Lantheus Holdings presented primary analysis results from the Phase 3 SPLASH trial of 177Lu-PNT2002, a PSMA-targeted radioligand therapy, at the ESMO Congress 2024 in Barcelona. The study focused on patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on androgen receptor pathway inhibitor (ARPI) therapy. The SPLASH trial met its primary endpoint, demonstrating a statistically significant improvement in radiographic progression-free survival (rPFS).
Improved Radiographic Progression-Free Survival
The SPLASH trial revealed that patients treated with 177Lu-PNT2002 had a median rPFS of 9.5 months, compared to 6.0 months for those in the ARPI control arm. This represents a 29% reduction in the risk of radiographic progression or death, with a hazard ratio (HR) of 0.71 (p=0.0088).
Significant Overall Response Rate
In addition to the primary endpoint, the study showcased a significantly higher overall response rate (ORR) in the 177Lu-PNT2002 arm. The ORR was 38.1% compared to 12.0% in the ARPI arm (p=0.0021). Notably, 9.3% of patients in the 177Lu-PNT2002 arm achieved complete responses.
Enhanced Quality of Life
Patients receiving 177Lu-PNT2002 also experienced a statistically significant improvement in the time to reduction of health-related quality of life (HRQoL), as measured by the Functional Assessment of Cancer Therapy—Prostate (FACT-P). The median time to deterioration by FACT-P was 8.1 months in the 177Lu-PNT2002 arm versus 5.3 months in the control arm (HR 0.59; CI: 0.44, 0.80; p =0.0005).
Interim Overall Survival Data
While the overall survival (OS) data are still maturing, interim results, with 46% of protocol-specified target OS events reached, showed a hazard ratio of 1.11 (0.73, 1.69; p=0.6154). Crossover-adjusted hazard ratios, using methods such as Two-Stage and Inverse Probability Censoring Weighting, were <1.00, suggesting a potential survival benefit. Further updates are expected once data are available for 75% of the protocol-specified target OS events.
Favorable Safety Profile
177Lu-PNT2002 demonstrated a favorable safety profile compared to the ARPI control arm. Only 3.0% of patients treated with 177Lu-PNT2002 halted or reduced therapy due to treatment-emergent adverse events (TEAEs), compared to 11.5% in the ARPI arm. Serious TEAEs were also less frequent in the 177Lu-PNT2002 arm (17.1%) compared to the ARPI arm (23.1%).
Study Design
The Phase 3 SPLASH trial is a multicenter, randomized, open-label study that randomized 412 patients with PSMA-expressing mCRPC who had progressed on ARPI therapy. Patients were randomized 2:1 to receive either 177Lu-PNT2002 or ARPI (abiraterone or enzalutamide). Patients in the ARPI arm who experienced radiographic progression were allowed to crossover to receive 177Lu-PNT2002.
Expert Commentary
Oliver Sartor, M.D., Director of Radiopharmaceutical Trials and Professor of Medical Oncology at the Mayo Clinic in Rochester, Minnesota, stated, “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.”
About 177Lu-PNT2002
177Lu-PNT2002 is a PSMA-targeted radioligand therapy candidate that combines a PSMA-targeted ligand, PSMA-I&T, with the beta-emitting radioisotope lutetium-177. Lantheus holds exclusive worldwide commercialization rights (excluding certain Asian territories) to 177Lu-PNT2002, in-licensed from POINT Biopharma (a Lilly company). The FDA granted Fast Track designation for 177Lu-PNT2002 in April 2023 for the treatment of mCRPC.
