Eli Lilly's lutetium zadavotide guraxetan (177Lu-PNT2002) has shown promising results in the Phase III SPLASH trial for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) who have progressed on one line of androgen receptor pathway inhibitors (ARPIs). The data, presented at the European Society of Medical Oncology (ESMO) Congress 2024, compared 177Lu-PNT2002 to ARPIs like Astellas’ Xtandi (enzalutamide) or Janssen’s Zytiga (abiraterone acetate).
Mechanism of Action and Trial Design
177Lu-PNT2002 comprises a ligand that binds to prostate-specific membrane antigen (PSMA) on prostate cancer cells, facilitating drug internalization, and a radioisotope emitting radiation to destroy nearby cancerous cells. The SPLASH trial's primary endpoint was radiographic progression-free survival (rPFS). The trial design addressed a critical need for effective treatments in mCRPC patients who have progressed on initial ARPI therapy.
Efficacy and Survival Analysis
The first interim analysis of the SPLASH trial revealed that 177Lu-PNT2002 achieved a median rPFS of 9.5 months (95% CI: 7.4, 10.0), while the ARPI arm had a median rPFS of 6 months (95% CI: 4.7, 7.9), with a hazard ratio (HR) of 0.71 (95% CI: 0.55, 0.92, p = 0.0088). However, the overall survival (OS) analysis initially showed a hazard ratio (HR) of 1.14 (95% confidence interval [CI]: 0.54, 2.53), favoring the control arm. This was largely influenced by a high crossover rate (84.6%) from the control arm to the 177Lu-PNT2002 arm. After adjusting for crossover, the HR for OS was reduced to 0.68 (95% CI: 0.44, 1.04), suggesting a potential survival benefit.
Regulatory and Market Landscape
Despite the initial negative OS result, the FDA might view 177Lu-PNT2002 favorably, considering the high crossover rate, similar to the approval of Novartis’ Pluvicto (lutetium vipivotide tetraxetan) based on the VISION trial. GlobalData’s analyst consensus forecast projects 177Lu-PNT2002 sales reaching $1.7 billion by 2030, while Pluvicto is expected to reach $4.3 billion in the same period. Eli Lilly aims to compete with Pluvicto, which is already undergoing label expansion trials, such as the Phase II UpFrontPSMA trial in metastatic hormone-sensitive prostate cancer (mHSPC).
Dosing and Administration Advantages
177Lu-PNT2002 presents a more convenient dosing schedule compared to Pluvicto, involving a lower dosage (6.8 GBq versus 7.4 GBq), longer intervals between cycles (eight weeks versus six weeks), and fewer cycles (four cycles versus six). This patient-friendly regimen could influence treatment preferences among physicians and patients.
