This will be a pragmatic, phase II, registry-based cohort-multiple randomized controlled trial (cmRCT) embedded within an ongoing prospective cancer radiotherapy registry. Eligible patients are those with hormone-sensitive metastatic prostate cancer who have responded to systemic therapy, defined by the absence of PSA progression, and who are eligible for MDRT. All eligible subjects will be enrolled into the registry and followed longitudinally for oncologic and toxicity outcomes.

From this registry, patients will be randomly selected (1:1) to be offered the experimental arm, which consists of MDRT delivered to metastatic sites identified on imaging in patients who have already initiated systemic therapy (Figure 1). Those not selected will continue to receive standard of care systemic therapy +/- standard of care radiotherapy if clinically indicated. Nor patients or physicians will be blinded.

Following the initial course of MDRT, prostate-specific antigen (PSA) will be measured, with a minimum assessment at 3 months. This PSA value will be used to determine whether the PSA level has decreased below 0.2 ng/mL. If the PSA remains ≥ 0.2 ng/mL, repeat PSMA-PET will be performed, and a second course of MDRT will be delivered to consolidate residual metastatic lesions.

In this phase II real-world randomized trial, we will determine if AnChoRing (Addition of MDRT for consolidation of response) sites of PSMA PET visible disease when responding to systemic therapy improves the proportion of patients achieving a PSA < 0.2 ng/mL and extends failure-free survival compared to the standard of care.

Inclusion Criteria:

• Enrolled in PERa (CHUM CER 17.032) and randomly selected for ANCHOR-Prostate.
• Diagnosis of hormone-sensitive metastatic prostate cancer having responded to systemic therapy.
• PSA non-progressing
• ECOG 0-2
• Metastatic disease suitable for MDRT.
• Primary tumor must have received definitive local treatment (surgery or radiotherapy) with no evidence of local recurrence, or be planned for treatment at the time of MDRT.

Exclusion Criteria:

• Planned intermittent systemic therapy.
• Planned radio-ligand therapy.