The Phase 3 SPLASH trial results, presented at the European Society for Medical Oncology (ESMO) 2024 Congress, reveal that 177Lu-PNT2002, a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), significantly improves outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on androgen receptor pathway inhibitors (ARPI). The study demonstrated a 29% reduction in the risk of radiographic progression or death compared to standard ARPI therapy.
The multicenter, randomized, open-label SPLASH trial enrolled 412 patients with PSMA-expressing mCRPC who had progressed on ARPI and were not receiving chemotherapy. Participants were randomized 2:1 to receive either 6.8 GBq of 177Lu-PNT2002 for up to 4 cycles or abiraterone or enzalutamide. Patients in the control arm were allowed to cross over to the investigational therapy upon radiographic progression; 84.6% of patients initially on ARPI switched to 177Lu-PNT2002.
Efficacy Outcomes
Oliver Sartor, MD, director of radiopharmaceutical trials at the Mayo Clinic and study author, reported a hazard ratio (HR) of 0.71 for radiographic progression-free survival (rPFS) in patients treated with 177Lu-PNT2002 versus ARPI (95% CI, 0.55 – 0.92; P = .0088). The median rPFS was 9.5 months in the 177Lu-PNT2002 arm compared to 6.0 months in the ARPI arm.
Furthermore, the objective response rate (ORR) per blinded independent central review was 38.1% in the 177Lu-PNT2002 arm, versus 12.0% in the control arm (P = .0021). A prostate-specific antigen (PSA) reduction of ≥50% (PSA50) was achieved in 35.7% of patients in the 177Lu-PNT2002 arm, compared to 14.6% in the ARPI arm. The median duration of response was 9.4 months with 177Lu-PNT2002 versus 7.3 months with ARPI. The study also showed a 36% improvement in time to opioid use due to cancer-related pain (HR, 0.64; 95% CI, 0.42 – 0.98; P = .0366).
Overall Survival and Safety
While the trial demonstrated an 11% improvement in overall survival (OS) with 177Lu-PNT2002 versus ARPI, this difference was not statistically significant (HR, 1.11; 95% CI, 0.73 – 1.69; P = .6154). However, the researchers noted positive interim crossover-adjusted overall survival hazard ratios.
The safety profile of 177Lu-PNT2002 was favorable, with only 3.0% of patients halting or reducing their regimen due to treatment-emergent adverse events (TEAEs), compared to 11.5% of patients receiving ARPI. Serious TEAEs were reported in 17.1% of patients on 177Lu-PNT2002 versus 23.1% in the control arm.
Clinical Implications
These results suggest that 177Lu-PNT2002 could offer a significant benefit for patients with PSMA-positive mCRPC who have progressed on ARPI therapy. The observed improvements in rPFS, ORR, PSA response, and quality of life, coupled with a manageable safety profile, position 177Lu-PNT2002 as a promising treatment option in a setting where limited choices are available. The FDA granted Fast Track designation to 177Lu-PNT2002 in April 2023 for the treatment of mCRPC.
Jeff Humphrey, MD, chief medical officer of Lantheus, stated that the interim analysis suggests an improved quality of life for patients receiving 177Lu-PNT2002. All patients who receive 177Lu-PNT2002 are scheduled for follow-up through 5 years after the initial dose, with the primary outcome being rPFS.
