New PSMAddition data show 58% lower risk of PSA progression with Pluvicto® in metastatic hormone-sensitive prostate cancer

Novartis' Pluvicto Shows 58% Lower PSA Progression Risk in mHSPC

Novartis announced new data from the PSMAddition study, demonstrating improved prostate-specific antigen (PSA) responses with Pluvicto (lutetium (177Lu) vipivotide tetraxetan) combined with standard of care (SoC) in PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC). Patients treated with Pluvicto plus SoC experienced a 58% lower risk of PSA progression (HR 0.42; 95% CI: 0.30-0.59) compared to SoC alone. The combination therapy also led to a higher frequency and depth of PSA response, with more patients achieving deep PSA reductions (<0.2 ng/mL) at 12, 24, and 48 weeks. Regulatory submissions have been filed in the US, China, and Japan, with decisions anticipated in H2 2026.

• The PSMAddition study revealed that combining Pluvicto with standard of care (androgen receptor pathway inhibitor [ARPI] + androgen deprivation therapy [ADT]) resulted in a 58% lower risk of PSA progression compared to SoC alone. This statistically significant finding (HR 0.42; 95% CI: 0.30-0.59) underscores Pluvicto's potential to delay disease progression in PSMA-positive metastatic hormone-sensitive prostate cancer.
• Patients receiving Pluvicto plus SoC achieved substantially deeper and more durable PSA reductions. For instance, at Week 48, 87.4% of patients in the Pluvicto combination arm achieved a PSA nadir of <0.2 ng/mL, compared to 74.9% in the SoC alone arm. This sustained deep response suggests a more profound impact on disease control and patient outcomes.
• The safety and tolerability profile of Pluvicto in the PSMAddition study was consistent with previous trials (PSMAfore and VISION), with Grade ≥3 adverse events reported in 50.7% of the Pluvicto plus SoC arm versus 43% in the SoC alone arm. Novartis has already submitted regulatory applications in the United States, China, and Japan, with decisions expected in the second half of 2026, indicating a clear path towards potential market expansion.

PSMAddition Data: Deepening PSA Response in mHSPC

The STAMPEDE Trial evaluated metformin 850 mg twice daily added to standard care in 1874 patients with metastatic hormone-sensitive prostate cancer across 112 hospitals in the UK and Switzerland. The study demonstrated no significant overall survival benefit, with median survival of 67.4 months in the metformin group versus 61.8 months in the standard care group (HR 0.91, 95% CI 0.80-1.03; p=0.15). However, metformin significantly reduced adverse metabolic side-effects associated with androgen deprivation therapy. Safety analysis revealed grade 3 or worse adverse events in 57% of metformin patients versus 52% in the control group, with the side-effect profile primarily consisting of diarrhea and increased gastrointestinal events.

The ARON-3 Study examined enzalutamide in a real-world setting across 424 patients from 29 cancer centers in 9 countries. The intervention demonstrated robust efficacy with 76% of patients achieving PSA90 response (≥90% PSA reduction) at a median time of 6.0 months, and 59% achieving ultra-low PSA levels (≤0.2 ng/ml) at 8.3 months. Median time on treatment was 31.8 months with median overall survival not reached. The safety profile was favorable, with grade 3-4 adverse events occurring in only 9-10% of patients regardless of age group.

The EXTRA-PC Trial investigated masofaniten (EPI-7386) 600 mg twice daily combined with enzalutamide 160 mg daily plus androgen deprivation therapy in treatment-naïve mHSPC patients. In the first stage enrollment of 13 patients, 77% achieved PSA <0.2 ng/mL at 6 months (95% CI: 50%-92%), meeting the threshold to advance to stage 2. The combination demonstrated an acceptable safety profile with minimal progression, as only one patient developed metastatic castration-resistant prostate cancer and died during the median 9.9-month follow-up period.

Pluvicto's Potential to Redefine mHSPC Standard of Care

Recent evidence demonstrates that combination therapies have established superior efficacy compared to androgen deprivation therapy (ADT) monotherapy in metastatic hormone-sensitive prostate cancer (mHSPC). Studies from 2018 onward, including the pivotal CHAARTED and STAMPEDE trials, showed that ADT combined with docetaxel-based chemotherapy provided substantial overall survival improvements of 14-22 months compared to ADT alone. Similarly, the LATITUDE and STAMPEDE trials established that ADT plus abiraterone/prednisone achieves identical survival benefits to chemohormonal treatment, offering an alternative for patients unsuitable for chemotherapy. However, despite this evidence, 20-60% of eligible patients remain undertreated due to geographic, financial, and systemic barriers.

Comparative analyses of newer androgen receptor pathway inhibitors (ARPIs) reveal distinct efficacy profiles in mHSPC. A 2024 retrospective analysis of 82 patients demonstrated that enzalutamide significantly prolonged PSA progression-free survival (HR 2.244; 95% CI 1.366-3.685, p=0.001), radiographic progression-free survival, castration-resistant prostate cancer progression-free survival, and overall survival compared to bicalutamide. Apalutamide similarly showed significant advantages in PSA-PFS (HR 5.071; 95% CI 1.711-15.032; P=0.003) and CRPC-PFS compared to bicalutamide, with both enzalutamide and apalutamide achieving superior deep PSA responses. Notably, abiraterone in combination with ADT did not demonstrate significant advantages in delaying disease progression when compared with these newer ARPIs.

Treatment selection challenges persist due to the absence of head-to-head trials and overlapping selection criteria across studies. Current evidence suggests that patients with high-volume disease may benefit most from chemohormonal treatment, while combination ADT plus ARPI represents a viable alternative. The PANTHER study specifically highlighted improved outcomes in Black patients treated with combination therapies, addressing important disparities in treatment access and outcomes. Safety profiles across combination regimens show manageable toxicity, with no significant differences in overall adverse event rates among the newer ARPIs, though ADT-related adverse events including osteoporosis, cardiovascular disease, and diabetes remain considerations for long-term treatment planning.

Beyond mHSPC: Pluvicto's Expanding Radioligand Therapy Pipeline

Lutetium (177Lu) vipivotide tetraxetan is being investigated across multiple prostate cancer settings beyond its FDA-approved indication, with trials focusing on earlier disease stages and alternative treatment sequences. Current research encompasses taxane-naive populations, extended dosing regimens, and combination therapy approaches to optimize patient outcomes.

• Taxane-naive metastatic castration-resistant prostate cancer (mCRPC): The PSMAfore trial (NCT04689828) is a phase 3 randomized controlled study comparing Lu-PSMA-617 (7.4 GBq every 6 weeks for six cycles) versus androgen receptor pathway inhibitor (ARPI) change in patients who progressed on previous ARPI therapy, with crossover permitted after radiographic progression

• Chemotherapy-naive mCRPC patients: A randomized, parallel-group, open-label phase 2 non-inferiority trial comparing Lu-PSMA-617 (6.0-7.4 GBq every 8 weeks, up to 4 cycles) versus docetaxel (75 mg/m² every 3 weeks, up to 10 cycles) in patients with high PSMA-expressing lesions

• Extended dosing schedule optimization: The FLEX-MRT trial is a phase 2 randomized controlled study comparing standard fixed dosing (6 cycles) versus extended flexible dosing (up to 12 cycles with potential treatment holidays) in mCRPC patients, with response assessment guided by SPECT/CT and PSMA PET/CT imaging

• Earlier disease stage exploration: Investigations are underway to evaluate Lu-PSMA-617 in earlier prostate cancer stages, potentially as first-line systemic treatment or in hormone-sensitive disease settings to delay chemotherapy exposure and improve long-term outcomes

• Combination therapy development: Active research is exploring Lu-PSMA-617 combinations with chemotherapy, PARP inhibitors, and immunotherapy agents using parallel-group and dose-escalation study designs to enhance therapeutic efficacy

Pluvicto: A New Frontier in Hormone-Sensitive Prostate Cancer

The recent data from the PSMAddition study marks a pivotal moment for Pluvicto, Novartis's lutetium-177 PSMA radioligand therapy, as it demonstrates compelling efficacy in PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC). This represents a significant strategic move, extending the therapy's potential utility beyond its established role in metastatic castration-resistant prostate cancer (mCRPC) into an earlier, larger patient population. The observed 58% reduction in the risk of PSA progression and the achievement of deeper, more frequent PSA responses with Pluvicto combined with standard of care are strong indicators of its potential to redefine treatment expectations in mHSPC.

This expansion into mHSPC carries several key implications:

• It positions Pluvicto for substantial market growth, significantly broadening its addressable patient base and reinforcing Novartis's leadership in the burgeoning field of targeted radioligand therapies.

• The strong clinical profile suggests a potential shift in the standard of care for mHSPC, offering a new, highly effective treatment intensification strategy that could improve long-term outcomes for patients.

However, the path forward is not without considerations. While regulatory submissions are underway in major markets, approvals are not anticipated until H2 2026, introducing a period of uncertainty. The evolving competitive landscape in mHSPC also means that continued innovation and differentiation will be crucial. Furthermore, while LuPSMA has demonstrated limited toxicity in advanced disease, the long-term safety and durability of response in this earlier disease setting will be closely scrutinized as real-world evidence accumulates. This development underscores a broader trend in prostate cancer management: the strategic deployment of precision therapies earlier in the disease continuum to maximize patient benefit and reshape therapeutic paradigms.