Adding metastasis-directed therapy to ADT extends PFS in oligometastatic prostate cancer

Adding metastasis-directed therapy (MDT) to androgen deprivation therapy (ADT) significantly prolonged progression-free survival (PFS) in patients with oligometastatic prostate cancer, according to preliminary data from the phase 2 EXTEND trial (NCT03599765) published in European Urology.¹

"The EXTEND trial demonstrated that the addition of MDT with radiation therapy to hormonal therapy improved PFS compared to hormonal therapy alone in patients with oligometastatic (1-5 metastatic lesions) prostate cancer," said co-author Sumit K Subudhi, MD, PhD, in correspondence with Urology Times®. "In addition, the greatest clinical benefit with MDT plus hormonal therapy was observed in patients with evidence of systemic immune response (T cell receptor [TCR] expansion/contraction)."

In total, the trial enrolled 174 patients through clinical trial sites across the US.² There were 2 arms of the trial, consisting of patients who received continuous ADT (n = 87) and patients who received intermittent ADT (n = 87). Participants in each arm were randomly assigned 1:1 to receive MDT plus ADT (n = 45, continuous; n = 43, intermittent) or ADT alone (n = 42, continuous; n = 44, intermittent).

The primary end point for the trial was PFS, with key secondary end points including radiologic PFS (rPFS) and castration resistance-free survival (CRFS).

Among the patients who received continuous ADT (n = 87), the median follow-up was 31 months. In this cohort, the median PFS was 47 months (95% CI, 30 to NE) among patients who received MDT plus ADT compared with 22 months (95% CI, 13 to NE) among patients who received ADT alone (HR, 0.50; 95% CI, 0.23 to 1.08; P = .036). There were no statistically significant differences observed in the trial’s secondary end points in this arm.

The median follow-up for patients in the intermittent ADT arm (n = 87) was 47 months. In this arm, the median PFS was 28.4 months (95% CI, 23.6 to 47.9) with MDT plus ADT vs 15.8 months (95% CI, 14.0 to 22.6) with ADT alone (HR, 0.44; 95% CI, 0.25 to 0.78; P = .005). rPFS was also significantly longer in the MDT plus ADT arm, with a median rPFS of 34.7 months (95% CI, 27.2 to NE) in the combination arm vs 22.9 months (95% CI, 17.4 to 39.6) in the ADT alone arm (HR, 0.53; 95% CI, 0.29 to 0.96; P = .035).

At the time of the primary analysis, the median overall survival (OS) had not been reached in either arm.

The investigators also conducted a combined analysis, which included data from both the continuous ADT and the intermittent ADT arms. At a median follow-up of 42 months, MDT plus ADT continued to demonstrate significant improvements in PFS vs ADT alone. Specifically, the median PFS was 36 months (95% CI, 27 to 47) with MDT plus ADT vs 17 months (95% CI, 15 to 23) with ADT alone (HR, 0.45; 95% CI, 0.30 to 0.69; P < .001).

The combined analysis also showed improved rPFS with MDT plus ADT, with a median rPFS of 39 months (95% CI, 30 to 48) with the combination vs 26 months (95% CI, 22 to 46) with ADT monotherapy (HR, 0.63; 95% CI, 0.40 to 0.97; P = .038). In patients with oligometastatic hormone-sensitive prostate cancer, the combination of MDT plus ADT also demonstrated superior CRFS vs ADT alone (HR, 0.40; 95% CI, 0.19 to 0.82; P = .01). There were no significant differences in OS (P = .13), time to next-line systemic therapy (P = .47), or time to a new lesion (P = .14) between the 2 arms.

Regarding safety, there were no grade 4 or 5 toxicities reported in the MDT plus ADT arm. Grade 3 events that were deemed possibly related to treatment occurred in 6 patients in the MDT plus ADT arm and 2 patients in the ADT monotherapy arm.

“Together, these findings support a paradigm of MDT + ADT providing a clinical benefit to [oligometastatic prostate cancer] patients by delaying the inexorable progression of metastatic prostate cancer to the fatal disease state [androgen deprivation-resistant prostate cancer,]” the authors wrote. “The results of EXTEND showed that, regardless of the ADT approach (iADT vs cADT), the addition of MDT to ADT improved measures of systemic disease control.”

Follow-up in the EXTEND trial remains ongoing to evaluate the effects of treatment on OS, with final completion expected in December 2025.² However, according to the authors, the present findings warrant confirmatory phase 3 trials of the combination.

They also noted, “These hypothesis-generating findings warrant mechanistic confirmation in preclinical models and may inform the development of blood-based immune biomarkers and future clinical trials combining MDT + ADT with T-cell–targeted immunotherapies.”

REFERENCES

1. Sherry AD, Siddiqui BA, Haymaker C, et al. Continuous androgen deprivation therapy with or without metastasis-directed therapy for oligometastatic prostate cancer: The multicenter phase 2 randomized EXTEND trial. Eur Urol. 2025:S0302-2838(25)00396-3. doi:10.1016/j.eururo.2025.07.006

2. Systemic therapy with or without local consolidative therapy in treating patients with oligometastatic solid tumor. ClinicalTrials.gov. Last updated March 13, 2025. Accessed August 6, 2025. https://clinicaltrials.gov/study/NCT03599765