The addition of Radium-223 to enzalutamide yielded significant improvements in radiological progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer and predominant bone metastases, according to data from the phase III PEACE-3 trial.
Abiraterone and enzalutamide are standard of care options for first-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on androgen deprivation therapy (ADT). Thus far, no combination has been proven to increase radiological progression-free survival (rPFS) and overall survival (OS) in first line mCRPC. Radium-223 dichloride (Ra223) is an alpha particle-emitting calcium mimetic that selectively targets bone metastases and induces double-stranded DNA-breaks. PEACE-3, an EORTC/CTI/CUOG/LACOG/UNICANCER cooperative study, investigates whether the combination of enzalutamide and Ra223 improves cancer progression over enzalutamide alone in patients with mCRPC.
PEACE-3 is a randomised, international, multicentre, open-label phase III study that included men with mCRPC and bone metastases receiving ADT. Patients were randomised 1:1 to treatment with enzalutamide plus Radium-223 (the combination therapy group) or treatment with enzalutamide alone (the monotherapy group). Radium-223 was administered intravenously every 4 weeks at a dose of 55kBq/kg for 6 cycles. Enzalutamide was given orally in both groups at a dose of 160 mg every day. From March 2018, the additional administration of the bisphosphonate zoledronic acid or the monoclonal IgG2 antibody denosumab for the prevention of bone complications in adults with bone metastases became mandatory and was therefore also applied in the PEACE-3 study. Prior treatment with the cytostatic docetaxel or abiraterone was permitted for patients with metastatic hormone-sensitive prostate cancer. The primary outcome measure was rPFS. Key secondary outcome measures were OS, time to start of subsequent systemic therapy (TTNT), time to pain progression (TTPP), time to first symptomatic skeletal event (TTSSE) and safety.
In total, 446 men with mCRPC were randomised to the combination therapy group (N= 222) or the monotherapy group (N= 224). Baseline characteristics were comparable between groups. After a median follow-up of 42.2 months, the primary outcome measure, rPFS, was statistically significantly longer in the combination therapy group compared to the monotherapy group (19.4 vs. 16.4 months; HR[95%CI]: 0.69[0.54-0.87], p= 0.0009), with 24-month rPFS rates of 36% and 45%, respectively. In addition, the interim OS measured was statistically significantly longer in the combination therapy group compared to the monotherapy group (42.3 vs. 35.0 months; HR[95%CI]: 0.69[0.52-0.90], p= 0.0031). The study will proceed to final OS analysis because of non-proportionality. The estimate of proportion who started next systemic treatment at 24-months was 30% in the combination therapy and 51% in the monotherapy group, respectively (HR [95%CI]: 0.57[0.44-0.75]). For the estimate of proportion with pain progression and estimate of proportion with a symptomatic skeletal event at 24 months, no statistically significant differences were found between the two groups (combination therapy vs. monotherapy; 24-month TTPP: 48% vs. 45%; 24-month TTSSE: 18% vs. 18%).
Treatment-emergent adverse events (TEAEs) of grade ≥3 were reported in 28% and 19% of participants in the combination therapy and monotherapy groups, respectively, with the most common AEs being hypertension (33.5% vs. 34.4%), fatigue (5.5% vs. 1.8%) and fracture (5.1% vs. 1.3%). Eleven participants died due to an AE, but none of these deaths were related to treatment. The most common treatment-related AEs were hypertension (11.5% vs. 12.1%), fatigue (4.1% vs. 1.3%), and anaemia (2.8% vs. 0%).
Combination of enzalutamide and 6 cycles of Ra223 shows a statistically significant improvement in rPFS and OS. The improvement in rPFS is also supported by a statistically significant improvement in time to next systemic treatment. Drug-related grade ≥3 adverse events increased from 19% to 28% in the combination arm.
Reference
Gillessen S, et al. A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): first results of EORTC-GUCG 1333/PEACE-3. Presented at ESMO 2024; Abstract LBA1.
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