 0.15 to 0.40]) and those with ≤20 BM (13.4 v 4.2 months; HR, 0.21 [90% CI, 0.13 to 0.33]). The 1-year cumulative incidence of symptomatic skeletal-related events was lower with the combination (12.7% v 22.9%). Median overall survival was similar (20.2 v 21.1 months). Grade ≥3 treatment-related adverse events occurred in 56% versus 33% (combination v radium-223), primarily hematologic, including lymphopenia (31% v 9.1%), anemia (22% v 16%), and thrombocytopenia (6.8% v 3.6%).
Conclusion: Olaparib plus radium-223 significantly prolonged rPFS compared with radium-223 in men with mCRPC and BM. Despite increased hematologic toxicity, the regimen was manageable and supports further exploration of DNA damage–targeted strategies in this population.
Journal of Clinical Oncology , résumé, 2026