Pluvicto vs ARPI in Prostate Cancer: Is One Better?

1. 
   Major Breakthrough: FDA Expands Pluvicto Approval for Earlier Use in Advanced Prostate Cancer

   Bottom Line Up Front: The FDA's March 2025 expansion of Pluvicto (177Lu-PSMA-617) approval represents a paradigm shift in treating metastatic castration-resistant prostate cancer, now allowing use before chemotherapy and tripling the eligible patient population. The PSMAfore trial demonstrated a 59% reduction in disease progression risk compared to switching hormone therapies.

   A Game-Changing Development for Men with Advanced Disease

   On March 28, 2025, the U.S. Food and Drug Administration granted expanded approval for Pluvicto (lutetium Lu 177 vipivotide tetraxetan), marking one of the most significant advances in prostate cancer treatment in recent years. This groundbreaking decision allows men with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) to receive this targeted radioligand therapy much earlier in their treatment journey—before chemotherapy—after progression on just one androgen receptor pathway inhibitor (ARPI) like abiraterone or enzalutamide.

   This expansion approximately triples the number of eligible patients and addresses a critical treatment gap, as roughly half of men with mCRPC never live long enough to receive a second treatment under the previous approval criteria.

   The Science Behind the Success: PSMAfore Trial Results

   The FDA's decision was based on compelling data from the Phase 3 PSMAfore trial, which directly compared Pluvicto to switching to a different hormone therapy in 468 men with PSMA-positive mCRPC who had progressed on their first ARPI but had not yet received chemotherapy.

   Key Trial Findings:

   Progression-Free Survival: Pluvicto more than doubled the time before disease progression, with a median radiographic progression-free survival of 11.6 months compared to 5.6 months for men who switched to a different ARPI—representing a remarkable 59% reduction in the risk of disease progression or death.

   Overall Survival: While overall survival showed similar results in both groups (24.48 months vs 23.13 months), this outcome was likely confounded by the high crossover rate—60.3% of men initially assigned to switch hormone therapies eventually received Pluvicto after their disease progressed. When researchers adjusted for this crossover, they found a significant survival benefit favoring Pluvicto.

   Quality of Life Benefits: Men receiving Pluvicto maintained their quality of life scores for three months longer than those switching hormone therapies, with improvements in physical, functional, and emotional well-being. Time to worsening pain was also significantly delayed.

   Safety Profile: Well-Tolerated with Manageable Side Effects

   The safety data from PSMAfore reinforced Pluvicto's favorable tolerability profile compared to other cancer treatments:

   • Lower serious side effects: Fewer grade 3 or higher adverse events occurred with Pluvicto compared to switching ARPIs
   • Most common side effects: Dry mouth (57%, mostly mild), fatigue (53%), nausea (32%), and constipation (22%)
   • Manageable anemia: While 24% experienced anemia of any grade, only 6.2% had severe anemia
   • Preserved chemotherapy options: Pluvicto did not impair patients' ability to receive subsequent chemotherapy when needed

   Dr. Michael Morris, the study's principal investigator at Memorial Sloan Kettering Cancer Center, emphasized the significance: "The earlier indication for Pluvicto could really change our treatment paradigms for patients with mCRPC. It offers a targeted therapy that better delays disease progression compared to a second ARPI."

   How Pluvicto Works: Precision Medicine in Action

   Pluvicto represents a breakthrough in precision oncology for prostate cancer. The treatment combines lutetium-177, a beta-emitting radioactive isotope, with a targeting molecule that specifically binds to prostate-specific membrane antigen (PSMA)—a protein highly expressed on prostate cancer cells, especially in advanced disease.

   Once injected intravenously every six weeks for up to six doses, Pluvicto acts like a "smart missile," delivering targeted radiation directly to PSMA-positive cancer cells while largely sparing healthy tissue. This targeted approach explains both its effectiveness and relatively favorable side effect profile.

   Patient Selection and Treatment Process

   Not all men with mCRPC are candidates for Pluvicto. Patients must:

   • Have PSMA-positive disease confirmed by specialized PET imaging (using agents like Locametz)
   • Have progressed on at least one ARPI therapy
   • Be deemed appropriate to delay chemotherapy by their oncologist
   • Have adequate organ function for treatment

   The treatment involves receiving Pluvicto every six weeks for up to six doses, with careful monitoring for side effects and disease response.

   Manufacturing and Access Improvements

   Novartis has significantly expanded manufacturing capacity to meet the increased demand from this expanded approval. The company now operates multiple U.S. facilities and is establishing a third site in Carlsbad, California, to optimize delivery to West Coast patients. As of early 2025, more than 590 treatment sites were available, including 350 actively ordering sites, though access remains primarily through larger hospitals and academic medical centers.

   Looking Ahead: The Evolving Treatment Landscape

   This approval represents part of a broader evolution in prostate cancer care toward earlier use of more effective, targeted therapies. Other radioligand therapies are in development, and research continues into optimal sequencing and combination approaches.

   For patients and families, this development means:

   • Earlier access to an effective, well-tolerated treatment option
   • Potential to delay or avoid chemotherapy
   • Better preservation of quality of life
   • More time for new treatments to emerge

   As Gina Carithers, CEO of the Prostate Cancer Foundation, noted: "The now expanded approval of Pluvicto is an empowering development for the prostate cancer community."

   Key Takeaways for IPCSG Members

   1. Discuss PSMA testing with your oncologist if you have mCRPC and have progressed on your first hormone therapy
   2. Consider treatment timing carefully—this approval provides a new option before chemotherapy
   3. Ask about clinical trials for other promising treatments in development
   4. Understand that radioligand therapy requires specialized centers but access is expanding
   5. Quality of life matters—Pluvicto offers disease control with better tolerability than many alternatives

   ---

   SIDEBAR: What Should Men Currently on ARPI Therapy Consider About Pluvicto?

   If you're currently taking an ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide) for mCRPC, here are important considerations:

   Before Your Next Oncology Appointment:

   Ask About PSMA Testing: If you haven't had PSMA PET imaging, discuss whether this test could help determine your future treatment options. PSMA-positive disease is required for Pluvicto eligibility.

   Understand Your Current Response: If your ARPI is still working well (stable PSA, no new symptoms, stable scans), continuing current therapy is typically appropriate. Pluvicto becomes an option after ARPI progression.

   Plan Ahead for Progression: Discuss your oncologist's treatment plan for when your current ARPI stops working. With this new approval, Pluvicto is now a viable option before chemotherapy.

   Key Questions to Discuss:

   • "Am I a candidate for PSMA PET imaging?"
   • "What would be the next treatment step if my current therapy stops working?"
   • "Would I be eligible for Pluvicto based on my disease characteristics?"
   • "How would we monitor for progression on my current therapy?"

   Important Considerations:

   Don't Switch Prematurely: If your current ARPI is controlling your disease, there's no rush to change. The PSMAfore trial specifically studied patients who had already progressed on their first ARPI.

   Access and Timing: Pluvicto requires treatment at specialized centers. If you live in a rural area, discuss logistics and planning with your care team.

   Clinical Trials: Ask about clinical trials that might be available. Some studies are testing Pluvicto even earlier in the disease course or in combination with other treatments.

   What the PSMAfore Results Mean for You:

   • If you progress on your current ARPI, you now have a proven alternative to either switching to another hormone therapy or starting chemotherapy
   • The quality of life data suggests Pluvicto may allow you to maintain function and well-being better than switching to another ARPI
   • Having PSMA-positive disease on imaging could make you eligible for this targeted approach

   Remember: Treatment decisions should always be individualized based on your specific situation, overall health, preferences, and disease characteristics. This new approval simply provides another valuable option in your treatment toolkit.

   ---

   Sources and Citations

   1. Fizazi, K., et al. "177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial." The Lancet, 2024; 404(10459):1227-1239. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01653-2/abstract
   2. U.S. Food and Drug Administration. "FDA expands Pluvicto's metastatic castration-resistant prostate cancer indication." March 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication
   3. Novartis Pharmaceuticals. "FDA approves Novartis radioligand therapy Pluvicto for earlier use before chemotherapy in PSMA-positive metastatic castration-resistant prostate cancer." News release. March 28, 2025. https://www.novartis.com/news/media-releases/fda-approves-novartis-radioligand-therapy-pluvicto-earlier-use-chemotherapy-psma-positive-metastatic-castration-resistant-prostate-cancer
   4. Sartor, O., et al. "Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer." New England Journal of Medicine, 2021; 385(12):1091-1103. https://www.nejm.org/doi/full/10.1056/NEJMoa2107322
   5. Morris, M.J., et al. "Health-related quality of life and pain outcomes with [177Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION)." Lancet Oncology, 2023; 24(6):597-610.
   6. Fizazi, K., et al. "PSMAfore: HRQoL and Pain in a Phase 3 Study of 177Lu-PSMA-617 in Taxane-Naïve Patients with mCRPC." Presented at ASCO 2024. https://www.urotoday.com/conference-highlights/asco-2024/asco-2024-prostate-cancer/152475-asco-2024-psmafore-hrqol-and-pain-in-a-phase-3-study-of-177lu-psma-617-in-taxane-naive-patients-with-mcrpc.html
   7. ClinicalTrials.gov. "PSMAfore Trial (NCT04689828)." https://clinicaltrials.gov/ct2/show/NCT04689828
   8. U.S. Food and Drug Administration. "FDA approves Pluvicto for metastatic castration-resistant prostate cancer." March 23, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer
   9. Pluvicto vs ARPI in Prostate Cancer: Is One Better? 
   
   

---

This article was prepared for the Informed Prostate Cancer Support Group (IPCSG) newsletter based on peer-reviewed research, FDA announcements, and clinical trial data. For personalized medical advice, always consult with your healthcare team.