Test 3 – Enzalutamide Plus Radium-223 Improves Radiographic Outcomes in Metastatic Castration-Resistant Prostate Cancer

Juliet Plata
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Publish Date

Metastatic castration-resistant prostate cancer (mCRPC) represents a lethal phase of prostate cancer characterized by disease progression despite ongoing androgen-deprivation therapy (ADT).1,2 Although multiple systemic therapies have demonstrated improvements in radiographic progression-free survival (rPFS) and overall survival (OS), bone metastases remain a dominant driver of morbidity and mortality in this population.2,3 Radium-223 dichloride (Ra223), an alpha-emitting, bone-targeted radiopharmaceutical, and enzalutamide, a potent androgen-receptor pathway inhibitor, are both approved for use in mCRPC.4 The phase 3 EORTC 1333/PEACE-3 (ClinicalTrials.gov identifier: NCT02194842) trial evaluated whether combining enzalutamide with Ra223 as first-line therapy for mCRPC with bone metastases could improve cancer-control outcomes compared with enzalutamide alone.2

Radiopharmaceutical therapy has become an established component of mCRPC management, particularly for patients with bone-predominant disease.5 Ra223 selectively localizes to areas of increased osteoblastic activity, delivering high-energy alpha particles that induce DNA double-strand breaks in tumor cells and cells within the bone microenvironment.2,4,5 Prior randomized trials demonstrated that Ra223 improves OS and delays symptomatic skeletal events when used as monotherapy in selected mCRPC populations.4

Enzalutamide has shown consistent improvements in rPFS and OS in patients with asymptomatic or mildly symptomatic mCRPC progressing on.2,6 Given the distinct and potentially complementary mechanisms of action of enzalutamide and Ra223, combining them was hypothesized to improve disease control, particularly within bone metastases. The PEACE-3 trial was designed to test this strategy in a contemporary mCRPC population, incorporating protocol amendments to address fracture risk through mandatory use of bone-protecting agents (BPAs).2

Design and Methods

PEACE-3 was an international, randomized, open-label, academic, phase 3 trial conducted at 56 centers across 12 countries. Eligible patients had progressive mCRPC according to Prostate Cancer Working Group 3 criteria, were asymptomatic or mildly symptomatic, and had at least 2 bone metastases. Patients with visceral metastases were excluded.2

Between November 2015 and March 2023, 446 patients were randomized 1:1 to receive enzalutamide 160 mg daily alone or enzalutamide combined with 6 monthly intravenous injections of Ra223 (55 kilobecquerels per kilogram [kBq/kg]). Randomization was stratified by baseline pain score, prior docetaxel exposure, BPA use, and prior abiraterone treatment. Following protocol amendments in 2018, all patients were required to receive zoledronic acid or denosumab that was initiated before Ra223 administration.2

The primary endpoint was investigator-assessed rPFS. Key secondary endpoints included OS, time to next systemic treatment (TTNT), time to pain progression (TTPP), and time to first symptomatic skeletal event (TTSSE). Safety was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria.2

Results

Patient Characteristics and Treatment Exposure

All patients were randomized to either enzalutamide alone (n=224) or enzalutamide plus Ra223 (n=222). Baseline demographic and disease characteristics were well balanced between treatment arms. The median age was 70 years, most patients had World Health Organization performance status 0, and two-thirds of them had bone-only metastatic disease. Approximately 30% of patients had received prior docetaxel in the metastatic hormone-sensitive setting, and prior abiraterone exposure was uncommon.2

In the combination arm, 87.9% of patients completed all 6 planned Ra223 cycles. Median duration of enzalutamide exposure was longer in the combination arm than in the enzalutamide-alone arm.2

Radiographic Progression-Free Survival

The primary endpoint was met. The addition of Ra223 to enzalutamide significantly improved rPFS, with a hazard ratio (HR) of 0.69 (95% CI, 0.54-0.87; P =.0009). Median rPFS was 16.4 months in the enzalutamide arm and 19.4 months in the combination arm. Twelve- and 24-month rPFS rates were consistently higher with the combination, and treatment effects were generally consistent across prespecified subgroups.2

Overall Survival

An interim analysis of OS was conducted at 80% of the planned events. At this analysis, OS favored enzalutamide plus Ra223, with an HR of 0.69 (95% CI, 0.52-0.90; P =.0031). Median OS was 35.0 months in the enzalutamide arm and 42.3 months in the combination arm. Because the proportional hazards assumption was violated, the independent data monitoring committee recommended continuation of the trial to the final OS analysis to further characterize survival benefit.2

Secondary Endpoints

The combination significantly prolonged TTNT compared with enzalutamide alone (HR, 0.57; P <.0001). No statistically significant differences were observed between treatment arms for TTPP or TTSSE at the time of analysis.2

Safety and Skeletal Events

Grade ≥3 treatment-emergent adverse events occurred more frequently in the combination arm than in the enzalutamide-alone arm. The most common grade ≥3 events with the combination included hypertension, fatigue, fractures, anemia, and neutropenia. Fracture incidence was higher with enzalutamide plus Ra223; however, fracture rates were substantially lower among patients enrolled after mandatory BPA use was implemented, underscoring the importance of bone-protective therapy in this setting.2 Table 1 outlines key features of the EORTC 1333/PEACE-3 trial.2

Conclusion

In the phase 3 EORTC 1333/PEACE-3 trial, the addition of Ra223 to enzalutamide as first-line therapy for mCRPC with bone metastases significantly improved rPFS and delayed the need for subsequent systemic therapy.