SPLASH: 177Lu-PNT2002 achieves phase 3 outcomes for mCRPC

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) 177Lu-PNT2002, an investigative therapy from Lantheus, was associated with a 29% improvement in median risk of radiographic progression or death versus standard therapy in patients with metastatic castration-resistant prostate cancer (mCRPC), according to new findings from the phase 3 SPLASH trial.¹

The data, presented by study author Oliver Sartor, MD, director of radiopharmaceutical trials and professor of medical oncology at the Mayo Clinical during the European Society for Medical Oncology (ESMO) 2024 Congress in Barcelona, Spain, this week, showed 177Lu-PNT2002 additionally provided a 58.3% improved median radio progression-free survival duration compared to androgen receptor pathway inhibitors in patients with mCRPC.

177Lu-PNT2002 received a Fast Track designation for the treatment of mCRPC from the US Food and Drug Administration (FDA) in April 2023.

The new SPLASH data presented at ESMO 2024 proceed interim findings published in December 2023 showing the significant improvement in rPFS versus ARPI.² The latest update presented by Sartor included findings of significantly improved objective response rate (ORR), prostate-specific antigen reduction of ≥50% (PSA50), time to reduction of health-related quality of life (HRQoL), and time to opioid use due to cancer-associated patient among patients with PSMA-positive mCRPC who received 177Lu-PNT2002 after progressing on ARPI.¹

Sartor and colleagues additionally observed an 11% improvement in overall survival (OS) with the investigative therapy versus ARPI (hazard ratio [HR], 1.11; 95% CI, 0.73 – 1.69; P = .6154).

“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,” Sartor said in a statement accompanying the ESMO 2024 data. “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.”³

The phase 3, multicenter, randomized, open-label SPLASH trial assessed a 6.8 GBq dose of 177Lu-PNT2002 for ≤4 cycles in patients with PSMA-expressing mCRPC who had progressed on ARPI and were not receiving chemotherapy. Investigators randomized 412 multinational participants 2:1 to either investigative therapy or either abiraterone or enzalutamide. The trial’s protocol stipulated that patients in the latter arm who experience radiographic progression may cross over to the investigational therapy; at the time of the primary analysis, 84.6% of patients initially administered an ARPI dose switched to 177Lu-PNT2002.¹

All patients who receive 177Lu-PNT2002 are scheduled for follow-up through 5 years after the initial dose. Investigators are seeking a primary outcome of rPFS.

In the ESMO presentation, Sartor reported an HR of 0.71 for rPFS in patients treated with 177Lu-PNT2002 versus ARPI (95% CI, 0.55 – 0.92; P = .0088). Median rPFS was 9.5 months versus 6.0.

Additionally, ORR per blinded independent central review was 38.1% in the treatment arm, versus 12.0% in the control arm (P = .0021). More than one-third of 177Lu-PNT2002 patients achieved PSA50 response (35.7%), versus only 14.6% of the ARPI arm. Median duration of response was 9.4 months with the investigative therapy, versus 7.3 months. Treated patients additionally reported a 36% improved time to opioid use due to cancer-related pain (HR, 0.64; 95% CI, 0.42 – 0.98; P = .0366).

Regarding safety outcomes, investigators observed a favorable profile with 177Lu-PNT2002. Just 3.0% of patients on the therapy halted or reduced their regimen due to treatment-emergent adverse events (TEAEs), versus 11.5% of patients receiving ARPI. Another 17.1% of patients on treatment reported a serious TEAE, versus 23.1% of the control arm.

In a statement accompanying the new data, Jeff Humphrey, MD, chief medical officer of Lantheus, praised the further promising outcomes in the SPLASH trial and expressed optimism for the RLT’s future role in treating prostate cancer.³

“177Lu-PNT2002 is outperforming the control arm and showing an improved quality of life for patients based on this interim analysis,” Humphrey said. “We are grateful to the patients and investigators who participated in this trial thereby helping to advance this important potential treatment option.”

References

1. ^{Sartor O, et al. Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (ARPI) (SPLASH). Poster presented at: ESMO Congress 2024. Barcelona, Spain. September 13 – 17, 2024.}
2. ^{Clarke H. 177Lu-PNT2002 shows initial safety and efficacy in mCRPC. Urology Times. Published online December 19, 2023. Accessed September 15, 2024. https://www.urologytimes.com/view/177lu-pnt2002-shows-initial-safety-and-efficacy-in-mcrpc}
3. ^{GlobeNewswire. Lantheus Presents Results from the Primary Analysis of Phase 3 Pivotal SPLASH Trial in PSMA-Positive Metastatic Castration-Resistant Prostate Cancer During ESMO Congress 2024. Press release. Published September 15, 2024. Accessed September 15, 2024. https://www.morningstar.com/news/globe-newswire/9230188/lantheus-presents-results-from-the-primary-analysis-of-phase-3-pivotal-splash-trial-in-psma-positive-metastatic-castration-resistant-prostate-cancer-during-esmo-congress-2024}