Final results of a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC).

5074 Background: PC commonly expresses PSMA and has dose-responsive radiosensitivity. 177 Lu-based radioligands usually use an empiric dosing regimen. This 1st dose-escalation study of 177 Lu-PSMA-617 employed a dose-dense fractionation schedule intended to allow delivery of higher total doses to overcome radioresistance due to repopulation. Here, we report mature results of the study. Methods: Progressive mCRPC following > 1 potent ARPI (e. g. , abi/enza) and chemo (or unfit/refuse taxane) without limit of # prior therapies provided adequate organ function and ECOG PS 0-2. Treatment: single cycle of fractionated dose 177 Lu-PSMA-617 on D1 and D15. In Ph I dose-escalation, patients (pts) received one cycle of 7. 4 - 22 GBq followed by Simon 2-stage Ph II at 22. 2 GBq. PSMA expression was not required for treatment, but pre- and post-treatment 68 Ga-PSMA11 PET/CT and/or 177 Lu-PSMA-617 SPECT done. Primary efficacy by PSA changes with 2ndary outcomes with CT/bone scans, PSMA PET, circulating tumor cell (CTC; CellSearch) counts, plasma DNA (PCFSELECT), and survival. Results: Between 1/2017 – 2/2021, 50 pts treated with median PSA 164. 3, 35 (70%) CALGB (Halabi) poor risk. 47 (94%) bone, 38 (76%) nodal, 12 (24%) lung, 5 (10%) liver mets (4 additional pts with PSMA PET+ liver mets not apparent on CT). 29 (58%) with prior >2 ARPI, 29 (58%) with >1 chemo, 14 (28%) with Ra-223, 2 (4%) with 177 Lu-J591. 27 (54%) treated at 22 GBq. No dose-limiting toxicity during Ph I. 38 (76%) with any PSA decline, 27 (54%) with >50% PSA. Median rPFS 8. 3 mo 5. 6-16. 7, and OS 15. 7 mo 10. 9-20. 6. Of 17 RECIST measurable, 6 (35. 3%) responded, 7 (41. 2%) stable, 4 (23. 5%) progressed. Of 31 with paired CTC counts, 16 (52%) decreased, 5 (16%) were stable; 10 (32. 3%) converted to favorable/undetectable. Plasma DNA with high allele-specific ploidy and ARcopy number gain associated with OS (univariate). Treatment emergent adverse events (TEAE): 32 (64%) dry mouth, 22 (44%) pain flare, 22 (44%) fatigue, 19 (38%) nausea, 15 (30%) anemia, 15 (28%) thrombocytopenia (plts), 9 (18%) neutropenia (ANC). All TEAEs restricted to grade (Gr) 1-2 except 6 (12%) with Gr 3 anemia, 2 (4%) Gr 3/4 plts, 1 (2%) Gr 3 ANC. TEAE incidence and Gr were not related to dose. On multivariable analysis, 177 Lu dose administered (p=0. 09), CALGB risk (p=0. 04), prior chemo (p=0. 009), associated with OS; dose (p=0. 1), CALGB risk (p=0. 2), and AR copy number (p=0. 2) associated with PSA50 decline. Baseline PSMA imaging (by imaging score or SUVmax) was not associated with OS or response. Conclusions: A single-cycle of fractionated-dose 177Lu-PSMA-617 is safe. Despite no pre-selection for PSMA expression, most had PSA decline with favorable PFS and OS compared to historical controls and similar to PSMA-selected targeted radionuclide studies administering multiple cycles in a less dose-intense approach. Clinical trial information: NCT03042468.