Shankar Vallabhajosula

Purpose:To test the safety of two regimens at differing levels of radioactivity of prostate-specific membrane antigen (PSMA)–targeted α-radionuclide 225Ac-J591. Patients and Methods:Patients with progressive, metastatic androgen pathway modulation–resistant prostate cancer were enrolled in two parallel dose-escalation cohorts: (i) fractionated-dose regimen (single cycle of 45–65 KBq/kg of 225Ac-J591 on days 1 and 15; main cohort agnostic to prior receipt of 177Lu-PSMA and an additional cohort with prior receipt of 177Lu-PSMA) and (ii) multiple cycles of 225Ac-J591 (45–65 KBq/kg administered every 6 weeks for up to 4 cycles). PSMA PET was not utilized for eligibility. The primary endpoint was determination of dose-limiting toxicity (DLT) and recommended phase II dose (RP2D); the fractionated cohort was expanded. Results:Forty-two patients were enrolled in the fractionated-dose regimen (23 dose-escalation, 11 dose-expansion, and 8 after 177Lu-PSMA) and 18 in multiple-dose regimen. All received ≥1 prior androgen receptor pathway inhibitor, 72% received chemotherapy, and 18% received 177Lu-PSMA. Three patients had DLTs in the fractionated regimen with RP2D of 60 KBq/kg twice. Seven had DLTs in the multiple-cycle regimen; this regimen is not recommended for further development. Among adverse events of special interest, temporary hematologic toxicity was most common [93% thrombocytopenia (32% grade >3), 65% neutropenia (13% grade ≥3), and 63% anemia (20% grade ≥3)]; dry mouth occurred in 62% (2% grade 2). Across fractionated cohorts with or without prior 177Lu-PSMA, a >50% prostate-specific antigen (PSA) decline was the best response occurring in 60% of patients; 28% had a >50% PSA decline in multiple cycles. Conclusions:Fractionated dosing of 225Ac-J591 seems promising. Further investigation is underway.

Figure S3. Best individual PSA response

Figure S1. Best CTC and measurable disease response for each evaluable patient (A) Best CTC count response for each patient. (B) Measurable disease response by PCWG modified RECIST 1.1. Treatment cohort denoted by colors of individual bars: blue = fractionated dose, purple = multiple cycle, gold = fractionated post 177Lu-PSMA.

Figure S2: Hematologic toxicity over time

Figure S4. Patient reported outcome scores over time for fractionated-dose 225Ac-J591 Individual scores (dots) with median cohort FACT-P (A) and BPI-SF (B) scores for patients treated with combined fractionated dose cohorts

Table S1: Radioactivity dose levels by cohort

Table S2: Representativeness of Study Participants

Table S4: Worst grade of attributable adverse events of special interest through long term follow up with or without exposure to additional treatment

Table S5: PSA response by treatment group