Recent clinical trials and retrospective analyses have revealed that local interventions—including radiotherapy (RT) to the primary tumor—can substantially benefit patients with metastatic hormone-sensitive prostate cancer (mHSPC), even those with a high burden of disease. This evolving understanding challenges older paradigms and opens new possibilities for improving both quality of life and disease outcomes.

But what does high-burden mean? Multiple criteria define “high-burden” or “high-risk” metastatic prostate cancer. The CHAARTED trial stipulates at least four bone metastases (with at least one outside the axial skeleton) or visceral metastases. The LATITUDE trial uses a Gleason score ≥8, visceral metastases, and ≥3 bone metastases as key risk factors. Although these frameworks vary, the bottom line is that high-burden disease typically involves more widespread or aggressive metastases.

Several high-profile studies (notably the STAMPEDE trial) have already demonstrated that local RT to the primary prostate tumor improves failure-free survival and sometimes overall survival (OS) in low-volume mHSPC. This clear benefit for patients with a smaller metastatic load has naturally led oncologists to explore whether a similar approach could help those with a heavier metastatic burden.

What Is The Rationale for Radiotherapy in High-Burden mHSPC?

Seed-and-Soil Theory
Primary tumors can shed cells and produce soluble factors that enhance tumor growth at secondary sites. Eradicating or controlling the primary lesion may disrupt these processes, reducing “re-seeding” events.

Synergistic Systemic–Local Effects

• Hormonal Therapy + RT: ADT can sensitize tumor cells to radiotherapy, while RT itself can reduce the burden of disease in the prostate.
• Next-Generation AR Inhibitors: Abiraterone and other advanced androgen receptor pathway inhibitors may further enhance the effect of radiation by making tumor cells more susceptible to DNA damage.

Quality-of-Life Improvements
In advanced disease, local prostate-related symptoms—such as hematuria, urinary obstruction, and perineal pain—can substantially affect daily life. Radiotherapy often alleviates these symptoms without adding significant toxicity.

Which Trials Suggested The Rationale?

STAMPEDE Arm H
Although this arm did not demonstrate an OS advantage in the overall metastatic population, it did show improved failure-free survival. Patients also had fewer local complications, suggesting an important clinical benefit.

HORRAD Trial
Focused on men with de novo mHSPC, HORRAD found no definitive OS benefit but did reveal an improvement in time to PSA progression and a reduction in local events, reinforcing the notion that local RT helps reduce the symptomatic burden.

PEACE-1 Trial
By adding abiraterone ± RT to standard of care, PEACE-1 confirmed a positive impact on radiographic progression-free survival in low-volume disease. For patients with high-volume metastatic disease, RT did not significantly increase OS but delayed the onset of castration-resistant prostate cancer and reduced serious genitourinary (GU) events.

In a nutshell, despite the lack of a clear survival advantage in most high-volume populations, local radiotherapy can delay local progression, decrease GU complications and delay castration resistance.

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