CONFERENCE UPDATE: ESMO 2024

Enzalutamide + Ra223 shows rPFS benefits in asymptomatic or mildly symptomatic patients with bone-metastatic mCRPC: Results from the PEACE-3 trial

21 Feb 2025

STUDY DESIGN

Abiraterone and enzalutamide (ENZ) are established first-line treatments for patients with metastatic castration-resistant prostate cancer (mCRPC) who progress on androgen deprivation therapy (ADT).1 Radium-223 dichloride (Ra223), an alpha particle-emitting calcium mimetic, selectively targets bone metastases by inducing double-strand deoxyribonucleic acid (DNA) breaks.1 The ERA-223 trial, which tested the combination of abiraterone with Ra223, found no improvement in symptomatic skeletal event-free survival or overall survival (OS).1 No combination so far has been proven in both radiological progression-free survival (rPFS) and OS as a first-line mCRPC treatment.1 In response, the PEACE-3 trial, a collaboration of EORTC, CTI, CUOG, LACOG, and UNICANCER, was launched to assess whether combining ENZ with Ra223 (ENZ + Ra223) could enhance cancer progression outcomes compared to ENZ alone in mCRPC patients.1

The PEACE-3 trial is a randomized, multicenter, open-label, phase 3 trial that recruited men with mCRPC and bone metastases who were receiving ongoing ADT, with no known visceral metastasis and no prior treatment with either ENZ or Ra223 (n=446).1 Participants were randomized 1:1 to receive either ENZ 160mg once daily (n=224) or a combination of ENZ 160mg once daily with intravenous Ra223 every 4 weeks for 6 cycles (ENZ + Ra223) (n=222).1

The primary endpoint was rPFS.1 Key secondary endpoints included safety, OS, time to subsequent systemic therapy, time to pain progression, and time to first symptomatic skeletal event (SSE).1 This study reports the first results of PEACE-3 trial after a median follow-up of 42.2 months.1

FINDINGS

Primary endpoints:
  • The primary endpoint was rPFS1
  • At 24 months, rPFS was 45% in the ENZ + Ra223 arm compared to 36% in the ENZ arm1
  • The median rPFS was 19.4 months (95% CI: 17.1-25.3) in the ENZ + Ra223 arm vs. 16.4 months (95% CI: 13.8-19.2) in the ENZ arm (HR=0.69; 95% CI: 0.54-0.87; p=0.0009)1
Secondary endpoints:
  • Key secondary endpoints included safety, OS, time to subsequent systemic therapy, time to pain progression, and time to first SSE1
  • The median OS in the preplanned interim analysis, performed at 80% of events, was 42.3 months (95% CI: 36.8-49.1) in the ENZ + Ra223 arm and 35.0 months (95% CI: 28.8-38.9) in the ENZ arm (HR=0.69; 95% CI: 0.52-0.90; p=0.0031)1*
  • The estimated proportion of patients who started next systemic treatment at 24 months was 29.9% (95% CI: 23.6-36.4) with ENZ + Ra223 and 50.9% (95% CI: 43.6-57.6) with ENZ (HR=0.57; 95% CI: 0.44-0.75; p<0.0001)1
  • Additionally, the estimated proportion of patients with pain progression at 24 months was 48.3% (95% CI: 40.8-55.3) with ENZ + Ra223 and 44.6% (95% CI: 37.3-51.6) with ENZ (HR=1.02; 95% CI: 0.77-1.36; p=0.5341)1
  • A formal comparison of time to SSE was not conducted, as hierarchical testing for secondary endpoints was not significant for the preceding endpoint1
Safety:
  • Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 66% and 56% of patients in the ENZ + Ra223 and ENZ arms, respectively1
  • The most frequent grade ≥3 TEAEs in the ENZ + Ra223 arm were hypertension (33.5%), fatigue (5.5%), fracture (5.1%), anemia (4.6%), and neutropenia (4.6%)1
  • There was no increment of more than 5% in the grade ≥3 TEAEs of the ENZ + Ra223 arm in comparison to the ENZ arm1
  • Grade ≥3 drug-related adverse events (DRAEs) were 19% in the ENZ arm and 28% in the ENZ + Ra223 arm1
  • <10% of patients in both arms discontinued treatment due to DRAEs1
*The pre-set level of significance for interim analysis was ≤0.0034
Professor Silke Gillessen
Oncology Institute of Southern Switzerland,
Bellinzona, Switzerland

”These results support the combination of
ENZ + Ra223 (+ a bone-protecting agent) as a potential new
first-line mCRPC treatment option for patients with prostate cancer and bone metastases who have not received a prior
androgen receptor-pathway inhibitor

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