Feasibility and outcomes of response-adapted and retreatment 177 Lu-PSMA-617 therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

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184 Background: The depth and time to response vary among patients with mCRPC receiving Lutetium-177 prostate-specific membrane antigen-617 (Lu-PSMA) and the optimal treatment strategy is yet to be determined. This study aimed to evaluate the efficacy and safety of a response-adapted treatment schedule and retreatment beyond 6 cycles of Lu-PSMA in patients with mCRPC. Methods: This single-center retrospective study included patients treated with Lu-PSMA between June 2022 and March 2025 who either (1) paused treatment due to deep response to treatment before completing 6 cycles and underwent retreatment upon progression (group 1) or (2) received retreatment upon progression after response to the initial six cycles of Lu-PSMA (group 2). A deep response was defined by ≥90% decline from baseline in PSA and in tumor burden on post-treatment single-photon emission tomography. The decision to continue treatment was made by the treating oncologist based on PSA progression consistent with PCWG3 criteria. The outcomes of interest, included PSA decline of ≥50% (PSA50) and PSA progression-free survival (PSA-PFS) were assessed from baseline and from retreatment after progression. Overall survival (OS) was calculated from the start of initial Lu-PSMA therapy to the last follow-up or death. According to CTCAE v5.0, hematologic adverse events (AEs) of grade ≥3 and renal AEs of grade ≥2 were reported. Results: Of 250 patients who received Lu-PSMA, 22 (9%) patients with a median age of 73 years (IQR: 67-77) were included. Fourteen patients underwent retreatment after an initial favorable response, receiving a median of 4 cycles (range: 2-5) initially, followed by a median of 3 cycles (range: 1-5) upon retreatment. The remaining 8 patients received retreatment after completing the initial 6 cycles, with a median of 2 cycles (range: 1-7) upon retreatment. After a median follow-up of 27.9 months (IQR 18.7-36.1), 4 patients had died, and median OS was not reached (95% CI 30.5-NR). In group 1, the median PSA-PFS was 12.3 months (95% CI 8.3-NR) at initial treatment, and 9 patients (64%) achieved PSA50 upon retreatment with PSA-PFS of 7.1 months (95% CI 3.2-NR). In group 2, the median PSA-PFS was 12.5 (95% CI 11-NR) at initial treatment, and 3 (38%) patients achieved a PSA50 response upon retreatment, with a PSA-PFS of 4.9 months (95% CI 1.4-NR). Overall, 1 (5%) patient experienced G3 leukopenia during initial treatment, while upon retreatment, 5 (23%) experienced G3 anemia, 2 (9%) experienced G3 thrombocytopenia, 1 (5%) experienced G3 leukopenia, and 4 (18%) experienced G2 renal impairment. Conclusions: Response-adapted and retreatment beyond 6 cycles of Lu-PSMA is feasible in patients with mCRPC with an acceptable hematological safety profile, demonstrating encouraging PSA responses and PSA-PFS. Further studies with larger cohorts are warranted to confirm these findings.

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