Mature phase 1 follow up of alpha emitter 225Ac-J591 with 177Lu-PSMA-I&T in advanced prostate cancer.

185 Background: Targeted radionucleotide therapy (TRT) has become a standard of care. α-emitters have a higher energy transfer over a shorter range than β-emitters. PSMA-targeting antibodies have different biodistribution than small molecules and may improve intracellular retention based on pre-clinical models. Here, we present mature follow up of a phase 1 dose-escalation trial of 225Ac-J591 plus 177Lu-PSMA-I&T (aka PNT2002). Methods: Inclusion criteria:progressive mCRPC with ≥1 prior AR pathway inhibitor (ARPI), prior chemo (or unfit/refused), and with ≥1 lesion on PSMA PET where SUVmax >liver. 177Lu-PSMA-I&T (6.8 GBq) and 225Ac-J591 (30, 35, or 40 KBq/kg) given up to 2 doses 8 weeks apart. Primary outcome was dose-limiting limiting toxicity and recommended phase 2 dose (RP2D). Preliminary efficacy outcomes examined were overall survival (OS), progression-free survival (PFS), PSA response, and circulating tumor cell (CTC) changes. Results: 18 patients (6 at each dose level) with median age 70, median PSA of 54.4 (2.43-9614). Previous therapies: 11 (61%) with >1 ARPI, 12 (67%) chemo, 5 (28%) sip-T, 3 (17%) radium-223. Baseline CTCs: 15 detectable, 9 unfavorable. The median SUVmax of the most avid lesion on PSMA-PET was 31.4 (95% CI 11-82.7). Metastatic sites: 13 bone, 9 lymph node, 4 visceral. 8 (44%) were Halabi high risk. Treatment emergent adverse events (AEs) included neutropenia in 3 patients (17%), all Grade <2; thrombocytopenia occurred in 12 (67%) (3 GR 3); anemia in 10 (56%, 3 GR 3); 12 (67%) xerostomia (one Gr2); one (6%) with acute renal failure. Other AEs: 10 (56%) pain flare (1 Gr3 in pt with cord compression), 11 (61%) nausea (all Gr 1), 9 (50%) fatigue (all Gr 1). The RP2D of 225Ac-J591 was 35 KGBq/kg. 17 (94%) patients experienced a decline in PSA levels, with 11 out of 17 (64%) achieving PSA50 response. 4/5 patients (80%) converted from unfavorable to favorable CTC count, 4/8 (50%) from detectable to undetectable, 1 of 2 (50%) remained undetectable. Median biochemical PFS was 7.3 months (95% CI 2.7-15.8), and median OS was 29.8 mo (95% CI 7.4-NR), with 10 patients still alive at time of submission. 5 were progression free at one year, including 3 of 6 treated at RP2D. With longer follow up, no new safety signals were identified. Conclusions: The combination of PSMA-targeted alpha (via antibody) plus beta (via small molecule) was feasible. High grade AEs were rare and no new safety signals emerged with longer term follow up. Nearly all patients had PSA decline, and 5 had durable disease control off therapy. Clinical trial information: NCT04886986 .