Early Lu-177 PSMA Radioligand Therapy in Metastatic Non-castrate or Castration-Sensitive Prostate Cancer: Long-Term Results

Introduction: Metastatic castration-sensitive prostate cancer (mCSPC) is described as a phase of advanced prostate cancer when the patients have never received, or are no longer receiving androgen-deprivation therapy (ADT). The aim of this study was to evaluate the safety and efficacy of early ¹⁷⁷Lu-PSMA radioligand therapy (PRLT) in patients with mCSPC

Methods: A retrospective analysis was performed in a cohort of 24 patients with mCSPC (age 50-84 y, median age 69, Gleason-score 7-10, median 8) treated with Lu-177labeled PSMA ligands (2-7 cycles, median 4; with 5.5 – 11.7 GBq Lu-177 PSMA, median 7.8 GBq per cycle). These patients had histologically confirmed prostate adenocarcinoma, and had undergone prostatectomy, external beam radiation therapy or adjuvant ADT for localized disease, but were no longer receiving ADT (testosterone levels are higher than 50 ng/dL). In addition to PSA-decline, therapy response was assessed on CT and/or MRI images, depending on modality used at baseline, according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Imaging was performed prior to each PRLT cycle and at restaging. Disease Control Rate (DCR) was defined as complete response (CR), partial response (PR) and stable disease (SD). Best objective response rate (ORR) was defined as patients achieving CR and PR at follow-up according to the RECIST. Molecular response evaluation was evaluated according to European Organization for Research and Treatment of Cancer (EORTC) criteria. Kaplan-Meier survival analysis was performed to determine progression-free survival (PFS) defined as the time from the first PRLT until objective progression.

Results: The median follow-up time was 31.2 months (range 9.9-78 months). Reduction in PSA was observed in 22/24 (91.7 %) patients; 19/24 patients (79.2 %) demonstrated a PSA decline by >50 % and the best PCWG3 response was complete remission with undetectable PSA. Based on EORTC criteria, the disease control rate (DCR) at 3 months (3.2±1.0 m) post-PRLT was 83.3%, including CR in 2/24 (8.3%) PR in 10/24 (41.7%) and SD in 8/24 patients (33.3%). Best objective response rate (ORR) was 50.0%, encompassing CR in 2/24 (8.3%) and PR in 10/24 (41.7%). The median PFS based on EORTC criteria was 20.23 months. Based on RECIST 1.1, DCR at 3 months (3.2±1.0 m) post-PRLT was 91.7%, encompassing CR in 2/24 (8.3%) PR in 8/24 (33.3%) and SD in 12/24 patients (50.0%). Best objective response rate (ORR) was 41.7%, encompassing CR in 2/24 (8.3%) PR in 8/24 (33.3%). The median PFS based on RECIST 1.1 was 23.34 months. The median OS has not been reached at 6.5 years after start of PRLT. No CTCAE grade 3-4 toxicity was observed.

Conclusions: De novo systemic Lu-177 PSMA radioligand therapy in metastatic noncastrate or castration-sensitive prostate cancer is feasible, safe and effective. Early introduction of PRLT might provide an additional beneficial effect and further randomized controlled studies are warranted to determine the sequence of treatments in mCSPC.