Integrating Systemic Therapy and Metastasis-Directed Therapy in Oligometastatic Hormone-Sensitive Prostate Cancer

The treatment landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has evolved rapidly over the past decade. While androgen receptor pathway inhibitors (ARPIs) and chemotherapy remain the foundation of care, a subset of patients with limited metastatic burden, termed oligometastatic hormone-sensitive prostate cancer (omHSPC), may achieve additional benefit through metastasis-directed therapy (MDT). This review highlights how combining systemic and local therapies, guided by advanced imaging and molecular profiling, is reshaping management for this intermediate metastatic disease state.

Phase III trials such as CHAARTED, LATITUDE, STAMPEDE, ARCHES, ENZAMET, TITAN, and ARANOTE established ADT + ARPI ± docetaxel as the standard of care for mHSPC, producing substantial survival gains. Yet systemic therapy alone remains non-curative, and nearly all patients progress to castration resistance. This limitation has catalyzed interest in MDT, particularly stereotactic ablative radiotherapy (SABR) to achieve local disease control, delay systemic progression, and potentially prolong treatment-free intervals.

The clearest evidence supporting MDT comes from patients with metachronous omHSPC who recur after prior local therapy. The STOMP and ORIOLE phase II trials demonstrated that SABR significantly prolonged progression-free and ADT-free survival compared with observation, without compromising quality of life. A pooled analysis demonstrated MDT significantly prolongs PFS with an HR = 0.44 (95% CI: 0.29-0.66; p < 0.001). Building on these results, the EXTEND trial showed that adding MDT to intermittent or continuous ADT improved PFS (HR=0.25 and 0.50, respectively). The RADIOSA trial found that short-term ADT doubled clinical PFS compared with SABR alone (32.2 vs 15.1 months), and the PEACE V–STORM trial demonstrated higher four-year metastasis-free survival (76% vs 63%) with elective nodal irradiation added to SABR plus ADT. A meta-analysis from the X-MET (WOLVERINE) collaboration confirmed the benefit of MDT, showing improvements in PFS, radiographic PFS, and castration-resistance-free survival, with a trend toward better overall survival.

For synchronous/de novo omHSPC, MDT remains investigational but promising. Phase II multimodal approaches, such as TET and SOLAR, which integrated prostate-directed therapy, MDT, and short-term systemic therapy, achieved encouraging long-term control. Ongoing large randomized trials, including TERPS, STAMPEDE 2 (Comparison S), SWOG S1802, and START-MET, are evaluating whether adding SABR to standard systemic therapy (ADT + ARPI ± docetaxel + prostate RT) improves survival or allows systemic de-escalation in well-selected patients.

The introduction of PSMA-PET has transformed staging accuracy and MDT planning. In ORIOLE, patients with untreated PSMA-positive lesions had significantly worse outcomes, highlighting the need for complete ablation of all molecularly visible disease. Retrospective analyses show that many M0 patients, by conventional imaging, would be reclassified as oligometastatic with PSMA-PET, redefining disease boundaries. Meanwhile, genomic profiling continues to refine patient selection, with TP53, Rb1, BRCA1/BRCA2, and ATM alterations identifying aggressive disease that may benefit from intensified systemic therapy. Biomarker-driven trials such as KNIGHTS are testing MDT in combination with PARP inhibition and hormonal therapy in genomically high-risk omHSPC.

Major clinical guidelines now cautiously endorse MDT as part of multimodal care. The 2025 NCCN Guidelines support SABR for limited metastases, oligoprogression, or durable palliation; AUA/ASTRO/SUO recommendations encourage its use for PET-detected oligometastatic disease, while the EAU advises MDT primarily within research frameworks. As the field moves forward, defining the optimal sequencing, duration, and endpoints of MDT plus systemic therapy will be critical. Integration of PSMA-PET, circulating-tumor DNA, and genomic/transcriptomic biomarkers may enable greater precision in therapy. Ongoing studies such as PSMA-DC (radioligand therapy following SABR) and POSTCARD (SABR ± durvalumab) extend MDT beyond local control toward systemic immune and radioligand synergy.

The convergence of biologically guided systemic agents, advanced imaging, and stereotactic radiotherapy marks a new era of individualized treatment in prostate cancer. MDT, particularly SABR, has proven safe and effective in delaying progression and may soon complement next-generation systemic regimens as part of a unified, patient-centered strategy that redefines long-term control in omHSPC.

Written by: Xiaolei Shi,¹ Jarey H Wang,² Brian F Chapin,³ Ana Aparicio,⁴ Sumit K Subudhi,⁴ Phuoc T Tran,⁵ Ryan J Park,⁶ Matthew P Deek,⁷ Hong Zhang,⁸ Kevin C Bylund,⁸ Micheal Cummings,⁸ Andrew J Armstrong,⁹ Chad Tang,⁶ Philip Sutera¹⁰

Department of Hematology Oncology, University of Maryland Medical Center, Baltimore, MD, USA.
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Urology, MD Anderson, Houston, TX, USA.
Department of Genitourinary Medical Oncology, University of Texas MD Anderson, Houston, TX, USA.
Department of Radiation Oncology, University of Maryland, Baltimore, MD, USA.
Department of Genitourinary Radiation Oncology, University of Texas MD Anderson, Houston, TX, USA.
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA.
Duke Cancer Institute Center for Prostate and Urologic Cancers, Departments of Medicine, Surgery, Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA.

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