Pilot study of anti-prostate-specific membrane antigen (PSMA) antibody J591 for men with metastatic castration-resistant prostate cancer (mCRPC) and unfavorable circulating tumor cell (CTC) count.
120 Background: Elevated CTC counts are associated with a poor prognosis in men with mCRPC. PSMA targeted radionuclide therapy has been associated with decline in CTC count, but it remains unclear whether this effect results from radionuclide-induced cytotoxicity. J591 was engineered to have antibody-dependent cytotoxicity. A subset of patients was observed to have CTC count decline following imaging with 111In-J591, so a prospective study was launched to test the hypothesis that “naked” J591 leads to CTC count decline. Methods: In a Simon 2-stage dose de-escalation study, men with progressive mCRPC and unfavorable CTC count (CellSearch > 4) received a single dose of J591. Initial dose cohort 300 mg with de-escalation to 20 mg. CTC count was re-assessed 4, 8, and 12 weeks following therapy along with PSA and standard imaging. An optional PSMA PET was included prior to treatment. The primary endpoint was proportion of subjects with conversion to favorable CTC count ( < 5 CTCs/7.5 mL blood) and/or > 30% decline from baseline within 12 weeks post-treatment. Results: 10 men were enrolled, 9 of whom were evaluable (1 died of progressive mCRPC prior to post-treatment CTC count). Median age was 71.5 years (range 60-81), 78% had prior chemo, ECOG PS 1 in 45% and 2 in 55%. 7 of 9 (78%) evaluable subjects were Halabi CALGB prognostic poor risk category and 2 (22%) intermediate. 6 of 9 had pre-treatment PSMA PET/CT (three 89Zr-J591 and three 68Ga-PSMA11). Though not required, all scans showed > 1 lesion with SUVmax > liver SUV (range 9.12-70.15). 2 of 6 in the 300 mg cohort had CTC count decline; 1 of 6 converted to favorable count (9 to 0 with decrease of 35 to 12 in other). 3 were treated with 20 mg; 1 had CTC count decline of 316 to 112, but 0 converted to favorable count. Across both cohorts, 3 of 9 had a CTC count decline at any point in time, ranging from 65-100% decline. With the pre-specified 2-stage design, enrollment was halted for futility based upon the primary endpoint of 12-week CTC count. PSA values post-treatment increased in 8 (89%) patients and remained unchanged in 1 (11%) patient. Conclusions: Single-agent anti-PSMA antibody J591 may lead to decline in CTC count, though the study did not meet its primary endpoint. A combination or maintenance approach might be preferable and is worthy of exploration.