Pluvicto™ demonstrated consistent efficacy across key patient subgroups in metastatic hormone-sensitive prostate cancer

Novartis' Pluvicto Shows Consistent Efficacy in mHSPC Subgroups

Novartis announced that Pluvicto (lutetium Lu 177 vipivotide tetraxetan) plus standard of care (SoC) showed consistent radiographic progression-free survival (rPFS) improvement across key subgroups in PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC). Data from the Phase 3 PSMAddition trial, presented at ASCO 2026, revealed a 28% reduction in the risk of radiographic progression or death (HR 0.72; 95% CI: 0.58, 0.90) with Pluvicto plus SoC compared to SoC alone. This consistency was observed regardless of disease volume (high or low) or presentation (de novo or recurrent mHSPC), supporting its potential for early use. The safety profile was generally consistent across subgroups.

• The PSMAddition trial demonstrated consistent rPFS improvement with Pluvicto plus SoC across all evaluated subgroups. The overall hazard ratio for radiographic progression or death was 0.72 (95% CI: 0.58, 0.90). Specifically, for high volume disease, the HR was 0.72 (0.56 – 0.92); for low volume disease, 0.73 (0.42 – 1.27); for de novo mHSPC, 0.74 (0.54 – 1.01); and for recurrent mHSPC, 0.74 (0.53 – 1.04), reinforcing broad clinical applicability.
• Consistent secondary endpoint results, including PSA progression and time to mCRPC, further supported the primary findings. The safety profile was generally consistent across subgroups, with Grade ≥3 adverse events reported in 50.7% of patients in the Pluvicto plus SoC arm versus 43% on SoC alone. The most common all-grade adverse events included dry mouth, fatigue, nausea, hot flush, and anemia.
• Novartis has filed regulatory submissions for Pluvicto in the US, China, and Japan based on PSMAddition results, with first decisions anticipated in H2 2026. Additionally, promising Phase 1 data for Novartis' investigational actinium-based radioligand therapy, 225Ac-PSMA-617, from the AcTION trial, showed early antitumor activity and a manageable safety profile, supporting its ongoing development in two Phase 3 trials (PSMAcTION and AcTFirst) for mCRPC.

Pluvicto's Consistent Efficacy in PSMA+ mHSPC Subgroups

Recent clinical trial data demonstrates strong therapeutic outcomes across multiple treatment approaches for metastatic hormone-sensitive prostate cancer. The ARASENS and ARANOTE phase III trials evaluated darolutamide combined with androgen deprivation therapy in 1,974 patients, showing compelling survival benefits with risk of death reduction to 0.56 at one year, 0.76 at two years, and 0.75 at three years compared to placebo. These trials also demonstrated decreased risk of progression to castration-resistant prostate cancer within three years, with consistent overall survival benefits maintained across diverse patient subgroups stratified by demographic and clinical characteristics. The ARON-3 international multicenter study examined enzalutamide in 424 patients across 29 cancer centers, achieving a median time on treatment of 31.8 months with 76% of patients reaching PSA90 response and 59% achieving ultra-low PSA levels ≤0.2 ng/ml.

Network meta-analysis data reveals darolutamide triplet therapy demonstrates superior progression-free survival (HR 0.24, 95% CI 0.20-0.29) and overall survival (HR 0.54, 95% CI 0.44-0.66) compared to other treatment combinations. Comparative effectiveness studies of androgen receptor pathway inhibitors show equivalent outcomes when baseline characteristics are balanced, with 2-year progression-free survival rates of 74.1% for abiraterone acetate, 81.4% for apalutamide, and 85.6% for enzalutamide. The ENZAMET trial emulation analysis demonstrated that early docetaxel addition to enzalutamide did not improve survival regardless of disease volume, while docetaxel benefit was preserved when enzalutamide was not used, particularly in high-volume disease.

Safety profiles demonstrate distinct tolerability patterns across interventions, with darolutamide showing comparable toxicity to ADT alone (OR 0.99, 95% CI 0.71-1.39) while other ARPIs exhibited higher toxicity risks. Enzalutamide demonstrated increased risks of hypertension (OR 2.03) and fatigue (OR 3.22) compared to darolutamide, while abiraterone showed higher hypertension risk (OR 3.18). The EXTRA-PC phase II trial investigating masofaniten with enzalutamide achieved 77% PSA response <0.2 ng/mL at six months with acceptable safety, supporting continued development of dual androgen receptor blockade strategies. Grade 3-4 adverse events occurred in 9-10% of enzalutamide patients regardless of age, while comparative studies showed grade ≥3 events in 36.2% for docetaxel combinations, 10.9% for ARPI combinations, and 31.8% for triplet therapy regimens.

Positioning Pluvicto in the Evolving mHSPC Landscape

The standard-of-care landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has been substantially shaped by the demonstrated efficacy of new-generation androgen receptor signaling inhibitors (ARSIs) combined with androgen deprivation therapy. A comprehensive meta-analysis of seven trials encompassing 7,544 patients showed that adding new-generation anti-androgens (abiraterone, apalutamide, darolutamide, or enzalutamide) to ADT significantly improved overall survival with a pooled hazard ratio of 0.66 (95% CI, 0.61-0.71; P < 0.00001) and extended failure-free survival (pooled HR, 0.43; 95% CI, 0.39-0.47; P < 0.00001). These combination therapies have become the established standard, with abiraterone specifically improving median overall survival from 36.5 months to 53.3 months compared to medical castration alone.

Real-world evidence from recent studies provides nuanced insights into the comparative performance of different ARSIs in clinical practice. A 2024 retrospective analysis of 82 mHSPC patients revealed that enzalutamide and apalutamide demonstrated superior efficacy compared to bicalutamide, with enzalutamide significantly prolonging PSA-progression-free survival (HR 2.244; 95% CI 1.366-3.685, p=0.001) and overall survival (HR 2.06; 95% CI 1.183-3.585; P=0.005). Notably, abiraterone in combination with ADT did not demonstrate significant advantages in delaying disease progression when compared with other ARSIs, while enzalutamide and apalutamide exhibited preeminent efficacy with no substantial difference between these two agents.

Investigational approaches have yielded mixed results when compared to established standards of care. The randomized phase II SWOG S0925 trial testing cixutumumab, an insulin-like growth factor I receptor inhibitor, combined with androgen deprivation in 210 patients showed no improvement in overall survival (HR 1.01 [0.70-1.45]; p = 0.97), radiographic progression-free survival, or castration resistance-free survival compared to ADT alone. Additionally, emerging evidence suggests that PSMA-PET guided treatment intensification may require prospective validation, as retrospective data indicate that ARSI intensification did not improve castration resistance-free survival compared to ADT monotherapy in patients with PSMA-positive but CT-negative disease.

Expanding PSMA-Targeted RLT with Actinium Program

Lutetium Lu 177 vipivotide tetraxetan is being investigated across multiple indications beyond metastatic hormone-sensitive prostate cancer, with clinical trials exploring both earlier-line prostate cancer treatment and expansion into other solid tumors. These studies employ various intervention models ranging from randomized controlled trials to single-arm studies and combination therapy approaches.

• Metastatic castration-resistant prostate cancer (mCRPC) is being investigated in earlier treatment lines, particularly in the PSMAfore trial for taxane-naive patients who have not received chemotherapy, with the potential to improve long-term outcomes and delay chemotherapy exposure

• Glioblastoma (GBM) represents a novel indication under investigation, with radiopharmaceuticals administered locoregionally to bypass the blood-brain barrier through convection-enhanced delivery, local implantation, and stereotactic injections

• Combination therapy approaches are being actively explored across multiple studies, including combinations with chemotherapy, PARP inhibitors, immunotherapy, and antibody-interleukin-2 fusion proteins for enhanced tumor targeting

• Parallel assignment intervention models are employed in the PSMAfore phase 3 trial, where patients are randomly allocated (1:1) to receive either Lu-PSMA-617 at 7.4 GBq every 6 weeks for six cycles or androgen receptor pathway inhibitor changes

• Crossover design models are incorporated in major trials, allowing patients initially assigned to comparator treatments to cross over to Lu-PSMA-617 after confirmed radiographic progression, with 57% of patients in PSMAfore utilizing this option

• Single-arm intervention models are utilized in multiple studies, including prospective Phase-II trials administering 5.5 GBq per cycle for four cycles at 8-week intervals, with provisions for additional cycles based on response

• Multimodal intervention approaches are being investigated, including studies combining Lu-PSMA-617 with radical prostatectomy and bilateral orchiectomy in castrate-sensitive metastatic prostate cancer patients alongside hormonal therapy

Pluvicto's Early Promise in Hormone-Sensitive Prostate Cancer

The recent announcement regarding Pluvicto's performance in PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC) represents a significant potential expansion for radioligand therapy (RLT) into an earlier disease setting. Currently approved for metastatic castration-resistant prostate cancer (mCRPC) after prior androgen receptor pathway inhibition and taxane-based chemotherapy, this new data from the PSMAddition trial suggests a strategic shift. Demonstrating consistent radiographic progression-free survival improvement across diverse subgroups, including those with high or low disease volume and de novo or recurrent mHSPC, positions Pluvicto as a compelling option for patients earlier in their treatment journey.

This move into mHSPC could redefine the treatment paradigm for prostate cancer, offering a novel mechanism of action before patients develop castration resistance. It validates the growing interest in utilizing PSMA-targeted RLT earlier, a trend also supported by studies showing benefit in taxane-naive mCRPC and in combination with other agents.

However, several considerations arise with this potential expansion:

• Long-term safety: While the trial reported a consistent safety profile, the long-term implications of RLT, particularly regarding potential nephrotoxicity, bone marrow suppression, and xerostomia, will require careful monitoring in patients who may receive treatment for extended periods in an earlier setting.

• Patient selection: Efficacy is tied to sufficient PSMA expression. Ensuring appropriate patient selection through diagnostic imaging remains crucial, as heterogeneous PSMA expression or the development of resistance can occur.

• Evolving resistance: Even with effective initial responses, some patients may develop new lesions or show heterogeneous responses, underscoring the need for vigilant monitoring and the development of sequential or combination strategies.

The consistent efficacy across subgroups is a strong indicator of broad applicability, potentially delaying progression to mCRPC and improving overall patient outcomes. This development not only strengthens Pluvicto's market position but also reinforces the broader potential of theranostics in precision oncology, paving the way for further research into combination therapies and next-generation PSMA-targeted agents designed to mitigate side effects and overcome resistance.