Lu-PSMA Radioligand Therapy Shows Consistent Efficacy in mHSPC

Data presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting showed that Pluvicto™ (lutetium Lu 177 vipivotide tetraxetan) plus standard of care (androgen receptor pathway inhibitor [ARPI] + androgen deprivation therapy [ADT]) improved radiographic progression-free survival (rPFS) consistently across key subgroups in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC). Results from the phase II UpFrontPSMA trial, presented at the 2026 European Association of Urology (EAU) Annual Meeting, also showed that adding 177Lu-PSMA-617 to docetaxel improved outcomes in this setting.

In the PSMAddition subgroup analysis, Pluvicto demonstrated rPFS improvement regardless of disease volume (high or low) or metastatic presentation (de novo or recurrent), consistent with the primary endpoint showing a 28% reduction in the risk of radiographic progression or death (HR 0.72; 95% CI: 0.58, 0.90). The following hazard ratios were reported:

• Overall (n=1,114): HR 0.72 (0.58 – 0.90)
• High volume disease (n=779): HR 0.72 (0.56 – 0.92)
• Low volume disease (n=365): HR 0.73 (0.42 – 1.27)
• De novo (n=572): HR 0.74 (0.54 – 1.01)
• Recurrent (n=523): HR 0.74 (0.53 – 1.04)

The safety profile was generally consistent across subgroups. Grade ≥3 adverse events were reported in 50.7% of patients in the Pluvicto plus SoC arm versus 43% on SoC alone. The most common all-grade adverse events were dry mouth, fatigue, nausea, hot flush and anemia.

The phase III PSMAddition trial also demonstrated a significant improvement in rPFS with the addition of Pluvicto to ADT plus ARPI. At the time of the interim analysis, overall survival was immature and had not reached statistical significance. Data discussed at EAU 2026 noted that while time to worsening in pain intensity was similar between groups, the FACT-P analysis suggested an earlier deterioration in health-related quality of life in the combination arm, though more recent data presented at ASCO GU indicate these changes stabilize and recover after the treatment period.

More than 186,000 men are diagnosed annually with mHSPC globally, and most progress to castration-resistant disease within 20 months. The PSMA biomarker is present in more than 80% of patients with prostate cancer. Based on PSMAddition results, Novartis has filed regulatory submissions in the US, China and Japan, with first decisions expected in H2 2026.

At the EAU meeting, results from the UpFrontPSMA trial — the first randomized study evaluating 177Lu-PSMA-617 earlier in the disease course — showed that two cycles of 177Lu-PSMA-617 followed by six cycles of docetaxel met its primary endpoint of undetectable PSA at 48 weeks. In de novo high-volume mHSPC, 41% of patients in the combination arm achieved undetectable PSA at one year versus 16% with docetaxel alone. Grade 3–4 adverse events occurred in 29% of patients receiving the combination versus 27% with docetaxel alone. The presenter emphasized that the regimen was well tolerated, with most toxicity likely attributable to the backbone therapies, and noted this was a phase II study that should be considered hypothesis-generating.

Novartis also presented promising Phase 1 data from the AcTION trial for its investigational actinium-based radioligand therapy, 225Ac-PSMA-617, showing early antitumor activity with PSA declines and radiographic responses, as well as a manageable safety profile in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Two Phase 3 trials are enrolling: PSMAcTION evaluating 225Ac-PSMA-617 in mCRPC after Pluvicto, chemotherapy and ARPI, and AcTFirst evaluating it in frontline mCRPC.