Highlight
– The phase 2 GROUQ-PCS 9 trial shows that adding stereotactic body radiotherapy (SBRT) to standard systemic therapy (ADT plus enzalutamide) significantly doubles median radiographic progression-free survival (rPFS) in men with oligometastatic castration-resistant prostate cancer (CRPC).
– The trial enrolled 102 patients across 13 Canadian oncology centers with ≤5 metastases and demonstrated an rPFS of 4.6 years with SBRT addition compared to 2.3 years with systemic therapy alone.
– No new safety concerns were identified; both treatment arms had comparable toxicity profiles with impotence being the most common grade 3 treatment-related adverse event.
– These findings support integrating metastasis-directed therapy into management of oligometastatic CRPC to prolong disease control.
Study Background and Disease Burden
Prostate cancer remains a leading cause of cancer morbidity and mortality among men worldwide. Castration-resistant prostate cancer (CRPC), defined as progression despite androgen deprivation therapy (ADT), presents a significant treatment challenge. Within this population, a subset with limited metastatic burden—termed oligometastatic CRPC—is hypothesized to have distinct clinical behavior amenable to aggressive local therapies.
Currently, the standard systemic approach involves continuing ADT combined with androgen receptor axis-targeted agents such as enzalutamide. However, the role of metastasis-directed therapy (MDT), such as stereotactic body radiotherapy (SBRT) targeting all known metastatic sites, has been uncertain. While prior retrospective and single-arm studies suggested potential benefit, high-quality randomized data have been lacking. There is a clear unmet need to evaluate whether MDT can improve outcomes by delaying disease progression or extending survival with acceptable toxicity in oligometastatic CRPC.
Study Design
GROUQ-PCS 9 was a multicenter, open-label, randomized phase 2 trial conducted across 13 academic and community oncology centers in Canada. Eligible patients were men aged ≥18 years, with histologically confirmed oligometastatic CRPC defined as up to 5 metastatic lesions, progression after ADT, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.
Participants were randomized 1:1 to two treatment arms: standard systemic therapy with ADT plus enzalutamide 160 mg daily (ADT-ENZA) versus ADT-ENZA combined with SBRT directed at all oligometastatic sites (ADT-ENZA-SBRT). Randomization was stratified by metastatic site location and implemented using sealed opaque envelopes.
The primary endpoint was radiographic progression-free survival (rPFS), defined by standardized imaging criteria indicating disease progression. Secondary endpoints included safety, tolerability, and adverse event profiling. Intention-to-treat analysis was employed.
The trial was registered at ClinicalTrials.gov (NCT02685397) and was halted and completed at phase 2 stage after enrollment and follow-up.
Key Findings
Between October 2016 and July 2023, 102 patients were randomized (49 to ADT-ENZA and 53 to ADT-ENZA-SBRT). After excluding one patient per group due to early withdrawal or incomplete data, 100 patients formed the final analysis population.
The median age was 73 years, predominantly White ethnicity (80%), and ECOG performance status 0–2. The median follow-up was 4.8 years, providing robust long-term outcome data.
Radiographic progression-free survival was significantly prolonged in the SBRT arm. Median rPFS was 4.6 years (95% CI 3.7–not reached) with ADT-ENZA-SBRT versus 2.3 years (95% CI 1.4–3.7) with ADT-ENZA alone. The hazard ratio for disease progression or death was 0.48 (95% CI 0.27–0.86; p=0.014), indicating a 52% reduction in risk with MDT addition.
Regarding safety, no grade 4 toxicities or treatment-related deaths occurred. The most common grade 3 adverse event was impotence, reported in 57% of assessable patients in the ADT-ENZA group and 75% with ADT-ENZA-SBRT. Other adverse events were comparable between groups, confirming the favorable tolerability of adding SBRT.
These results robustly demonstrate that MDT with SBRT integrated into systemic therapy significantly delays disease progression in oligometastatic CRPC without increasing high-grade toxicities.
Expert Commentary
The GROUQ-PCS 9 trial represents a landmark study providing randomized evidence that metastasis-directed SBRT augments the efficacy of standard systemic therapy in oligometastatic CRPC. The doubling of median progression-free survival with well-tolerated toxicities fills a critical knowledge gap regarding the optimal treatment approach in this distinct clinical subset.
These findings align biologically with the concept that eliminating limited metastatic deposits may slow systemic spread and resistance evolution in CRPC. Nevertheless, OS and quality-of-life endpoints remain to be further explored in larger or phase 3 trials. Generalizability outside the Canadian healthcare setting should consider patient selection and access to advanced radiotherapy.
Current international guidelines recommend systemic therapy for CRPC, but the role of MDT is evolving. This high-quality evidence supports updating practice paradigms to incorporate SBRT in carefully selected oligometastatic CRPC patients.
Conclusion
The GROUQ-PCS 9 randomized phase 2 trial provides compelling evidence that adding SBRT to standard ADT and enzalutamide significantly improves radiographic progression-free survival in men with oligometastatic castration-resistant prostate cancer. This combined modality approach is well-tolerated and effectively doubles disease control duration compared to systemic therapy alone.
These data advocate for routine consideration of metastasis-directed SBRT within the oligometastatic CRPC treatment landscape to enhance patient outcomes. Ongoing research should evaluate survival benefits, quality-of-life impact, and cost-effectiveness to establish MDT as a standard of care.
References
1. Niazi T, Saad F, Tisseverasinghe S, et al. Metastases-directed therapy in addition to standard systemic therapy in oligometastatic castration-resistant prostate cancer in Canada (GROUQ-PCS 9): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2025 Sep;26(9):1158-1167. doi: 10.1016/S1470-2045(25)00351-1. PMID: 40907514.
2. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017 May 25;376(15):1420-1430.
3. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018 Jun 10;36(17):446-453.
4. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97.