A world-wide meta-analysis of the efficacy and safety of MDT in treatment of oligometastatic prostate cancer (omPC) was presented at the 2025 ASCO Genitourinary Cancers Symposium by Chad Tang comparing MDT+ ADT + Androgen Receptor Pathway Inhibitors (ARPI; i.e., Zytiga, Xtandi, etc.) and treatment to the prostate in newly diagnosed oligometastatic PC. The comparison was to ADT/ARPI and prostate irradiation. Tang’s study demonstrated that at 4 year’s follow-up the addition of MDT was significantly superior as to progression-free survival, radiographic-free survival, freedom from developing castration resistance, and overall survival (86% vs 75%).
Oligometastatic cancer refers to a tumor stage in which (conventionally) there are five or fewer metastases in lymph nodes or bone (not liver or lung). OmPC can present at initial diagnosis (de novo metastatic hormone-sensitive PC) or be found as recurrent omPC after primary treatment resulting from evaluation of a rising PSA. MDT with the “CyberKnife” is especially suitable for targeting the metastatic lesions resulting from its highly focused radiation delivery … and it can be repeated later if necessary.
The Tang findings were supported by the results reported in the July 2025 review by Sherry et al., (Euro Urol) evaluating continuous or intermittent androgen deprivation therapy with or without MDT for omPC as tested in the EXTEND Trial. At follow-up of 42 months in the intermittent group the mPFS was 28 months with MDT vs 16 months ADT only. In the continuous ADT group with the addition of MDT the mPFS was 47 vs 22 months. Adding MDT delayed the emergence of castration-resistant PC to 85 months vs 75 months.
Biology Supporting MDT and Treatment of the Prostate:
An untreated prostate contains a heterogeneous mix of malignant cells, some already resistant to hormone therapy or radiation. The prostate can serve as a reservoir for the subsequent spread of metastases. Prostate treatment when combined with systemic therapy lengthens overall survival by ~11% compared to no treatment to the prostate. Adding MDT increases the benefit.
Patterns of Recurrence: An argument favoring MDT was presented by Verma (Prost Can Prost Dis. 12/2025) who found that oligometastatic PC when treated only with systemic therapy and prostate radiotherapy without MDT showed that: “At progression, restaging with PSMA-PET/CT showed progression of index metastases in 75% of the patients, with about a quarter of the patients having progression only at the initial sites”. This suggests a potentially important role of MDT to treat the initial oligometastatic lesions.
The future behavior of oligometastatic lesions is unpredictable and not predicted by the level of PSA, PSA doubling time or Gleason score. Targeted radiation to initial lesions yields >90% local control. The 2017 ORIOLE trial showed that radiotherapeutic destruction of metastatic lesions releases intracellular neo-antigens into the cytoplasm that induce an immunologic T-cell response that attacks metastases too small to have been imaged – in a sense an “in situ” vaccine.
Safety and Efficacy of MDT: Miszczyk (European Urology. Feb. 2024) in a meta-analysis of world usage of MDT reported “a low toxicity profile [0% -2.5%].” He makes the point that MDT alone allows patients to avoid or defer the toxicity of ADT. Adding concomitant ADT, with its associated toxicity, does extend progression-free survival, but has minimal effect (as of 2024) in prolonging overall survival.
An Emerging Regimen Not Accompanied By Hormone Suppression:
177 Lu-PSMA (Pluvicto) Neoadjuvant to Stereotactic Body Radiotherapy (SBRT for Oligorecurrent PC) was studied in the LUNAR Trial (Kisham et al. JCO. 12/2025). This trial found that two cycles of 177 Lutetium prior to MDT with SBRT to < 5 metastatic lesions (without ADT) yielded progression-free survival of 17.6+ months vs 7.4 for MDT only. In early studies adding hormone suppression to MDT prolonged PFS but at the cost of testosterone suppression toxicity.
In the LUNAR trial local control of targeted lesions was 98% in both trial arms. A 6.7% decrease in lymphocytes and 6.8% incidence of dry mouth were the only significant adverse effects in the 177-Lu arm. The authors speculated that the increase in PFS resulted from Pluvicto treating un-imaged micro-metastatic disease.
BOTTOM LINE:
When metastatic cancer is found at initial diagnosis or develops after primary therapy, Metastasis Directed Therapy, with or without ADT, delays the onset of castration-resistance and lengthens both progression-free and overall survival.