Background: Lutetium-177 PSMA radioligand therapy ([¹⁷⁷Lu]Lu-PSMA-RLT) is an effective treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Prospective studies reported favourable efficacy and safety outcomes of up to 6 cycles of [¹⁷⁷Lu]Lu-PSMA. This study aimed to evaluate the efficacy and safety of [¹⁷⁷Lu]Lu-PSMA rechallenge therapy in patients with mCRPC who progressed after an initial course of [¹⁷⁷Lu]Lu-PSMA-RLT. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search was performed using relevant keywords in PubMed, EMBASE, and Scopus from establishment to March 2025. Primary endpoints included biochemical responses with a decline in prostate-specific antigen (PSA) of more than 50% and any PSA decline. Secondary outcomes included survival outcomes and treatment-related toxicity following rechallenge therapy with [¹⁷⁷Lu]Lu-PSMA. A random-effects model was used to generate pooled proportions through meta-analysis. Results: Eleven studies with 307 patients were included in the final analysis. Of these, 196 received 177Lu-PSMA RLT alone, and 111 received tandem 177Lu/225Ac-PSMA RLT. The pooled proportions of patients with more than a 50% PSA decline and any PSA decline were 0.45 (95% CI: 0.36–0.54) and 0.71 (95% CI: 0.61–0.80), respectively. In a total of 102 patients, 44 (43%) showed low-grade 1–2 xerostomia; however, no cases of serious xerostomia (grade ≥ 3) were reported. Moreover, the pooled proportion of patients experiencing grade ≥ 3 toxicity was 0.14 (95% CI: 0.09–0.19). Conclusion: Rechallenge therapy with [¹⁷⁷Lu]Lu-PSMA is a feasible and safe treatment option for late/end mCRPC patients. Tandem approaches with [225Ac]Ac-PSMA may help expand understanding of how to optimize outcomes after [¹⁷⁷Lu]Lu-PSMA progression. However, these findings require confirmation in prospective, randomized studies comparing different rechallenge strategies to define optimal sequencing and patient selection criteria in advanced prostate cancer.

Objective: To review the efficacy and safety of reduced dose compared to standard dose Enzalutamide treatment for patients with castration-resistant prostate cancer (CRPC). Methods: PubMed, Scopus, Web of Science, and Cochrane databases were searched for randomized controlled trials and cohort studies reporting the use of Enzalutamide in reduced and standard doses in patients with castration-resistant prostate cancer. Searches were limited to articles published in the English language. Outcome assessments included progression-free survival (PFS), overall survival (OS), adverse events, and serum prostate-specific antigen (PSA) response. Results: Ten studies met the inclusion criteria, including 2481 patients treated with Enzalutamide. Seven studies were retrospective cohorts, two were prospective trials, and one was a prospective cohort. No consistent relationship was identified between OS and PFS and the Enzalutamide dosage. Reduced doses of Enzalutamide decreased the incidence of adverse events, particularly among elderly patients. Conclusions: This systematic review suggests that reduced doses of Enzalutamide in CRPC may maintain therapeutic efficacy in selected patients while improving tolerability. However, inconsistent findings and methodological limitations highlight the need for prospective randomized trials to define optimal and individualized dosing strategies.