Updated follow up of a randomized, double-blinded phase II study of ketoconazole (keto), hydrocortisone (HC), and anti-PSMA antibody J591 labeled with 177Lu or 111In in patients (pts) with high-risk non-metastatic (met) castration-resistant prostate cancer (M0 CRPC).
Authors: Abdul Baseet Arham, Charlene Thomas, Issa Castaneda, Samuel Francis Ruder, Yousef Zakharia, Leonard Joseph Appleman, Joe Reginald Osborne, George Philips, Luke Nordquist, Anishka D'souza, Elizabeth Marie Wulff-Burchfield, Edwin Melencio Posadas, Neeraj Agarwal, Paul J. Christos, Nabil Adra, David M. Nanus, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2025)

172 Background: Up to 1/3 of pts develop biochemical relapse following primary therapy. Many are not cured with salvage local therapy, likely because of undetectable distant disease. PSMA is expressed on most PC and can be targeted by radiolabeled J591. 177 Lu is a predominantly β-emitting radionuclide and also has γ emission which allows imaging. 111 In is predominantly a γ emitter, also with some auger emission for therapy. Hormonal therapy is effective and may increase PSMA expression and radiosensitivity. In this DOD-funded study initiated in the pre-PSMA PET and AR signaling inhibitor era, we hypothesized that 177 Lu prolongs 18-month (mo) met-free survival (MFS) more than 111 In in pts with high risk, M0 CRPC when targeting PSMA via J591 in combo with keto and HC. Methods: Pts with high risk M0 CRPC (PSA DT &lt; 8 mo and/or absolute PSA &gt; 20 ng/mL) and serum testosterone &lt; 50 ng/mL with no evidence of metastatic disease on CT/MRI and bone scan were eligible. Treatment included a minimum 4 week lead-in with keto 400 mg TID and HC 20 mg AM, 10 mg PM (continued until unacceptable toxicity or development of mets) and a single infusion of J591 with 2:1 randomization to 177 Lu (70 mCi/m 2 ) or 111 In (5 mCi) in double-blinded fashion. 55 randomized pts provides 80% power to detect a difference in 18-mo MFS with one-sided alpha of 10%. Secondary endpoints include median MFS, overall survival, PSA response, and toxicity. Results: 55 pts with median age 68 (range 52 - 88), 75% prostatectomy, 23% primary radiation, 2% primary ADT; 19% local salvage therapy. Median PSA doubling time 3 mo (range 0.87 – 7.85), median baseline PSA 8.0 (range 1-78). In this intent to treat analysis (7 patients censored by 18 months), 31% of patients were without mets with 177 Lu compared to only 6.7% with 111 In (p=0.078) at 18 mo; biochemical PFS was 18.67 vs 8.87 mo, favoring 177 Lu in analyses censoring start of new treatment. Confirmed &gt; 50% PSA decline occurred in 82% with 177 Lu and 71% with 111 In. The median MFS of the total patient population was 20.93 (CI: 17.02-34.2) mo, median 22.47 (CI: 17.35 to 68.11) mo for 177 Lu vs 20.5 (9.23-NA) mo for 111 In, p=0.65. The median overall survival of the total patient population was 76.35 (CI: 65.64-115.29) mo, no difference between 177 Lu and 111 In, p=0.48. With a median follow up of 63.8 mo, no new long term safety signals were discovered. Conclusions: PSMA-targeted 177 Lu combined with secondary hormonal therapy improves 18-mo MFS compared to PSMA-targeted 111 In. In the context of the current era with PSMA PET, this approach supports the early use of PSMA-targeted radionuclide therapy in patients with low volume mCRPC. Clinical trial information: NCT00859781 .