Dr McKay on the Rationale for Evaluating Radium-223 Plus Olaparib in mCRPC With Bone Metastases

"Patients with mCRPC essentially have lethal prostate cancer, and most of those patients have bone metastases. Those are a source of great morbidity and an increased risk of mortality related to the disease. Radium-223 is a targeted radionuclide that targets the bone microenvironment."

Rana R. McKay, MD, a professor in the Departments of Medicine and Urology at the University of California (UC) San Diego School of Medicine, as well as a medical oncologist with UC San Diego Health, discussed the rationale for evaluating olaparib (Lynparza) in combination with the targeted alpha-emitting radiopharmaceutical radium-223 (Xofigo) for men with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases in the phase 2 COMRADE trial (NCT03317392).

McKay began by stating that mCRPC represents a lethal form of prostate cancer, with approximately 80% of affected patients developing bone metastases. These bone metastases are a significant source of morbidity and considerably increase the risk of mortality associated with the disease. In this microenvironment, a "vicious cycle" of bone turnover contributes to cancer cell growth and disease progression, she described.

Although several agents are approved to manage this condition, one key therapy is radium-223 (Xofigo), a radionuclide specifically designed to target the bone microenvironment, McKay said.

The COMRADE study's rationale stems from strategies aimed at sensitizing tumors to radionuclide therapy, McKay stated. The trial directly compares the combination of radium-223 plus olaparib against radium-223 alone, with the hypothesis that olaparib can act as a radiosensitizer to radium-223. McKay explained that the beneficial effect of radium-223 may be related to mechanisms such as synthetic lethality, chromatin remodeling, and arresting the cell in its most radiosensitive state, potentially also affecting tumor hypoxia. This research seeks to build upon the established efficacy of radium-223 by exploring whether olaparib can enhance its therapeutic impact, she concluded.