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PSMAaddition — ¹⁷⁷Lu-PSMA-617 + ADT + ARPI vs ADT + ARPI in 1L metastatic hormone-sensitive prostate cancer

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

Headline: Adding ¹⁷⁷Lu-PSMA-617 (Pluvicto) to ADT + an ARPI in 1L mHSPC produced a positive rPFS readout — moving PSMA-targeted radioligand therapy from 3L+ (VISION) into the hormone-sensitive setting for the first time.

At a glance

  • Sponsor: Novartis
  • PI / presenter: Oliver Sartor (Mayo Clinic)
  • NCT ID: NCT04720157
  • Phase: 3
  • Design: Open-label, 1:1 randomization, ¹⁷⁷Lu-PSMA-617 (six cycles q6w) + ADT + investigator-choice ARPI vs ADT + ARPI; PSMA-PET–positive disease required
  • N: ~1,144 randomized
  • Primary endpoint(s): rPFS by central review; key secondary OS
  • Comparator: ADT + ARPI (the post-ARASENS / TITAN intensification SOC)
  • Indication: Metastatic hormone-sensitive prostate cancer (mHSPC), PSMA-PET–positive
  • Line: 1L mHSPC

Headline result

Positive rPFS per topline (Novartis press release pre-meeting, confirmed at GU oral). Magnitude approximately HR 0.72 per post-meeting trade-press synthesis; median rPFS not yet reached in the experimental arm at interim. OS event count immature — mature OS expected at ASCO main meeting or ESMO 2026. Safety: known ¹⁷⁷Lu-PSMA xerostomia / cytopenia signal; no new safety findings.

Mechanism / class

¹⁷⁷Lu-PSMA-617 (Pluvicto): beta-emitting (lutetium-177) PSMA-targeted small-molecule radioligand. Approved 2022 (US) for post-taxane mCRPC based on VISION (OS HR 0.62). Label expanded 2025 to pre-taxane mCRPC via PSMAfore. PSMAaddition pushes the molecule into mHSPC — three lines earlier than the original indication, in a substantially larger and earlier-disease patient population.

Trial design deep dive

Study architecture. Open-label Ph3, 1:1 randomization, ~1,144 PSMA-PET–positive 1L mHSPC patients. Experimental arm: ¹⁷⁷Lu-PSMA-617 7.4 GBq IV q6w × up to 6 cycles + continuous ADT + investigator-choice ARPI (abi, enza, apa, or daro); control arm: ADT + ARPI alone. Crossover from control to ¹⁷⁷Lu-PSMA-617 permitted at radiographic progression. Stratification factors (per ClinicalTrials.gov): disease volume (high vs low per CHAARTED), prior local therapy, geographic region, ARPI choice. PSMA-PET eligibility required at least one PSMA-avid lesion and no PSMA-negative dominant disease.

Endpoint definitions. Primary: rPFS by blinded independent central review (PCWG3-modified RECIST, including bone-scan and PSMA-PET secondary read). Key secondary: OS, time to symptomatic skeletal event, time to castration resistance, ORR, safety, PRO.

Key subgroup analyses. - Disease volume (high vs low per CHAARTED) — rPFS benefit reportedly consistent (TBD magnitude per stratum). - De novo vs metachronous mHSPC — TBD; de novo typically higher-volume, may show larger absolute benefit. - ARPI backbone (abi vs enza vs apa vs daro) — interaction analysis TBD; not pre-specified for hypothesis testing. - PSMA-PET SUVmean tertiles — biomarker-rich subgroup, key for adoption gating; TBD.

Comparator context. ADT + ARPI is the post-ARASENS / TITAN / ENZAMET intensification SOC for mHSPC. PSMAaddition adds a third modality (radioligand) to the doublet, paralleling the ARASENS triplet (ADT + ARPI + docetaxel) but substituting RLT for chemo.

FDA / regulatory implications. Novartis sNDA filing anticipated 2026; FDA action likely H2 2026 / early 2027 contingent on OS interim. Priority review plausible given mHSPC unmet need and prior Pluvicto BTD history. NCCN update expected to add ¹⁷⁷Lu-PSMA + ADT + ARPI as a 1L mHSPC option for PSMA-PET+ disease, with PET availability and reimbursement as the practical gating issue.

Discussant takeaway

Discussant (Tanya Dorff, City of Hope) framed it as the biggest mHSPC expansion since ARASENS — but flagged the access / PET-eligibility bottleneck (PSMA-PET availability and reimbursement) as the practical adoption gate. Karim Fizazi noted that with both PEACE-3 (Ra-223) and PSMAaddition (¹⁷⁷Lu) positive in the same meeting, the next question is sequencing.

Practice-changing verdict

Yes, contingent on OS. rPFS positivity supports a Novartis sNDA filing in 2026; FDA action likely H2 2026 / early 2027. NCCN update expected to add ¹⁷⁷Lu-PSMA + ADT + ARPI as a 1L mHSPC option for PSMA-PET+ disease. Open question: which mHSPC patients benefit most — high-volume vs low-volume, de novo vs metachronous.

  • ASCO 2026 main: OS interim follow-up expected (forward-looking)
  • ESMO 2026: mature OS readout likely venue
  • AACR 2026 GU sessions: PSMA radioligand pharmacology
  • Other ASCO GU 2026 trials: PEACE-3 (Ra-223 alpha-emitter mCRPC); ²²⁵Ac-PSMA first-in-human

Sources