A Phase II, Nonrandomized Open Trial Assessing Pain Efficacy with Radium-223 in Symptomatic Metastatic Castration-resistant Prostate Cancer

Abstract Background Pain is a critical patient-reported outcome (PRO) in metastatic castration-resistant prostate cancer (mCRPC), with Prostate Cancer Working Group 3 and FDA guidelines recommending a standardized approach to its assessment in preapproval trials. No prior trial has examined pain palliation using the standard dose and schedule and endpoints of validated pain scales using contemporary PRO pain-assessment tools. We conducted a multicenter phase II study to fill this unmet medical need. Methods Patients were eligible to receive Ra-223 per its labelled indication if they had a Brief Pain Inventory (BPI) >/=3. The primary endpoint was a 30% decrease in BPI Worst Pain from baseline to Week 8, sustained at Week 12 without escalation of medication on the World Health Organization (WHO) analgesic ladder. Secondary endpoints included changes in Brief Fatigue Inventory (BFI) Worst fatigue and BPI pain interference. If six of 27 subjects (22%) met the primary endpoint, the trial would expand by another 36 subjects. Results Twenty-nine subjects were accrued. Nine of 29 (31%) subjects met the primary endpoint, with 21 (72%) evaluable for the primary endpoint. Among responders: median worst pain declined 62% (range 36–100) at Week 8 and 63% (range 38–100) at Week 12; median reduction of pain interference with general activity and sleep at Week 12 was 62% (range 18–100) and 53% (range 8–100) respectively; median reduction in worst fatigue of 45% (range 10–85) at Week 12. Conclusions This was the first prospective trial using standard Ra-223 doses, contemporary pain endpoints, and modern PRO collection tools, and found that Ra-223 palliated pain, reduced fatigue, and improved pain interference. The pain response rate easily exceeded the requirements for expansion to the second phase, but the trial was closed due to slow accrual. Larger accrual in this population is likely more feasibly addressed as secondary endpoints in the phase III setting.