LBA1 - 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

Background

PEACE-3, an EORTC/CTI/CUOG/LACOG/UNICANCER cooperative study, investigates whether the combination of Enzalutamide and Ra223 (ENZ-RAD) improves cancer progression over Enzalutamide alone (ENZ) in patients with mCRPC.

Methods

Men with mCRPC and bone metastases were randomized 1:1 to ENZ or ENZ-RAD. As of 03/2018, co-administration of zoledronic acid or denosumab was obligatory. The primary endpoint was radiological progression-free survival (rPFS). Secondary endpoints include overall survival (OS), time to subsequent systemic anti-neoplastic therapy, time to pain progression, and time to first symptomatic skeletal event.

Results

From 11/2015 to 03/2023, 446 men were enrolled. The median age was 70 years (IQR: 65-76). The median follow-up duration was 42.2 months (mo); 87.9 % of patients in the ENZ-RAD arm who started Ra223 completed the scheduled 6 cycles. The hazard ratio (HR) for rPFS was 0.69 (95% CI 0.54-0.87; p=0.0009), with a median rPFS of 16.4 (95%CI 13.8-19.2) mo in the ENZ arm and 19.4 (95%CI 17.1-25.3) mo in the ENZ-RAD arm. The HR for OS was 0.69 (95% CI 0.52-0.90; p=0.0031), with median OS in the preplanned interim analysis, performed at 80% of events, of 35.0 (95%CI 28.8-38.9) mo in the ENZ arm and 42.3 (95%CI 36.8-49.1) mo in the ENZ-RAD arm. The study will proceed to final OS analysis because of non-proportionality. Treatment-emergent adverse events (TEAE) ≥ grade 1 were reported in 96.4% and 100%, ≥ grade 3 in 55.8% and 65.6% of the patients in ENZ and ENZ-RAD, respectively. Most frequent grade ≥ 3 TEAE in the ENZ-RAD arm were hypertension (34%), fatigue (6%), anemia (5%), and neutropenia (5%). No TEAE ≥ grade 3 was increased by more than 5% in the ENZ-RAD arm vs the ENZ arm.

Conclusions

PEACE-3 demonstrates that adding 6 cycles of Ra223 to enzalutamide as first-line therapy for mCRPC significantly improves rPFS. An interim analysis shows a statistically significant OS benefit favoring the ENZ-RAD combination, and a final OS analysis will be performed for further confirmation of this result.

Clinical trial identification

NCT02194842.

Editorial acknowledgement

Legal entity responsible for the study

EORTC.

Funding

Bayer Healthcare Pharmaceuticals Inc; Astellas Pharma Europe.

Disclosure

S. Gillessen: Financial Interests, Institutional, Advisory Board, 2022: Amgen, AstraZeneca, Bayer, MSD Merck Sharp & Dohme, Myriad Genetic, Orion; Financial Interests, Institutional, Advisory Board, 2023: BMS, Daiichi Sankyo, Innomedica, Ipsen, Boehringer Ingelheim, Innomedica, Bayer; Financial Interests, Institutional, Invited Speaker, 2022: ESMO, Silvio Grasso Consulting; Financial Interests, Institutional, Other, Interview 2022: PeerVoice; Financial Interests, Institutional, Invited Speaker, 2023: SAKK, Meister ConCept GmbH, ASCO GU, EPG Health, S. Grasso Consulting, AdMeTech Foundation; Financial Interests, Institutional, Other, Faculty activity 2022: WebMD-Medscape; Financial Interests, Personal, Other, Travel support 2022: AstraZeneca; Financial Interests, Personal, Invited Speaker, 2022: DESO, SAKK; Financial Interests, Personal, Other, Travel support 2023: Bayer; Financial Interests, Institutional, Invited Speaker, 2024: Intellisphere LLC; Financial Interests, Personal, Other, Travel support 2024: Gilead; Financial Interests, Personal, Invited Speaker, Speaker OncoSummit 02.2024: Meister ConCept GmbH; Financial Interests, Personal, Other, Travel Support 2024: Intellisphere LLC; Financial Interests, Institutional, Other, Scientific Committee Pfizer Forschungspreis 2022/2023: Pfizer; Financial Interests, Institutional, Other, Consulting Agreement: TOLREMO; Financial Interests, Personal, Invited Speaker, 2023/2024: ESMO; Financial Interests, Institutional, Advisory Board, 2024: Ipsen, Macrogenics; Financial Interests, Personal, Other, Part of a patent for a biomarker, but (for the moment) no income, but I could not write none in the dropdown menu: Proteomedix/Onconetix; Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator: Astellas; Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. A. Choudhury: Financial Interests, Personal, Invited Speaker: Bayer, Elekta, AstraZeneca, Janssen, Roche; Financial Interests, Personal, Writing Engagement: Merck; Financial Interests, Personal and Institutional, Research Grant: Elekta; Non-Financial Interests, Other, Editor in Chief: BMJ Oncology; Non-Financial Interests, Institutional, Product Samples: Astex. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Pfizer, Myovant, Novartis, AstraZeneca, Merck; Financial Interests, Institutional, Local PI: Novartis, Astellas, Bayer, Janssen, Sanofi, BMS, Amgen, Pfizer, Merck; Financial Interests, Institutional, Coordinating PI: AstraZeneca. E. Gallardo: Financial Interests, Personal, Advisory Board: Sanofi, Janssen, Astellas, Pfizer, Bayer, Roche, Ipsen, Eisai, EUSA Pharma, BMS, AstraZeneca, Merck, Merck, Daiichi Sankyo, Techdow, Novartis, Lilly, Pfizer, Advanced Accelerator Applications, GSK, Recordati; Financial Interests, Personal, Invited Speaker: Sanofi, Janssen, Astellas, Pfizer, Bayer, Roche, Ipsen, Eisai, EUSA Pharma, BMS, Merck, Daiichi Sankyo, MSD, Menarini, Rovi, Leo Pharma, Boehringer Ingelheim, Advanced Accelerator Applications; Financial Interests, Institutional, Local PI: Astellas, Medivation, Ipsen, Janssen, Pfizer, Lilly, Pfizer-Merck, MSD, BMS, Bayer, Daiichi Sankyo, Roche, AstraZeneca, Novartis, Seattle Genetics, Incyte, Aveo, Exelixis, Immunicum, Mediolanum, Clovis, QED Therapeutics, Debiopharm, Macrogenics; Non-Financial Interests, Principal Investigator, National (Spanish) coordinator for clinical trials: Anthos; Non-Financial Interests, Leadership Role, Member of the Board: SOGUG; Non-Financial Interests, Leadership Role, Member of the Board of Long Survivors Working Group: SEOM. A. Soares: Financial Interests, Personal, Advisory Board: Janssen, Pfizer, Bayer, AstraZeneca, Adium, Roche, MSD, Novartis; Financial Interests, Personal, Invited Speaker: Janssen, AstraZeneca, Sanofi, MSD; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Personal, Steering Committee Member: Exelixis; Non-Financial Interests, Advisory Role: LACOG; Non-Financial Interests, Leadership Role: LACOG; Other, Medical educational company - owner and founder: Brazilian Information Oncology - BIO. Y. Loriot: Financial Interests, Personal, Advisory Board: Merck Kga, Pfizer, Gilead, Seattle Genetics, Tahio; Financial Interests, Personal, Other, lectures, advisory boards: MSD, AstraZeneca, Astellas, Janssen; Financial Interests, Personal, Other, lectures, advisory boards: Roche, BMS; Financial Interests, Institutional, Research Grant: Janssen, Sanofi, MSD, Roche, Celsius; Financial Interests, Institutional, Steering Committee Member: Janssen; Financial Interests, Steering Committee Member: MSD, Astellas, Gilead/Immunomedics, Tahio; Financial Interests, Personal, Steering Committee Member: Basilea; Financial Interests, Institutional, Local PI: Pfizer, MSD, Janssen, Exelexis, AstraZeneca, Pfizer, Merck Kga, BMS, Astellas, Gilead, Incyte; Financial Interests, Institutional, Coordinating PI: Janssen; Non-Financial Interests, Member: ESMO, ASCO, AACR; Non-Financial Interests, Other, scientific committee: ARC. R.S. McDermott: Financial Interests, Personal, Advisory Board: Pfizer, Amgen, BMS, Bayer, Janssen, Clovis; Financial Interests, Personal, Invited Speaker: MSD, Ipsen, Astellas; Financial Interests, Personal, Invited Speaker, Speaker at Ad board: Merck Serono; Financial Interests, Institutional, Coordinating PI: MSD; Financial Interests, Institutional, Local PI: Clovis, BMS, Regeneron, Bayer, Astellas; Financial Interests, Institutional, Local PI, Clinical Trial: Seagen. A. Rodriguez-Vida: Financial Interests, Personal, Invited Speaker: roche, BMS, Janssen, AstraZeneca, Ipsen; Financial Interests, Personal, Advisory Board: MSD, Pfizer, Astellas, Bayer, Merck. F.J.S. Melo Cruz: Financial Interests, Personal, Invited Speaker, Lecture: MSD; Financial Interests, Personal, Invited Speaker: Bayer, Astellas; Financial Interests, Personal, Advisory Board: Bayer, Jansen; Financial Interests, Institutional, Local PI: MSD, Roche, Bayer, Novartis, AstraZeneca. K.G. Daugaard: Financial Interests, Personal, Advisory Board, Prostate cancer: Janssen; Financial Interests, Personal, Advisory Board, Prostate Cancer: Astellas, Bayer, MSD; Financial Interests, Personal, Advisory Board, Anticoagulation therapy: BMS; Financial Interests, Personal, Advisory Board: AA; Financial Interests, Institutional, Coordinating PI: BMS, Roche, MSD, Lilly; Financial Interests, Institutional, Local PI: Janssen. R. Yamamura: Financial Interests, Institutional, Local PI: Amgen, AstraZeneca, Bayer, BMS, Exelixis, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi. C. Coens: Financial Interests, Personal, Full or part-time Employment, Full time employee of EORTC as clinical trial statistician: EORTC; Financial Interests, Institutional, Funding, EORTC received funding from Bayer to provide clinical trial services: Bayer. B. Tombal: Financial Interests, Personal, Advisory Board: Astellas, Bayer, Amgen, Janssen, Sanofi, Myovant, Novartis (AAA), Pfizer, Astellas, MSD, AstraZeneca; Financial Interests, Personal, Invited Speaker: Astellas, Amgen, Ferring, ACCORD; Non-Financial Interests, Member of Board of Directors, Past President: European Organisation of Research and Treatment of Cancer (EORTC); Non-Financial Interests, Member of Board of Directors, Education in the field of Oncology: ISSECAM. All other authors have declared no conflicts of interest.