Lantheus Holdings presented positive results from the primary analysis of its Phase 3 SPLASH trial, evaluating 177Lu-PNT2002 in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on androgen receptor pathway inhibitor (ARPI) therapy. The data, presented at the European Society of Medical Oncology (ESMO) Congress 2024, highlight the potential of 177Lu-PNT2002 as a treatment option for this patient population with limited choices.
The SPLASH trial met its primary endpoint, demonstrating a statistically significant improvement in radiographic progression-free survival (rPFS). Patients treated with 177Lu-PNT2002 had a median rPFS of 9.5 months compared to 6.0 months for those on ARPI, resulting in a 29% reduction in the risk of radiographic progression or death (HR 0.71; p = 0.0088).
Efficacy and Response Rates
Beyond the primary endpoint, 177Lu-PNT2002 also showed encouraging results in several secondary endpoints. The objective response rate (ORR) was 38.1% in the 177Lu-PNT2002 arm compared to 12.0% in the ARPI arm (p = 0.0021). Furthermore, 35.7% of patients in the 177Lu-PNT2002 arm achieved a PSA50 reduction compared to 14.6% in the ARPI arm. The median time to deterioration in health-related quality of life, as measured by the Functional Assessment of Cancer Therapy—Prostate (FACT-P), was 8.1 months for 177Lu-PNT2002 versus 5.3 months for ARPI (HR 0.59; p = 0.0005).
Overall Survival and Safety
Interim overall survival (OS) data, with 46% of protocol-specified target OS events reached, showed a hazard ratio of 1.11 (0.73, 1.69; p = 0.6154). However, crossover-adjusted HRs using various methods suggested a potential survival benefit with 177Lu-PNT2002, with hazard ratios ranging from 0.68 to 0.85. Notably, 84.6% of patients in the control arm crossed over to receive 177Lu-PNT2002 after disease progression.
The safety profile of 177Lu-PNT2002 was also favorable, with fewer treatment-emergent adverse events (TEAEs) leading to therapy discontinuation or reduction compared to ARPI (3.0% vs. 11.5%). Serious TEAEs were also less frequent in the 177Lu-PNT2002 arm (17.1% vs. 23.1%).
Implications and Future Directions
"We are encouraged by the initial results from the SPLASH trial, with 177Lu-PNT2002 demonstrating improvement compared to ARPI change in radiographic progression-free survival, positive interim crossover-adjusted overall survival hazard ratios, as well as improved quality of life," said Oliver Sartor, M.D., Director of Radiopharmaceutical Trials and Professor of Medical Oncology at the Mayo Clinic in Rochester, Minnesota. "These initial data underscore the importance of PSMA-targeted RLTs, including 177Lu-PNT2002, as potential treatment options for patients who have limited choices after progressing on ARPI therapy."
The findings from the SPLASH trial suggest that 177Lu-PNT2002 could offer a valuable treatment option for patients with mCRPC who have progressed on ARPI therapy. Further maturation of the overall survival data is anticipated to provide a more comprehensive understanding of the treatment's long-term benefits. Lantheus expects to provide an update once data are available for 75% of protocol-specified target OS events.
