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PEACE-3 / EORTC 1333 — Enzalutamide + radium-223 vs enzalutamide alone in bone-metastatic mCRPC

Abstract: Oral · Session: Oral Abstract Session — Prostate, Day 3 (Sat Feb 28, 2026), Moscone West · Embargo: lifted on presentation

Headline: Adding radium-223 to enzalutamide cut the risk of death by 24% (OS HR 0.76, 95% CI 0.60–0.96, one-sided p=0.0096) in bone-mets mCRPC — re-validates the alpha-emitter + ARPI combination with modern bone-protective agents and follows the positive rPFS readout at ESMO 2024.

At a glance

  • Sponsor: EORTC (with Bayer / Astellas drug supply)
  • PI / presenter: Silke Gillessen (IOSI, Bellinzona) — presented the OS readout
  • NCT ID: NCT02194842
  • Phase: 3
  • Design: Open-label, 1:1 randomization, enzalutamide + radium-223 vs enzalutamide alone, with mandatory bone-protective agent (denosumab or zoledronic acid)
  • N: ~446 randomized
  • Primary endpoint(s): rPFS (read out ESMO 2024); key secondary OS (this readout)
  • Comparator: Enzalutamide monotherapy
  • Indication: Bone-metastatic mCRPC, asymptomatic / mildly symptomatic, 1L mCRPC setting
  • Line: 1L mCRPC (post-ADT, may include prior docetaxel for mHSPC)

Headline result

OS HR 0.76 (95% CI 0.60–0.96, one-sided p=0.0096). Median OS 42.3 vs 35.0 months (post-meeting trade-press summary). The prior rPFS readout at ESMO 2024 reported HR 0.69 (median rPFS 19.4 vs 16.4 months). Critically, fracture rates were similar between arms because of mandatory bone-protective therapy — addressing the safety concern that sank the ERA-223 (abi + Ra-223) combination in 2018.

Mechanism / class

Radium-223 (Xofigo): alpha-emitting calcium mimetic, targets osteoblastic bone metastases. Approved 2013 for symptomatic CRPC bone-mets monotherapy (ALSYMPCA OS positive). Enzalutamide: 2nd-gen androgen receptor inhibitor. PEACE-3 is the first Ph3 to combine the alpha-emitter with an ARPI and rigorous bone protection — the design lesson learned from ERA-223.

Trial design deep dive

Study architecture. Open-label academic-sponsored (EORTC) Ph3, 1:1 randomization, 446 bone-metastatic mCRPC patients with asymptomatic / mildly symptomatic disease. Experimental arm: enzalutamide 160 mg PO daily + radium-223 55 kBq/kg IV q4w × 6 cycles; control arm: enzalutamide monotherapy. Protocol amended mid-trial after ERA-223 (2018) to mandate a bone-protective agent (denosumab 120 mg SC q4w or zoledronic acid 4 mg IV q4w) in both arms. Stratification factors: prior docetaxel for mHSPC, opioid use for cancer pain, geographic region.

Endpoint definitions. Primary: rPFS (PCWG-modified RECIST, including bone-scan lesion counts and soft-tissue progression) — readout ESMO 2024. Key secondary in this GU readout: OS (time from randomization to death from any cause, one-sided alpha 0.025).

Key subgroup analyses. - Prior docetaxel for mHSPC vs ARPI-naive — OS benefit reportedly consistent (TBD magnitude per stratum). - Extent of bone disease (≤6 lesions vs >6) — TBD; ALSYMPCA precedent suggests larger benefit in higher-burden disease. - Bone-protective agent received (denosumab vs zoledronic acid vs none pre-amendment) — fracture-rate equivalence is the headline safety finding. - Visceral metastases at baseline — small subset; Ra-223 mechanism is bone-restricted.

Comparator context. Enza monotherapy is a standard 1L mCRPC option for ARPI-naive patients (post-PREVAIL/AFFIRM). PEACE-3 positions Ra-223 as an additive bone-directed agent rather than competing with PSMA RLT for the soft-tissue compartment.

FDA / regulatory implications. Investigator-initiated EORTC trial; Bayer is expected to pursue a label expansion for combination use with enzalutamide + bone-protective agent. No PDUFA on the horizon — filing strategy TBD. NCCN prostate update likely to elevate enza + Ra-223 (with mandatory bone-protective agent) as a Category 1 option in bone-mets mCRPC. Filing in EU via EMA also anticipated given EORTC sponsorship.

Discussant takeaway

Discussant (Karim Fizazi, Gustave Roussy) framed it as a "rehabilitation of radium-223" in the modern ARPI era. Stephen Freedland (Cedars-Sinai) emphasized the mandatory bone-protective agent as a non-negotiable protocol element. Open question: how this competes against ¹⁷⁷Lu-PSMA-617 (PSMAfore, PSMAaddition) for the same bone-mets niche.

Practice-changing verdict

Yes. NCCN prostate update likely to elevate enza + Ra-223 (with bone-protective agent) as a Category 1 option in bone-mets mCRPC. Bayer expected to pursue a label expansion. ASCO 2026 main meeting will host a bone-mets subgroup follow-up.

  • ASCO 2026 main: bone-mets subgroup follow-up expected (forward-looking)
  • ESMO 2026: survival update with longer follow-up
  • AACR 2026 GU sessions: alpha-emitter radiobiology
  • Other ASCO GU 2026 trials: PSMAaddition (1L mHSPC ¹⁷⁷Lu-PSMA); ²²⁵Ac-PSMA first-in-human

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