Novartis' Pluvicto (lutetium (177Lu) vipivotide tetraxetan) has demonstrated a clinically meaningful and statistically significant benefit in radiographic progression-free survival (rPFS) for patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) following androgen receptor pathway inhibitor (ARPI) therapy. The Phase III PSMAfore trial results, presented at the 2023 European Society for Medical Oncology (ESMO) Congress, indicate a potential shift in the treatment paradigm for advanced prostate cancer.
Efficacy and Outcomes
The PSMAfore trial met its primary endpoint, showing a 59% reduction in the risk of radiographic disease progression with Pluvicto compared to a change in ARPI (HR 0.41; 95% CI: 0.29, 0.56; p<0.0001). An updated analysis, with a median of 8.6 months longer follow-up, confirmed the clinical benefit, more than doubling the median rPFS to 12.0 months versus 5.6 months with ARPI change (HR 0.43; 95% CI: 0.33, 0.54).
"The rPFS data are impressive and the treatment effect is comparable with what was observed in the VISION trial," said Dr. Oliver Sartor, PSMAfore Co-Principal Investigator. "We look forward to a future where Pluvicto may be a viable therapy for patients in need of alternative, earlier options."
Quality of Life Improvements
Patients treated with Pluvicto experienced improved quality of life, maintaining their FACT-P total score for 3 months longer (7.5 vs. 4.3 months) and delaying worsening pain (BPI-SF) by 5.0 versus 3.7 months compared to those on ARPI change. A PSA decline of at least 50% was also more than 2.5 times more frequent with Pluvicto.
Safety Profile
The trial demonstrated a favorable safety profile for Pluvicto, with most adverse events being Grade 1-2. The most frequently reported all-grade AEs included dry mouth (57.3%), asthenia (31.7%), nausea (31.3%), anemia (24.2%), and fatigue (22.9%).
Overall Survival Data
At the second interim OS analysis (45% of events), the pre-specified crossover-adjusted OS analysis showed a hazard ratio of 0.80 (95% CI: 0.48, 1.33). However, the unadjusted intent-to-treat OS analysis was confounded by a high crossover rate (84%) to Pluvicto after ARPI discontinuation due to radiographic progression. The trial is ongoing to assess OS, with the next interim analysis expected in 2024.
Implications for Treatment Paradigm
"These promising results from PSMAfore could change the treatment paradigm for advanced prostate cancer by allowing patients to potentially avoid or delay taxane-based chemotherapy, which carries a heavy burden of side effects," said Jeff Legos, Executive Vice President, Global Head of Oncology Development at Novartis.
About the PSMAfore Study
The PSMAfore study (NCT04689828) is a Phase III, open-label, multi-center, 1:1 randomized trial comparing Pluvicto to a change in ARPI (abiraterone or enzalutamide) in PSMA-positive mCRPC patients who have not received taxane-containing regimens. The primary endpoint was rPFS, and a key secondary endpoint is overall survival (OS).
About Pluvicto
Pluvicto is an intravenous radioligand therapy (RLT) that combines a targeting compound (ligand) with a therapeutic radionuclide (lutetium-177). It binds to PSMA-expressing cells, including prostate cancer cells, delivering targeted radiation to disrupt replication and induce cell death. Pluvicto is approved in the U.S., E.U., and other countries for PSMA-positive mCRPC patients who have been treated with ARPI and taxane-based chemotherapy.
