The SPLASH trial has revealed that Lutetium-177-PNT2002 significantly improves radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on androgen-receptor pathway inhibitors (ARPI). The study, presented at ESMO 2024, showed a 29% reduction in the risk of radiographic progression or death compared to alternate ARPI therapy, marking a significant advancement in the treatment landscape for this patient population.
Key Findings from the SPLASH Trial
The SPLASH trial randomized patients with progressive mCRPC and PSMA-avid PET scans in a 2:1 ratio to either Lutetium-177-PNT2002 (6.8 gigabecquerels every eight weeks for four cycles) or an alternate ARPI (enzalutamide or abiraterone). Patients had to have progressed after at least one ARPI and could not have received taxanes for mCRPC, although prior taxane use for castrate-sensitive prostate cancer was permitted. The primary endpoint was rPFS, with secondary endpoints including overall survival (OS), objective response rate, time to skeletal events, and PSA50 response.
The primary endpoint, rPFS, was positive with a hazard ratio of 0.71 (p=0.0088), with median rPFS of 9.5 months in the Lutetium arm versus 6.0 months in the ARPI arm. Median follow-up was approximately one year. Objective response rates also favored the Lutetium arm, with a complete response rate of 9.3% and a partial response rate of 28.9% per RECIST criteria. PSA responses were also significantly better in the Lutetium arm, with 35.7% experiencing a 50% or greater decrease in PSA compared to 14.6% in the ARPI arm. Biochemical progression-free survival also favored the Lutetium arm, with a hazard ratio of 0.58.
Safety and Tolerability
Treatment-emergent adverse events were more favorable in the Lutetium arm compared to the ARPI change arm. Grade 3 or higher adverse events occurred in 30.1% of patients in the Lutetium arm versus 36.9% in the ARPI arm. Serious adverse events were also less frequent in the Lutetium arm (17.1%) compared to the ARPI arm (23.1%). Discontinuation rates were notably lower in the Lutetium arm (1.9%) compared to the ARPI arm (6.2%), and dose reductions were minimal (1.1%).
Impact of Crossover on Overall Survival
Overall survival (OS) was similar between the two arms, with a hazard ratio of 1.11. However, a significant 84.6% of eligible patients in the ARPI arm crossed over to the Lutetium-177 arm after progression, which likely confounded the OS analysis. Adjusted analyses, though not primary endpoints, also indicated positive trends.
Expert Commentary
According to Dr. Oliver Sartor from the Mayo Clinic, the unique dosing schedule of Lutetium-177-PNT2002 (6.8 gigabecquerels every eight weeks for four cycles) differentiates it from Lutetium-177-PSMA-617, which is typically dosed at 7.4 gigabecquerels every six weeks for up to six doses. The SPLASH trial's dosing regimen was influenced by FDA guidance. Dr. Sartor also noted that while renal toxicity was minimal, salivary toxicity might be slightly less with Lutetium-177-PNT2002 due to the dosing schedule. He emphasized the importance of considering tolerability and the potential for a “kinder or gentler therapy” when choosing between different agents.
Future Directions
The field of radiopharmaceuticals is rapidly evolving, with ongoing research focused on dose optimization, alpha particles, new isotopes (such as lead-212 and actinium), and combination therapies. The SPLASH trial provides valuable insights into the role of Lutetium-177-PNT2002 in the treatment of advanced prostate cancer, offering clinicians another option to consider in their treatment strategies.
