PCa Commentary | Volume 199 – March 2025

Posted by Edward Weber | March 2025

Prostate-directed Therapy in Oligo-Metastatic Hormone-Sensitive Prostate Cancer (omHSPC) — The New Paradigm

A consensus has emerged that in mHSPC prostate-directed therapy improves overall survival. This treatment is appropriate in the 20% – 30% of men with high-risk or locally advanced cancer (Gleason Score 8 – 10, PSA >20 ng/mL and local spread around the gland) who, at diagnosis, have five or fewer metastatic sites beyond the pelvis (M1 disease). This condition is termed oligometastatic. STAMPEDE is the seminal study that demonstrated the benefit of radiation therapy to the prostate in omHSPC. This trial randomized about 1000 men into two cohorts comparing  ADT +/- docetaxel (standard of care) to the same treatment plus prostate radiotherapy to the prostate. About half of the men had a low-volume metastatic burden (< 5 sites) vs high-burden. Metastases to bone occurred in 89% of men in each arm. Conclusion: Radiation to the prostate conferred a 3-year 10% overall survival benefit for men with low-volume metastatic disease. The high-volume group did not benefit in terms of overall survival from radiation.

Recent studies supporting the benefit of prostate-directed radiation:

A study by Baccaglini et al., ACTA ONCOLOGICA, 2022, combined data of 46,541 prostate cancer patients with low-volume disease (five lesions or less) who were treated with ADT + abiraterone, docetaxel, enzalutamide or apalutamide with or without prostate radiation: The 3-year cancer-specific survival for those receiving prostate-directed therapy was 48.2% vs 26.3% with no local treatment.

A study by Morgan et al., Prostate Cancer and Prostatic Diseases, 2021, involved 410 men with low-volume mHSPC treated with radiation to the prostate vs. no radiation. Result: At a median follow-up of 61 months the median OS was 47.4 months for the treated group vs. 26.3 months for men receiving no radiation to their prostate.

An additional report by Morgan et al., Euro Urol, July 2024, (“Prostate Radiotherapy in Low-Volume Metastatic Hormone-Sensitive Prostate Cancer: A Network Meta-analysis”) gave the highest treatment priority to  ADT + APRI-like drugs (Xtandi, Zytiga, Nubeqa, Erleada) plus prostate radiotherapy in low-burden omHSPC. Additionally, Morgan found a 5-year reduction of severe genitourinary symptoms (urinary obstruction, ureteric stents, and pain) and a delay in the emergence of castration resistance in those men whose prostate was treated.

Tisseverasinghe et al., Euro Assn Urol, 2024 addressed the benefit of prostate-directed radiation, concluding, “Primary RT [to the prostate] offers significant benefits in managing both low-burden and high-burden mHSPC by reducing the subsequent need for urinary interventions.” “The ADT+ RT had better urinary and bowel function at 3, 6, and 12 months with better radiographic progression-free survival in both the low-volume and high-volume groups.”

What is the biologic rationale for prostate-directed therapy?

Dr. Robert Hamilton, Princess Margaret Cancer Center, in a 2019 issue of UroToday, offered four reasons:

1. “Aggressive clones can be identified in the prostate after systemic therapy.”
2. “Intact primary tumor can serve as a constant supply of metastatic cells.”
3. “Through secreted cytokines and growth factors, the primary tumor can prime distant metastatic niches to encourage [circulating tumor cell] implantation.”
4. “Local symptoms are problematic in the late stages of the disease if they remain untreated,” such as urinary obstruction requiring intervention, hematuria, and pain.

Radiation to the prostate can enhance a systemic anti-tumor immune response to un-imagined micrometastases as was seen in the early ORIOLE trial.

Increasing acceptance of Metastases Directed Therapy (MDT) for oligometastatic prostate cancer:

Since the STAMPEDE trial, there has been emerging interest in (MDT) wherein 5 or fewer metastatic sites are targeted with spot radiation (i.e., CyberKnife or Accuray) combined with or without ADT. A relevant issue is whether the MDT regime should include prostate-directed radiation.

Radiation treatment of de novo oligometastatic prostate cancer (MDT) combined with prostate-directed radiation — is there clinical trial support?

The STAMPEDE trial data supports prostate-directed radiation in low-volume oligometastatic disease combined with hormone therapy. The next step would be combining all three:

MDT + hormone therapy and prostate-directed radiation. Communication with Dr. Dan Spratt, a radiation oncologist expert in PC research, revealed that there is ongoing research as to the role of radiation to the prostate in the MDT regimen. A STAMPEDE2 trial (called METAVOVA with a projected enrollment of ~2000 patients) evaluates prostate-directed radiotherapy combined with MDT and systemic therapy vs. MDT plus hormone therapy (no prostate radiation).

The METANOVA trial (NCT06150417; actively recruiting) studies patients with 1-5 bone or extra-pelvic lymph node metastases imaged by CT, bone scan, and MRI. Those imaged by PET/CT may exhibit 1-10 bone metastases or extra-pelvic lymph nodes. Patients with extra-pelvic nodes seen only on PET (not seen on CT, bone scan, or MRI) require specific eligibility features and a high score of >.89 on Decipher, a genomic risk classifier. This study should give definite evidence of the benefit of prostate-directed radiotherapy to MDT/ADT for oligometastatic prostate cancer.

A cautionary note was raised in a phase 1 exploration of treating >10 sites assessing the safety and feasibility of CyberKnife or Accuray radiation delivery to >10 sites of oligometastatic disease (NCT05508464 “ARREST”). In Nguyen et al., (Int Radiation Oncol Biol Phys, 2024) the average number of sites treated per person was 16 raising a technical challenge since each site required a median of 31 minutes for treatment.

Bottom Line:

Clinical trials and biological rationale support prostate-directed radiotherapy combined with metastases-directed therapy (MDT) in the treatment of both low- and high-volume metastatic hormone-sensitive prostate cancer.

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