A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE)

Abstract

Given that radium-223 is a radiopharmaceutical that induces DNA damage, and olaparib is a PARP inhibitor that interferes with DNA repair mechanisms, we hypothesized their synergy in mCRPC. We sought to demonstrate the safety and efficacy of olaparib + radium-223. We conducted a multicenter phase 1 3+3 dose escalation study of olaparib with fixed dose radium-223 in patients with mCRPC with bone metastases. The primary objective was to establish the RP2D of olaparib, with secondary objectives of safety, PSA response, alkaline phosphatase response, radiographic progression-free survival (rPFS), overall survival (OS), and efficacy by homologous recombination repair (HRR) gene status. Twelve patients were enrolled; all patients received a prior androgen receptor signaling inhibitor (ARSI) (100%) and 3 patients (25%) prior docetaxel. Dose-limiting toxicities (DLTs) included cytopenias, fatigue, and nausea. No DLTs were seen in the observation period however delayed toxicities guided the RP2D. The RP2D of olaparib was 200 mg orally twice daily with radium-223. The most common treatment-related adverse events were fatigue (92%) and anemia (58%). The rPFS at 6 months was 58% (95% CI 27-80%). Nine patients were evaluable for HRR gene status; one had a BRCA2 alteration (rPFS 11.8 months) and one had a CDK12 alteration (rPFS 3.1 months). Olaparib can be safely combined with radium-223 at the RP2D 200mg PO BID with fixed dose radium-223. Early clinical benefit was observed and will be investigated in a phase 2 study.

PARP inhibitors in metastatic prostate cancer

“…Initial phase I data published noted that the recommended dose of olaparib was reduced to 200mg twice daily as compared to the typical dosing used in monotherapy due to anemia and thrombocytopenia observed at higher doses ( 54 ). Updated phase I results from this study reported that of 12 patients enrolled, all patients had received prior ARSI therapy, and 3 patients received prior docetaxel ( 55 ). Dose limiting toxicities included cytopenias, fatigue, and nausea.…”

Lu-177-Labeled Hetero-Bivalent Agents Targeting PSMA and Bone Metastases for Radionuclide Therapy

“…Bone metastases from various cancers are a major cause of morbidity, severe pain, and mobility difficulties. The mechanisms of bone metastasis are many, and the current treatments vary. − Radionuclide treatment using Ra-223 (Xofigo) for bone pain has been approved by the FDA, providing a novel treatment to patients with castration-resistant prostate cancer with symptomatic bone metastases . It would be reasonable to assume that bone metastasis of the PSMA tumor might not be a uniform process during the progression of prostate cancer.…”

Actinium-225 targeted alpha particle therapy for prostate cancer

“…The combination of beta particle therapies, with PARPi, like Olaparib, has been a subject of research interest 82 , 83 . A recent phase I study specifically investigated the safety profile of combining Olaparib with 223 Ra in patients with mCRPC, indicating the growing interest and exploration of this combination in clinical settings 84 .…”