On 15 September 15 2024 results for the Phase III SPLASH trial were presented at the European Society of Medical Oncology (ESMO) Congress 2024.

The trial compares Eli Lilly’s lutetium zadavotide guraxetan (177Lu-PNT2002) with the androgen receptor pathway inhibitors (ARPIs), Astellas’s Xtandi (enzalutamide) or Janssen’s Zytiga (abiraterone acetate), in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) positive for prostate-specific membrane antigen (PSMA) who have progressed on one line of ARPIs.

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177Lu-PNT2002 is formed of two components: a ligand that binds to PSMA on the surface of prostate cancer cells, which then internalises the drug, and a radioisotope that emits radiation, which destroys nearby cancerous cells. Novartis’s Pluvicto (lutetium vipivotide tetraxetan) was already approved in this setting in 2023 after positive results from its Phase III VISION trial.

The FDA is likely to look favourably on 177Lu-PNT2002

The majority of the results presented at ESMO in 2024 had previously been published, but the presenter explained that there had not been enough events to conduct the second interim analysis. This is likely due to the 84.6% of patients who progressed on the control crossing over to receive 177Lu-PNT2002. The most recent overall survival (OS) analysis showed a hazard ratio (HR) of 1.14 (95% confidence interval [CI]: 0.54, 2.53), which would indicate that the control arm had a better survival rate than the experimental arm.

However, when adjusted for crossover, the HR was reduced to 0.68 (95% CI: 0.44, 1.04). The efficacy of the drug is demonstrated by it reaching its primary endpoint, radiographic progression-free survival (rPFS). In its first interim analysis, 177Lu-PNT2002 had a median rPFS of 9.5 months (95% CI: 7.4, 10.0) while the alternate ARPI arm had a median rPFS of 6 months (95% CI: 4.7, 7.9) with an HR of 0.71 (95% CI: 0.55, 0.92, p = 0.0088). Key opinion leaders are concerned that the control was inappropriate. However, the current ESMO treatment guidelines note that a patient who has progressed on either Xtandi or Zytiga is to receive docetaxel.

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Despite the negative OS result, the FDA is likely to look favourably on 177Lu-PNT2002 due to the high proportion of patients crossing over from the control to the experimental arm. Pluvicto’s Vision trial, which saw a similar crossover rate and therefore no significant increase in OS over ARPIs, ended with an FDA approval. GlobalData’s analyst consensus forecast estimates that 177Lu-PNT2002 will reach sales of $1.7 billion in 2030 while Pluvicto will reach sales of $4.3 billion in the same year. Eli Lilly must catch up in this space, as Pluvicto is already in label expansion trials, such as the Phase II UpFrontPSMA trial in metastatic hormone-sensitive prostate cancer (mHSPC), which also presented positive data in the same ESMO session.

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However, 177Lu-PNT2002 has a distinct advantage over Pluvicto, as it has a lower dosage (6.8 GBq versus 7.4 GBq), a longer duration between each cycle (eight weeks versus six weeks), and a reduced number of cycles (four cycles versus six). It remains to be seen whether physicians and patients will end up favouring the newer therapy with the more patient-friendly dosing over the first-in-class Pluvicto.