Evaluation of [ ²²⁵ Ac]Ac‐PSMA‐617 vis‐a‐vis Rechallenge [ ¹⁷⁷ Lu]Lu‐PSMA‐617 PRLT Versus Cabazitaxel or Oral Metronomic Chemotherapy in mCRPC: An Observational Analysis of Outcome and Toxicity Profiles in a Real‐World Clinical

ABSTRACT Introduction A subset of prostate cancer progresses to aggressive state of metastatic castration‐resistant prostate cancer (mCRPC), wherein multiple therapeutic options demonstrate limited success rates. In this observational study, we aimed to evaluate the efficacy, toxicity, and survival outcomes of (a) [ 225 Ac]Ac‐PSMA‐617, (b) rechallenge [ 177 Lu]Lu‐PSMA‐617, (c) cabazitaxel, and (d) oral metronomic cyclophosphamide treatments in postdocetaxel mCRPC patients with progressive disease following initial course of [ 177 Lu]Lu‐PSMA‐617 or without previous [ 177 Lu]Lu‐PSMA‐617 PRLT (PSMA‐targeted radioligand therapy). Methods The study reviewed the medical records of mCRPC patients who had documented disease progression following treatment with androgen receptor pathway inhibitors and docetaxel. These patients had multiple therapeutic options and treated with [ 225 Ac]Ac‐PSMA‐617(alpha based‐PRLT) or rechallenge [ 177 Lu]Lu‐PSMA‐617 or chemotherapy with cabazitaxel or metronomic cyclophosphamide. We stratified the latter group (chemotherapy) based on prior exposure to initial course of [ 177 Lu]Lu‐PSMA‐617 as received and not received. We evaluated and analyzed the response outcomes from these therapies under five headings: (a) symptomatic response, (b) biochemical response, (c) functional and anatomical imaging response, (d) survival outcomes, and (e) toxicity profiles. Results A total 66 mCRPC patients were included and analyzed in this study. These patients were divided into two cohorts. Cohort 1 ( n = 49 patients) received initial course of [ 177 Lu]Lu‐PSMA‐617 and cohort 2 ( n = 17 patients) not received initial course of [ 177 Lu]Lu‐PSMA‐617. The patients were divided into arm A to F based upon treatment received as follows: Cohort 1‐ arm A ( n = 15 patients) received [ 225 Ac]Ac‐PSMA‐617, arm B ( n = 18 patients) received rechallenge [ 177 Lu]Lu‐PSMA‐617, arm C ( n = 8 patients) received cabazitaxel, arm D ( n = 8 patients) received metronomic cyclophosphamide. Cohort 2‐ arm E ( n = 14 patients) cabazitaxel and arm F ( n = 3 patients) metronomic cyclophosphamide. Patients in arm A showed favorable response outcomes in terms of symptomatic response evaluation and quality‐of‐life performance, biochemical and imaging response evaluation, with a PSA decline of > 50% and disease control rate (DCR) of 60% patients and 80% respectively. Patients treated with rechallenge [ 177 Lu]Lu‐PSMA‐617 and chemotherapy also showed modest response rates. For toxicity profiles, arm A and arm B patients had mild and manageable toxicities, contrary to arm C, D, E, and F, wherein severe clinical and hematological toxicities were observed in a significant fraction of patients. Median progressive free survival (PFS) for the overall cohort (cohort 1 and 2) was 5 months (95% CI: 4–7 months), with no significant difference across treatment arms ( p = 0.28). Median overall survival (OS) for entire cohort was 12 months (95% CI: 9–15 months) with significantly longer OS in arm A and E patients compared to other arms ( p = 0.0358). Conclusion Postdocetaxel mCRPC patients with progressive disease following initial course of [ 177 Lu]Lu‐PSMA‐617 when treated with [ 225 Ac]Ac‐PSMA‐617PRLT showed favorable and encouraging clinical, biochemical, and imaging response rates along with longer PFS and OS with minimal treatment‐related toxicities. Rechallenge [ 177 Lu]Lu‐PSMA‐617 and chemotherapy‐based approaches also provided clinical benefit in selected patients, reflecting the range of salvage treatment strategies employed in real‐world practice. Future large‐sized, prospective randomized trials are needed to establish the efficacy of all these treatments particularly alpha‐based PRLT in clinical practice of mCRPC patients.