3 - 177 Lutetium-PSMA Neoadjuvant to Ablative Radiotherapy for Oligorecurrent Prostate Cancer; Primary Endpoint Analysis of the Phase II LUNAR Randomized Trial
Presenter(s)
A. U. Kishan1, L. Valle1, H. Wilhalme2, C. Felix3, R. Nabong4, J. E. Juarez Casillas4, K. Flores4, T. M. M. Ma5, V. Ludwig4, Z. Ells6, M. Dahlbom6, J. B. Weidhaas1, D. Telesca7, M. N. Nakayama4, M. Rettig8, R. E. Reiter9, M. Allen-Auerbach6, J. Czernin6, M. L. Steinberg1, and J. Calais6; 1Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, 2University of California, Los Angeles, Los Angeles, CA, 3Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, 4UCLA, Los Angeles, CA, 5University of Washington, Seattle, WA, 6Ahmanson Translational Theranostics Division, University of California, Los Angeles, Los Angeles, CA, 7Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, 8Department of Medical Oncology, University of California, Los Angeles, Los Angeles, CA, 9Department of Urology, University of California, Los Angeles, Los Angeles, CA
Purpose/Objective(s): Metastasis-directed stereotactic body radiotherapy (SBRT) in recurrent oligometastatic hormone sensitive prostate cancer (omHSPC) improves progression-free survival (PFS), while prostate-specific membrane antigen (PSMA)-targeting radioligand therapy (RLT) improves survival in castration resistant disease. We hypothesized that adding PSMA-targeting RLT to metastasis-directed SBRT will improve PFS in patients with omHSPC.
Materials/Methods:
We randomized patients with recurrent omHSPC, characterized by 1-5 lesions outside the prostate or prostate bed on PSMA PET/CT in a 1:1 fashion to receive either SBRT to all metastatic lesions vs. 2 cycles of neoadjuvant 177Lu-PSMA PNT2002 (6.8 GBq/cycles) 6-8 weeks apart followed by SBRT to all metastatic lesions. Stratification was based on number of lesions (1 vs. 2-3 vs. 4-5) and PSMA-based stage (N1/M1a vs. M1b vs.M1c). The primary endpoint was PFS, with progression defined as PSMA-avid lesions seen at the time of biochemical progression or on a scheduled PSMA PET/CT performed 12 months after SBRT completion, initiation of salvage therapy, or death. We used a randomized phase II design with a one-sided alpha of 0.1 and a power of 0.80, yielding a target accrual of 90 patients. PFS was compared using one-sided log-rank test based on Kaplan-Meier estimates. Exploratory analyses focused on associations between immunologic parameters and germline variants with PFS.Results: From September 2022 to November 2023, 92 patients were randomized (n=47 SBRT alone, n=45 177Lu-PSMA+SBRT); 5 patients randomized to SBRT alone dropped out prior to therapy. Median age was 69 and median PSA was 1.1 ng/dL, with 38% of patients having M1b disease and 43% of patients having solitary lesions. At a median followup of 20 months, the addition of 177Lu-PSMA to SBRT significantly prolonged PFS (median 18 months vs. 7 months, p<0.0001). On multivariable analysis adjusted for PSA, prior hormonal therapy, and lesion count, the addition of 177Lu-PSMA to SBRT significantly improved PFS (hazard ratio [HR]: 0.32, 95% CI 0.18-0.55; p<0.001). Grade =3 lymphopenia was seen in 7% and 5% of patients receiving 177Lu-PSMA+SBRT and SBRT, respectively, with no other grade =3 toxicities attributable to treatment. There was a significant between-arm differences in productive T-cell receptor rearrangements at 90 days (p=0.02) and a significant association between productive rearrangements at 90 days and progression (HR 0.46). Predictive models based on germline SNPs in 22 genes predicted progression in both arms (AUC 0.75 vs. 0.59 with clinical variables alone), with SNPs in TGFB1 being particularly prognostic.
Conclusion: The addition of 177Lu-PSMA to SBRT more than doubled PFS in this cohort of men with omHSPC, meeting the primary endpoint of the trial, without significantly increasing toxicity.