Alkaline Phosphatase and Prostate-specific Antigen Response in Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide Alone or in Combination with Radium-223: Ad Hoc Analysis of the PEACE-3 Consortium Trial

Design, setting, and participants Exploratory post hoc analysis of the international, randomised, open-label phase 3 PEACE-3 trial including 446 patients with asymptomatic or mildly symptomatic mCRPC and bone metastases. Overall, 441 and 436 patients were evaluable for ALP and PSA, respectively. Intervention Enzalutamide 160 mg daily alone or combined with six-monthly injections of radium-223 (55 kBq/kg). Outcome measurements and statistical analysis ALP response was defined as a ≥30% decline from baseline (ALP-30), and PSA response as a≥50% decline (PSA-50) or ≥90% decline (PSA-90). Confirmed responses required consecutive measurements ≥21 d apart. Time-to-event endpoints were analysed using Kaplan-Meier and Cox models. Results and limitations At 6 months, confirmed ALP-30 response was 56.5% with the combination versus 50.8% with enzalutamide alone. Median time to confirmed ALP-30 response was 2.4 versus 3.7 months (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.12–1.78; p = 0.003), and time to ALP normalisation was 2.0 versus 4.5 months (HR 2.05, 95% CI 1.46–2.88; p < 0.001). Confirmed PSA-90 response at 6 months was 50.5% versus 34.1% ( p = 0.001), with median time to confirmed PSA-90 response of 5.6 versus 22.1 months (HR 1.48, 95% CI 1.13–1.93; p = 0.004). Limitations include the exploratory post hoc design, the absence of multiplicity adjustment, and the lack of an analysis linking biomarker responses to clinical outcomes. Conclusions Adding radium-223 to enzalutamide was associated with faster and more frequent ALP and deep PSA responses. These findings support additional antitumour activity of radium-223 when combined with enzalutamide. ADVANCING PRACTICEWhat does this study add?This study shows that adding six cycles of radium-223 to enzalutamide not only improves alkaline phosphatase (ALP) and prostate-specific antigen (PSA) response rates but also accelerates ALP normalisation and the achievement of deep PSA declines (PSA-90) in asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer with bone metastases. It provides the first robust evidence that radium-223 enhances PSA dynamics when combined with an androgen receptor pathway inhibitor, suggesting a direct additive antitumor effect beyond modulation of the bone microenvironment.Clinical RelevanceThis adhoc analysis of the PEACE3 study, which demonstrated an overallsurvival benefit when adding radium223 to enzalutamide versus enzalutamide alone, provides insight into the biological responses underlying that effect. The combination induces faster and deeper ALP and PSA declines, including substantially higher PSA90 rates, suggesting enhanced antitumor activity. These biomarker improvements are consistent with the survival advantage observed in the main trial. Overall, the findings support ALP and PSA dynamics as early indicators of treatment benefit in patients with mCRPC and bone metastases. Associate Editor: Elena Castro.Patient SummaryIn men with advanced prostate cancer that had spread to bone, adding radium-223 to enzalutamide produced faster and deeper changes in blood markers of cancer and bone activity. Further analyses are needed to determine how these biomarker changes relate to patient outcomes.