PT-112 Update: Phase 2 Biomarker Findings Pave Way for Phase 3 in End-Stage Prostate Cancer

Since FDA cleared PT-112 for a pivotal phase 3 trial in May 2025 (we talked about it here) following a successful end-of-phase-2 meeting, fresh insights illuminate why this novel platinum-based agent merits excitement for late-line metastatic castration-resistant prostate cancer (mCRPC). PT-112 stands apart from traditional platinums: its pyrophosphate structure drives osteotropism (high bone accumulation alongside soft tissue penetration) and triggers immunogenic cell death via ribosomal inhibition, not mere DNA crosslinking, potentially awakening immune responses in AR-independent disease.

The phase 2 dose-finding study targeted fragile patients (median 5+ prior lines: docetaxel, cabazitaxel, ARPIs; ~40% post-Pluvicto), where marrow exhaustion from radiation and chemo demands tailored dosing.

In roughly half the cohort analyzed, baseline profiles screamed aggressiveness: MYC amplification (38%), RB deletion (40%), TP53 mutations (52%), PTEN loss (44%), BRCA2 aberrations (25%), and scant SPOP mutations, all hallmarks of neuroendocrine-like, AR-non-responsive end-stage mCRPC far beyond early-line settings.

Yet PT-112 delivered: >50% Alk phos declines (with pain relief), majority LDH improvements, high CTC conversions to zero across arms (dose-independent), and ctDNA fraction reductions, strongest in Arm 3 where longevity amplified effects. High baseline LDH/Alk phos/CTC/ctDNA predicted worse outcomes (PSA meaning is weaker here), but on-treatment shifts correlated with benefit, resetting expectations from PSA-centrism.

Safety aligned with expectations: myelosuppression (anemia/leukopenia), inflammatory flares (e.g., RA exacerbation hinting at immunogenicity), fatigue, mild GI (manageable), no G4/5 signals.

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