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CAPItello-281 — Capivasertib + abiraterone vs placebo + abiraterone in PTEN-deficient 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: Capivasertib (AKT inhibitor) + abiraterone improved rPFS over placebo + abi in PTEN-deficient mHSPC — the first Ph3 to validate PTEN-deficiency as a prospective biomarker for AKT-pathway intervention in hormone-sensitive prostate cancer.

At a glance

  • Sponsor: AstraZeneca
  • PI / presenter: Karim Fizazi (Gustave Roussy)
  • NCT ID: NCT04493853
  • Phase: 3
  • Design: Double-blind, 1:1 randomization, capivasertib + abi + prednisone + ADT vs placebo + abi + prednisone + ADT; PTEN-deficiency by IHC required at enrollment
  • N: ~1,000 randomized; PTEN-deficient by central IHC
  • Primary endpoint(s): rPFS; key secondary OS, time to PSA progression
  • Comparator: Placebo + abiraterone + ADT (the post-LATITUDE intensification SOC for high-volume mHSPC)
  • Indication: PTEN-deficient mHSPC (~40-50% of mHSPC patients)
  • Line: 1L mHSPC

Headline result

Positive rPFS per AZ topline (pre-meeting press release) and confirmed at the GU oral presentation. Magnitude per trade-press synthesis: rPFS HR ~0.66; median rPFS not yet reached in capivasertib arm. PRO assessments (patient-reported outcomes) were emphasized at the presentation — capivasertib added GI / hyperglycemia toxicity but did not erode global health-related QoL. OS immature.

Mechanism / class

Capivasertib: oral pan-AKT (1/2/3) inhibitor. Approved 2023 (US) for HR+/HER2- breast cancer with PIK3CA/AKT1/PTEN alterations (CAPItello-291). PTEN loss is one of the most common genomic alterations in prostate cancer (~40-50% of metastatic disease) and drives AKT-pathway activation. Mechanistically the rationale parallels the breast-cancer CAPItello-291 success — biomarker-selected AKT inhibition with an established backbone.

Trial design deep dive

Study architecture. Double-blind, placebo-controlled Ph3, 1:1 randomization, ~1,000 PTEN-deficient mHSPC patients. Experimental arm: capivasertib 400 mg PO BID (4 days on / 3 days off) + abiraterone 1,000 mg PO daily + prednisone 5 mg BID + ADT; control arm: matched placebo + abi + prednisone + ADT. PTEN-deficiency required by central immunohistochemistry on archival or fresh tumor at screening. Stratification factors (per ClinicalTrials.gov): disease volume (high vs low per CHAARTED), prior docetaxel for mHSPC, geographic region.

Endpoint definitions. Primary: rPFS by investigator (PCWG3-modified RECIST). Key secondaries: OS, time to PSA progression, time to symptomatic skeletal event, ORR, safety, PRO (FACT-P, BPI-SF).

Key subgroup analyses. - Disease volume (high vs low) — TBD; LATITUDE backbone has greatest benefit in high-volume. - Prior docetaxel for mHSPC — TBD. - PTEN IHC depth (complete vs partial loss) — central pathology continuum; biomarker-grading analysis is the key translational readout. - De novo vs metachronous mHSPC — TBD.

Comparator context. Abiraterone + prednisone + ADT is the post-LATITUDE intensification SOC for high-volume mHSPC and a common 1L choice across volumes. CAPItello-281 layers capivasertib on top, parallel to how PSMAaddition adds RLT to the ADT + ARPI doublet — but for a biomarker-selected ~40–50% of patients.

FDA / regulatory implications. AZ sNDA filing for capivasertib + abi in PTEN-deficient mHSPC anticipated 2026; FDA action likely H2 2026 / 2027 contingent on OS maturity. Companion-diagnostic strategy is the regulatory wildcard — AZ partnered with Roche/Ventana for the breast-cancer PTEN IHC; whether prostate uses the same assay (or a genomic loss readout) is TBD. NCCN prostate guideline anticipated to require PTEN testing in mHSPC if FDA approves.

Discussant takeaway

Discussant (Stephen Freedland, Cedars-Sinai) framed it as the first prospective biomarker-selected Ph3 win in mHSPC — the field has long talked about precision-oncology in prostate cancer but trials like CHAARTED, LATITUDE, ARASENS treated all comers. Fizazi himself emphasized that PTEN-IHC testing infrastructure is the next bottleneck: most US labs do not routinely run prostate PTEN IHC.

Practice-changing verdict

Yes if confirmed at OS. AZ filing likely 2026. NCCN prostate guideline anticipated to require PTEN testing in mHSPC if FDA approves. Open question: which PTEN-deficiency assay (IHC vs genomic loss) becomes the regulatory standard, and how this regimen sequences against ¹⁷⁷Lu-PSMA (PSMAaddition) for the overlapping mHSPC population.

  • ASCO 2026 main: OS interim expected (forward-looking)
  • ESMO 2026: mature OS readout
  • AACR 2026 GU sessions: AKT / PI3K pathway in prostate biology
  • Other ASCO GU 2026 trials: PSMAaddition (1L mHSPC competitor); BRCAAway (HRR-altered mCRPC PARPi combo)

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