Regulatory Divergence in PSMA Targeted Therapy: Implications for European Market Access

Novartis withdrew its European Medicines Agency (EMA) application to expand the indication for Pluvicto® (lutetium (177Lu) vipivotide tetraxetan). The company sought to include adult patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have not yet received chemotherapy. The Committee for Medicinal Products for Human Use (CHMP) determined that the control arm in the supporting PSMAfore Phase 3 study was not adequate to support approval in the European Union.

Regulatory Split Across the Atlantic

The withdrawal highlights a clear transatlantic difference in how the same clinical evidence is interpreted. While PSMA targeted therapy with Pluvicto gained approval for pre-chemotherapy mCRPC in the United States, Japan, and China based on the PSMAfore study, European regulators found the chosen comparator arm insufficient. This decision does not reflect any concerns about the quality, efficacy, or safety of Pluvicto and has no impact on its existing approved indications or ongoing trials outside the EU.

Despite the CHMP’s position, multiple leading medical societies strongly endorse the clinical value of PSMA targeted therapy in this earlier treatment setting. Guidelines from the European Society for Medical Oncology (ESMO), European Association of Urology (EAU), American Society of Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN) all support its use. The discrepancy underscores how differing expectations around comparator selection can restrict patient access even when robust evidence and clinical consensus exist.

Design of the PSMAfore Trial

The PSMAfore trial was a multicenter, open-label, randomized Phase 3 study that compared 177Lu-PSMA-617 to a switch in second-line androgen receptor pathway inhibitor (ARPI) therapy in taxane-naïve patients with PSMA-positive mCRPC who had progressed after one prior ARPI. European regulators questioned the suitability of this control arm in the European treatment context. In contrast, the same dataset met the evidentiary standards of the FDA, Japan’s PMDA, and China’s NMPA, leading to successful label expansions in those regions.

Market Access and Health Economic Implications

This outcome creates immediate challenges for radioligand therapy adoption across Europe. By limiting the approved use of Pluvicto to post-chemotherapy mCRPC, the decision restricts earlier-line access despite strong guideline recommendations and real-world evidence of benefit. From a health economics standpoint, it may negatively affect cost-effectiveness assessments, incremental cost-effectiveness ratios (ICERs), and overall budget impact, as the therapy’s full value is best realized before chemotherapy exposure.

The situation also signals broader difficulties in securing aligned global access for innovative oncology treatments. It is likely to influence future trial designs, with sponsors potentially needing region-specific comparator arms to satisfy varying regulatory expectations. Novartis has reaffirmed its commitment to prostate cancer research and may pursue additional studies or a revised submission to address the CHMP’s concerns.

(Source: Novartis withdraws EMA application for Pluvicto expansion)