By Fineline Cube 
Novartis AG (NYSE: NVS) announced the voluntary withdrawal of its Type II variation application to the European Medicines Agency (EMA) seeking approval of Pluvicto™ (lutetium Lu 177 vipivotide tetraxetan) for prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) in patients prior to chemotherapy.
The decision follows feedback from the EMA’s Committee for Medicinal Products for Human Use (CHMP), which indicated it would not support approval due to concerns over the control arm design in the pivotal PSMAfore Phase III trial. Novartis emphasized the withdrawal is unrelated to Pluvicto’s quality, efficacy, or safety profile and does not impact existing approvals, ongoing trials, or other regulatory submissions globally.
Regulatory Context & Trial Background
| Element | Detail |
|---|---|
| Drug | Pluvicto™ (¹⁷⁷Lu-PSMA-617), a radioligand therapy |
| Indication Sought | Pre-chemotherapy PSMA-positive mCRPC |
| Pivotal Study | PSMAfore (NCT04689828) – randomized vs. second-generation androgen receptor pathway inhibitors (ARPIs) |
| CHMP Concern | Control arm lacked cross-over design or direct comparator to standard-of-care sequencing |
| Global Approvals | Already approved for this indication in U.S., Japan, and China based on same data |
| Current EU Status | Approved only for post-chemotherapy mCRPC (since 2023) |
Clinical & Commercial Implications
- U.S. Benchmark: FDA accepted the ARPI control arm, citing unmet need in pre-chemo setting; median rPFS benefit was significant (HR 0.43).
- EU Divergence: CHMP appears to require more stringent comparators (e.g., docetaxel or head-to-head vs. newer agents like darolutamide).
- Revenue Impact: Limited near-term effect—Pluvicto generated $1.2 billion in 2025, with >80% from U.S. and post-chemo use.
- Path Forward: Novartis may resubmit with additional real-world evidence or initiate a new EU-specific trial with modified design.
Strategic Positioning in Radioligand Therapy
- Franchise Strength: Pluvicto remains the first and only approved PSMA-targeted radioligand therapy globally.
- Pipeline Expansion: Ongoing trials in earlier disease settings (metastatic hormone-sensitive PC) and combination regimens (with PARP inhibitors, immunotherapy).
- Manufacturing Scale: Novartis has invested >$1 billion in global radioligand production capacity, signaling long-term commitment despite regional setbacks.
Forward‑Looking Statements
This brief reflects current regulatory developments. Future submissions, trial outcomes, and market access decisions remain subject to evolving agency requirements and clinical data.-Fineline Info & Tech