Abstract CT143: Results of combined targeting of prostate-specific membrane antigen (PSMA) with alpha-radiolabeled antibody 225Ac-J591 and beta-radiolabeled ligand 177Lu-PSMA I&T: preclinical and initial phase 1 clinical data in patients with metastatic castration-resistant prostate cancer (mCRPC)

Background: PSMA is overexpressed by the majority of PC and may be targeted by both antibodies (mAb) and small molecule ligands (SML), each with differing PSMA binding sites, kinetics, and biodistributions. mAbs have long circulating times (exposing organs such a bone marrow) but are too large to target normal tissue luminal PSMA expression in salivary glands, small bowel, and kidney; SMLs rapidly diffuse to all PSMA+ sites and are excreted by the kidneys within hours. Alpha emitters have high potency over a short range whereas beta emitters have lower energy over a significantly longer range. We hypothesized that combining mAb and SML targeting plus combining alpha and beta emitters offered complementary benefits and would be safe and effective. Methods: A series of cell line and xenograft studies were performed to test mAb vs SML vs combo binding, uptake, and efficacy. A phase I/II clinical trial was initiated, enrolling patients with progressive, PSMA+ (by PSMA PET) mCRPC following potent AR pathway inhibition and chemotherapy (or chemo ineligible/refused)[NCT04886986]. The primary endpoint of phase I is assessment of dose-limiting toxicity (DLT) with secondary endpoints of response, progression-free and overall survival, genomic and imaging correlatives, and patient-reported outcomes. Results: Binding studies demonstrated that mAb plus SML binding was additive rather than competitive in LNCaP and CWR22Rv1 cell lines. Uptake of 177Lu-mAb plus -SML in LNCaP, CWR22rv1, and PC3/PSMA xenograft models demonstrated synergism, with 44-65% greater tumor radioactivity in combination than the sum of the individual agents. Intracellular tracking studies indicate that the mAb re-directs SML to lysosomes from recycling endosomes, maintains retention of SML in tumor cells, and, therefore, prolongs intra-tumoral radioactivity exposure. Survival was prolonged in animals receiving 225Ac-mAb plus 177Lu-SML vs either drug alone (or control). Nine men with median age 68 (range 55-87), PSA 140 (2.4-9614) have been enrolled in both of 2 planned dose-escalation cohorts. 89% with bone, 44% lymph node, 22% liver, 22% lung metastases; 88% with detectable CTC count (75% unfavorable). All had at least 1 metastatic lesion with PSMA PET SUVmax > liver SUVmean, with SUVmax of the single hottest lesion ranging from 11.6-69.9. For the primary endpoint, 0 of 3 with DLT in cohort 1, and with follow up ongoing, no DLT has occurred to date in 6 patients in cohort 2. Of evaluable patients,