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.
Molecular cancer therapeutics. 2023 Feb 10 [Epub ahead of print]
Elizabeth Pan, Wanling Xie, Archana Ajmera, Arlene Araneta, Christina Jamieson, Edmund Folefac, Arif Hussain, Christos E Kyriakopoulos, Adam Olson, Mamta Parikh, Rahul Parikh, Biren Saraiya, S Percy Ivy, Eliezer M Van Allen, Neal I Lindeman, Bose S Kochupurakkal, Geoffrey I Shapiro, Rana R McKay
University of California, San Diego, La Jolla, CA, United States., Dana-Farber Cancer Institute, Boston, MA, United States., University of California San Diego Medical Center, United States., The Ohio State University Wexner Medical Center, Columbus, Ohio, United States., University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States., University of Wisconsin-Madison, Madison, WI, United States., University of Pittsburgh Medical Center, Pittsburgh, PA, United States., University of California, Davis, Sacramento, CA, United States., University of Kansas Medical Center, Kansas City, KS, United States., Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States., National Cancer Institute National Institutes of Health, Bethesda, MD, United States., Brigham and Women's Hospital, Boston, MA, United States., Dana-Farber Cancer Institute & Harvard Medical School, Boston, MA, United States.