Dr Saad on the Rationale for the PEACE-3 Trial in mCRPC With Bone-Predominant Disease

“Because it's a form of radiation therapy that's infused, one of the questions [that remains] is: [what is] it’s long term safety [profile of radium-233]? Would [patients] be developing other issues over time, and one of the most concerning issues would be the [development] of secondary malignancies [from] the radiation [received] years ago."

Fred Saad, CQ, MD, FRCS, FCAHS, director of prostate cancer research at Montreal Cancer Institute, as well as a full professor in the Department of Surgery and a uro-oncologist in the Department of Urology at the University of Montreal Hospital Center, discussed the rationale for the phase 3 PEACE-3 trial (NCT02194842), which evaluated the combination of radium-223 dichloride (Xofigo) and enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) with bone-predominant disease.

According to Saad, the trial was designed to build upon prior data supporting the efficacy of radium-223 while addressing long-term safety concerns associated with radiopharmaceutical therapy. Radium-223, the first alpha-emitting radioligand therapy approved for prostate cancer, demonstrated significant overall survival (OS) and symptomatic skeletal event (SSE) improvements in the pivotal phase 3 ALSYMPCA trial (NCT00699751). However, Saad noted that questions have persisted regarding the potential for delayed toxicities, particularly secondary malignancies, with the use of bone-directed radionuclide therapy. These concerns stem from historical oncology experience, such as patients with early-stage seminoma who developed secondary cancers decades after receiving prophylactic radiation therapy.

Given these long-term safety considerations, the PEACE-3 trial sought to determine whether integrating radioligand therapy with an androgen receptor inhibitor could enhance disease control and delay skeletal complications without compromising safety. Investigators placed particular emphasis on monitoring for long-term adverse effects, including potential treatment-related secondary malignancies, while assessing efficacy outcomes.

According to Saad, this study represents one of the largest and longest evaluations of a bone-targeted radiopharmaceutical in prostate cancer, involving more than 1400 patients and over 7 years of follow-up.

Saad emphasized that the overarching aim of this trial is to help inform clinical practice by defining the role of radioligand therapy in mCRPC management, and providing critical insights into the long-term treatment of patients with bone-predominant disease.