PSMA-Targeted Therapies for Prostate Cancer: Move Treatment Earlier in Disease Course

 

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PSMA-Targeted Therapies for Prostate Cancer: Move Treatment Earlier in Disease Course

Landmark FDA approval expands access to radioligand therapy while new research explores next-generation treatments

By [Your Name] for the IPCSG Newsletter

The landscape of prostate cancer treatment has undergone a seismic shift in recent months, with groundbreaking advances in prostate-specific membrane antigen (PSMA)-targeted therapies offering new hope to patients across different stages of the disease. Most significantly, the FDA's March 2025 expansion of Pluvicto (lutetium-177-PSMA-617) approval now allows treatment before chemotherapy, potentially tripling the number of eligible patients.

Major FDA Approval Expands Treatment Access

On March 28, 2025, the FDA approved a crucial expansion of Pluvicto's indication, allowing its use in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibitor (ARPI) therapy and are considered appropriate to delay taxane-based chemotherapy. This represents a major paradigm shift, moving effective radioligand therapy much earlier in the treatment sequence.

"The expanded FDA approval substantially increases the number of patients now eligible for treatment with 177Lu-PSMA-617," explains Dr. Michael Morris, Principal Investigator of the study and lead author of the pivotal research published in The Lancet. "This type of precision medicine is a game changer for people whose prostate cancer has spread outside of the prostate despite treatment with hormonal therapy."

The approval was based on compelling results from the PSMAfore trial, which demonstrated that Pluvicto reduced the risk of radiographic progression or death by 59% compared to switching to a different ARPI therapy. The study showed that Pluvicto more than doubled median radiographic progression-free survival to 9.3 months versus 5.6 months with ARPI change.

The Science Behind PSMA Targeting

PSMA is a protein overexpressed on the surface of most prostate cancer cells but largely absent on normal cells, making it an ideal target for precision medicine approaches. Pluvicto combines a PSMA-targeting compound with lutetium-177, a radioactive particle that delivers targeted radiation directly to cancer cells while sparing healthy tissue.

The treatment represents what experts call "theranostic" medicine—the ability to both see and treat cancer using the same targeting mechanism. As Dr. Lisa Bodei from Memorial Sloan Kettering explains, "We have a theranostic motto, which is 'We see what we treat, and we treat what we see.'"

Next-Generation Alpha Therapies Show Promise

While lutetium-177 delivers beta radiation, researchers are increasingly exploring alpha-emitting radionuclides that may offer even greater therapeutic potential. Actinium-225 PSMA therapies have emerged as particularly promising, with the alpha particles delivering more potent, shorter-range radiation that may be more effective against resistant disease.

Recent multicenter data published in early 2025 from the WARMTH Act study followed 448 patients across seven centers who received actinium-225 PSMA therapy. Results showed a median overall survival of 15.5 months and progression-free survival of 7.9 months, with particularly encouraging outcomes in patients who hadn't received prior taxane chemotherapy or lutetium-177 therapy.

Several actinium-225 agents are advancing through clinical trials, including:

• 225Ac-PSMA-62 (ACCEL trial): A next-generation PSMA ligand designed to reduce side effects while maintaining efficacy
• 225Ac-FL-020: Recently granted FDA Fast Track designation for accelerated development
• Combination approaches: Studies combining actinium-225 with lutetium-177 to potentially maximize benefits while minimizing toxicity

Innovative Combination Strategies

Researchers are actively exploring combination therapies to enhance the effectiveness of PSMA-targeted treatments. Key approaches include:

PSMA + Immunotherapy: The PRINCE trial and other studies are investigating whether radiation from PSMA therapy can activate the immune system, potentially turning "cold" tumors into "hot" ones that respond better to immunotherapy.

PSMA + Hormonal Therapy: The ENZA-p trial demonstrated promising results combining lutetium-177 PSMA with enzalutamide, showing superior outcomes compared to enzalutamide alone.

PSMA + Chemotherapy: Studies are exploring optimal timing and combinations with taxane chemotherapy to maximize synergistic effects.

Alpha + Beta Combinations: Researchers are investigating combinations of different radioligands to optimize therapeutic impact while managing side effects.

Earlier Treatment Settings Under Investigation

The success in advanced disease has prompted researchers to explore PSMA therapies in earlier settings:

• Hormone-sensitive disease: The PSMAddition trial is evaluating lutetium-177 PSMA in newly metastatic patients
• Oligometastatic disease: Studies are examining whether PSMA therapy can control limited metastatic disease
• Neoadjuvant setting: The LuTectomy trial is exploring PSMA therapy before surgery in high-risk localized disease

PSMA Imaging Continues to Advance

Parallel advances in PSMA PET imaging are improving patient selection and treatment monitoring. Multiple FDA-approved PSMA tracers now provide superior detection compared to conventional imaging, with studies showing 85-92% accuracy in disease staging compared to 38-65% with traditional methods.

The integration of PSMA PET into treatment guidelines has become standard practice, enabling physicians to:

• Better select patients for therapy
• Monitor treatment response
• Guide decisions about continuing or switching treatments
• Plan radiation therapy with unprecedented precision

Managing Treatment Side Effects

While PSMA therapies are generally well-tolerated, patients and families should be aware of potential side effects. The most common include:

• Dry mouth (xerostomia): The most frequent side effect, occurring because salivary glands express some PSMA
• Fatigue: Usually mild to moderate and temporary
• Temporary decreases in blood counts: Requiring monitoring but typically manageable
• Kidney function effects: Rare but monitored through regular blood tests

Researchers are actively working on strategies to minimize these effects, including protective agents and optimized dosing schedules.

Looking Ahead: The Future of PSMA Therapy

The rapid evolution of PSMA-targeted treatments represents one of the most significant advances in prostate cancer care in decades. Dr. Oliver Sartor, a leading researcher in the field, notes: "The clinical development of PSMA-targeting radioligand therapy has provided important insights into the treatment of metastatic castration-resistant prostate cancer. The trial data demonstrated a clear clinical benefit in delaying disease progression in eligible patients, offering an additional therapeutic approach."

Current research directions include:

• Novel PSMA-targeting agents with improved properties
• Alternative radioisotopes (thorium-227, copper-67, others)
• Combination with emerging therapies like PARP inhibitors
• Earlier intervention strategies
• Personalized dosing approaches

What This Means for Patients

For patients and families in the IPCSG community, these advances offer several key takeaways:

1. Expanded Options: More patients now qualify for effective PSMA therapy earlier in their treatment journey
2. Improved Outcomes: Clinical trials consistently show meaningful improvements in progression-free survival and quality of life
3. Future Promise: The pipeline of new PSMA therapies continues to grow, with multiple approaches in development
4. Individualized Care: PSMA PET imaging enables truly personalized treatment decisions

Patients interested in PSMA therapies should discuss eligibility with their oncology team and consider consultation at centers with expertise in radioligand therapy.

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Sources and Citations

1. 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
2. Morris, M.J., Castellano, D., Herrmann, 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
3. Novartis. "FDA approves Novartis radioligand therapy Pluvicto® for earlier use before chemotherapy in PSMA-positive metastatic castration-resistant prostate cancer." 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., de Bono, J., Chi, K.N., 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. Sathekge, M.M., Lawal, I.O., Bal, C., et al. "Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study." The Lancet Oncology, 2024; 25(2):175-183. https://www.sciencedirect.com/science/article/abs/pii/S1470204523006381
6. Ninatti, G., Scilipoti, P., Pini, C., et al. "Time for action: actinium-225 PSMA-targeted alpha therapy for metastatic prostate cancer - a systematic review and meta-analysis." Theranostics, 2025; 15(8):3386-3399. https://www.thno.org/v15p3386.htm
7. Memorial Sloan Kettering Cancer Center. "FDA Expands New Treatment for Metastatic Prostate Cancer: Targets a Protein Called PSMA." https://www.mskcc.org/news/fda-approves-promising-therapy-advanced-prostate
8. Bidkar, A.P., Flavell, R.R. "Actinium-225 targeted alpha particle therapy for prostate cancer." Theranostics, 2024; 14(10):3895-3918. https://pmc.ncbi.nlm.nih.gov/articles/PMC11103494/
9. Aggarwal, R., et al. "Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: An open-label, dose-expansion, phase 1 trial." The Lancet Oncology, 2023; 24:1266–1276.
10. Kendi, A.T., et al. "Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials." Journal of Nuclear Medicine, 2023; 64(6):862-870. https://pubmed.ncbi.nlm.nih.gov/36895851/
11. Hofman, M.S., et al. "Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial." The Lancet Oncology, 2024; 25(1):99-107.
12. European Journal of Nuclear Medicine and Molecular Imaging. "The role of PSMA-based radioligand therapy in hormone-sensitive prostate cancer." 2025. https://link.springer.com/article/10.1007/s00259-025-07083-8
13. UroToday. "ASCO GU 2025: ACCEL: [Ac-225]-PSMA-62 Phase Ia/Ib/II Clinical Trial." February 2025. https://www.urotoday.com/conference-highlights/asco-gu-2025/asco-gu-2025-prostate-cancer/158157-asco-gu-2025-accel-ac-225-psma-62-phase-ia-ib-ii-clinical-trial-to-characterize-efficacy-safety-tolerability-and-dosimetry-in-oligometastatic-hormone-sensitive-and-metastatic-castration-resistant-prostate-cancer.html
14. Mena, E., Lindenberg, L., Choyke, P.L. "Update on PSMA-based Prostate Cancer Imaging." Seminars in Nuclear Medicine, 2025; 55(1):124-136. https://www.sciencedirect.com/science/article/abs/pii/S0001299824000898
15. Cleveland Clinic. "PSMA-Targeted Therapy: Purpose & Results." March 19, 2025. https://my.clevelandclinic.org/health/treatments/24775-psma-targeted-therapy

For more information about PSMA therapies and clinical trials, patients are encouraged to speak with their oncology team or contact major cancer centers offering these treatments.