Chasing the Culprit: targeting metastatic index lesions in oligometastatic hormone-sensitive prostate cancer | Prostate Cancer and Prostatic Diseases

Chasing the Culprit: Should We Treat Metastatic "Index Lesions" Early or Wait?

BLUF (Bottom Line Up Front): New research reveals that 73% of oligometastatic prostate cancer patients who progress do so at their original metastatic sites ("index lesions"), raising critical questions about whether these spots should be treated immediately with metastasis-directed therapy (MDT) or monitored and treated later if they grow. This debate has major implications for treatment decisions in early metastatic disease, with multiple clinical trials now underway to determine the optimal approach.

The Game-Changing Question

For men diagnosed with oligometastatic hormone-sensitive prostate cancer (omHSPC)—meaning the cancer has spread to just a few sites (typically 1-5 lesions)—treatment decisions have become increasingly complex in the PSMA PET era. The standard of care includes hormone therapy (ADT), often combined with newer drugs like abiraterone or enzalutamide, plus radiation to the prostate itself. But here's the million-dollar question: what about those metastatic spots that PSMA PET picks up? Should doctors radiate them immediately, or watch and wait?

A new editorial in Prostate Cancer and Prostatic Diseases, responding to research by Verma and colleagues, brings this debate into sharp focus and offers important insights for patients navigating these decisions.

What the Research Shows

The Verma study followed 79 men with newly diagnosed oligometastatic prostate cancer (1-5 lesions, 72% with bone metastases) who received standard systemic therapy and prostate radiation but no radiation to their metastatic lesions. After a median follow-up of 39 months, here's what happened:

• 19% of patients experienced disease progression
• Among those who progressed, 73% relapsed at the original metastatic site they started with
• In 27% of cases, progression was confined exclusively to that original site—no new metastases appeared elsewhere
• Another 47% progressed at the index site plus developed new metastases

"This finding carries important clinical implications," write editorial authors Salvatore Cozzi and Thomas Zilli. "If most patients relapse at previously PSMA-identified but untreated metastatic foci, it strongly supports the hypothesis that such untreated hormone-sensitive lesions can act as reservoirs for disease progression and clonal evolution."

The Two Competing Strategies

Strategy 1: Treat All Visible Disease Upfront

The rationale for immediate metastasis-directed therapy is threefold:

1. High local control rates: Ablative radiation achieves local control exceeding 90% with minimal additional side effects
2. Potential to delay progression: Retrospective studies suggest MDT may postpone the need for additional therapies and potentially improve survival
3. Prevent seeding: Treating oligometastatic sites early might prevent cancer cells from spreading further and reduce treatment-resistant clones

The phase II SOLAR trial exemplified this comprehensive approach, combining local treatment of the prostate, MDT to all metastatic sites, and intensified systemic therapy for a fixed duration. Results showed durable remission off therapy after testosterone recovery in the majority of selected patients with de novo omHSPC.

Strategy 2: Watch and Treat Later

An alternative approach defers MDT until restaging PSMA PET shows evidence of progression. This strategy relies on:

• Close PSA monitoring
• Serial PSMA PET imaging to guide selective salvage MDT
• Treatment only for patients who develop oligoprogressive disease
• Avoiding upfront treatment for patients likely to progress rapidly to widespread disease

The Verma findings add nuance by showing that progression sometimes remains confined to original lesions, potentially allowing delayed but still effective salvage MDT.

The Clinical Trials That Will Decide

Several major randomized trials are actively investigating whether MDT improves outcomes when added to standard therapy:

• STAMPEDE-2 (NCT06320067)
• OLIGO-PRESTO (NCT04115007)
• PLATON (NCT03784755)
• STARMET (NCT05209243)

Additionally, trials like ARTO and GROUQ-PCS 9 are examining the deferred MDT strategy, using PSMA PET to guide salvage treatment at progression.

"These arguments, while compelling, remain hypothesis-generating and have yet to be validated in randomized phase III trials," the editorial authors note.

The PSMA PET Complication

The editorial highlights an important consideration: interpreting PSMA PET for restaging, particularly at low PSA values, requires caution. Persistent PSMA uptake may reflect either:

• Early resistant disease requiring treatment
• Post-treatment changes like inflammation or "pseudo-progression" that don't require intervention

Interestingly, in the Verma study, 5 of 79 patients showed PSMA uptake in the prostate gland despite prior radiation. This underscores the complexity of using PSMA imaging to guide treatment decisions.

On the other hand, repeated PSMA imaging in patients with low PSA could enable earlier intervention—catching progression before it becomes biochemically or clinically apparent.

What This Means for Patients

The key takeaway? Untreated PSMA-positive metastatic sites may be the principal drivers of progression in newly diagnosed oligometastatic prostate cancer. These untreated lesions could:

• Persist over time
• Evolve into castration-resistant disease
• Become the dominant sites of progression in the CRPC phase

The observation that some patients progressed exclusively at a single site suggests that comprehensive local control of all PSMA-positive disease may delay or even prevent systemic spread.

Notably, no baseline factors—including Gleason grade, lymph node status, number of metastases, or PSA nadir—predicted which patients would progress at index lesions, "underscoring the unpredictability of metastatic behavior in the absence of local intervention."

Questions to Ask Your Doctor

If you're facing oligometastatic prostate cancer, consider discussing:

1. Should we treat all visible metastases now or monitor with PSMA PET?
2. Am I eligible for any clinical trials comparing these approaches?
3. How frequently should we use PSMA PET for monitoring?
4. What's your interpretation of PSMA uptake on my scans—active disease or post-treatment changes?
5. Could an adaptive strategy work for my situation?

The Path Forward

"While randomized evidence is still awaited, this study enhances our understanding of disease biology and the evolving role of PSMA-guided therapy in the omHSPC setting," the authors conclude.

The integration of PSMA imaging with PSA kinetics and potentially genomic profiling is expected to help refine patient selection and optimize MDT timing in future studies. For now, patients and physicians must navigate this evolving landscape together, balancing the potential benefits of aggressive local treatment against the risk of overtreatment in a disease whose behavior remains difficult to predict.

---

Sources

1. Cozzi S, Zilli T. Chasing the Culprit: targeting metastatic index lesions in oligometastatic hormone-sensitive prostate cancer. Prostate Cancer and Prostatic Diseases. 2025. https://doi.org/10.1038/s41391-025-01052-w

2. Verma P, Maitre PKG, Murarka N, Choudhury S, Ghosh S, Agrawal A, et al. Progression of index metastases in oligometastatic hormone-sensitive prostate cancer: Implications for metastases directed therapy? Prostate Cancer and Prostatic Diseases. 2025. https://doi.org/10.1038/s41391-025-01056-6

3. Nickols NG, Tsai S, Kane N, Tran S, Ghayouri L, Diaz-Perez S, et al. Systemic and tumor-directed therapy for oligometastatic prostate cancer: the SOLAR Phase 2 trial in De Novo oligometastatic prostate cancer. European Urology. 2024;86:190-193. https://doi.org/10.1016/j.eururo.2024.03.001

4. Mazzone E, Cannoletta D, Quarta L, Chen DC, Thomson A, Barletta F, et al. A comprehensive systematic review and meta-analysis of the role of prostate-specific membrane antigen positron emission tomography for prostate cancer diagnosis and primary staging before definitive treatment. European Urology. 2025;87:654-671. https://doi.org/10.1016/j.eururo.2024.09.012

5. Miszczyk M, Rajwa P, Yanagisawa T, Nowicka Z, Shim SR, Laukhtina E, et al. The efficacy and safety of metastasis-directed therapy in patients with prostate cancer: a systematic review and meta-analysis of prospective studies. European Urology. 2024;85:125-138. https://doi.org/10.1016/j.eururo.2023.09.012

6. Zilli T, Achard V, Dal Pra A, Schmidt-Hegemann N, Jereczek-Fossa BA, Lancia A, et al. Recommendations for radiation therapy in oligometastatic prostate cancer: An ESTRO-ACROP Delphi consensus. Radiotherapy and Oncology. 2022;176:199-207. https://doi.org/10.1016/j.radonc.2022.10.005

7. Gillessen S, Turco F, Davis ID, Efstathiou JA, Fizazi K, James ND, et al. Management of patients with advanced prostate cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC). European Urology. 2025;87:157-216. https://doi.org/10.1016/j.eururo.2024.09.017

8. Le Guevelou J, Cuccia F, Flippot R, Ferrera G, Terlizzi M, Zilli T, et al. The current landscape of stereotactic body radiation therapy for metastatic castration-resistant prostate cancer. Prostate Cancer and Prostatic Diseases. 2025;28:546-556. https://doi.org/10.1038/s41391-024-00891-9

9. Mesci A, Ahmadi E, Ali A, Gouran-Savadkoohi M, Evelyn Tsakiridis E, Biziotis OD, et al. (18)F-DCFPyL (PSMA) PET as a radiotherapy response assessment tool in metastatic prostate cancer. Clinical and Translational Radiation Oncology. 2023;39:100583. https://doi.org/10.1016/j.ctro.2023.100583

10. Hotta M, Nguyen K, Thin P, Armstrong WR, Sonni I, Farolfi A, et al. Kinetics of PSMA PET signal after radiotherapy in prostate cancer lesions: A single-center retrospective study. Radiotherapy and Oncology. 2025;207:110869. https://doi.org/10.1016/j.radonc.2025.110869

11. Beaufils M, Meynard L, Bernard-Tessier A, Brenot-Rossi I, Guerin M, Tauty A, et al. PET imaging for metastatic castration sensitive prostate cancer (mCSPC) for patients with PSA response after systemic therapy: A multicentric ambispective analysis. Journal of Clinical Oncology. 2025;43(suppl 5):37. https://doi.org/10.1200/JCO.2025.43.5_suppl.37

12. STAMPEDE-2 Trial. ClinicalTrials.gov Identifier: NCT06320067. https://clinicaltrials.gov/study/NCT06320067

13. OLIGO-PRESTO Trial. ClinicalTrials.gov Identifier: NCT04115007. https://clinicaltrials.gov/study/NCT04115007

14. PLATON Trial. ClinicalTrials.gov Identifier: NCT03784755. https://clinicaltrials.gov/study/NCT03784755

15. STARMET Trial. ClinicalTrials.gov Identifier: NCT05209243. https://clinicaltrials.gov/study/NCT05209243

Chasing the Culprit: targeting metastatic index lesions in oligometastatic hormone-sensitive prostate cancer | Prostate Cancer and Prostatic Diseases