Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer (EXTEND): A Multicenter, Randomized Phase II Trial

Abstract

<h3>Purpose/Objective(s)</h3> There has been increased utilization of metastasis directed therapy (MDT) for oligometastatic prostate cancer. Despite data demonstrating the benefit of upfront hormone therapy (HT) and synergy between radiation and HT, there exists no randomized trials testing their combination. As it is accepted by most clinicians and men with prostate cancer that time off HT holds intrinsic value, we evaluated whether the addition of metastasis directed therapy (MDT) to intermittent HT in men with oligometastatic prostate cancer facilities time off HT by improving PFS and eugonad PFS. <h3>Materials/Methods</h3> EXTEND (NCT03599765) is a phase II randomized basket trial for multiple solid tumors testing whether the addition of MDT improves PFS. The primary endpoint was pre-specified to be independently assessed and reported for the prostate intermittent HT basket at 41 events. Men with ≤5 metastases were randomized after ≥2 months of HT to continuing HT with or without MDT. HT consisted of a luteinizing hormone-releasing hormone agonist/antagonist with or without a 2^nd generation androgen-receptor targeting agent (SART). The primary endpoint was progression, defined as death or radiographic, clinical, or biochemical progression. A planned HT break occurred 6 months after enrollment, after which HT was withheld until progression. The study was designed to have 80% power to detect an improvement in median PFS from 18 to 36 months, with a type I error of 0.1. Exploratory analysis included flow cytometry and TCR sequencing from peripheral blood at baseline and 3 months follow up. <h3>Results</h3> Between Sept 2018 to Nov 2020, 87 men were randomized, 43 combined therapy and 44 to HT-only. Arms were well balanced. At a median follow-up of 22.1 months (range 13.0 to 39.3 months), 41 events were observed. PFS was improved by the receipt of MDT (median not reached vs 15.8 months for HT-only, P<0.001; HR=0.25 [95% CI, 0.12 to 0.55]). Among secondary endpoints, time from eugonad testosterone levels (>150 ng/dL) to progression was improved by MDT (median not reached vs 6.1 months, P=0.03), as was time to appearance of new lesions (2-year rate 33% vs 41%, P=0.04). Three grade 3 toxicities were observed in each arm. Subgroup analysis identified PFS improvement with MDT in patients who received (HR=0.24 [95% CI, 0.08 to 0.71]) or did not receive a SART (HR=0.36 [95% CI, 0.15 to 0.83]). Flow cytometry and TCR sequencing demonstrated increases in markers of T cell activation, proliferation, and clonal expansion limited to the combined therapy arm. <h3>Conclusion</h3> EXTEND represents the first randomized study to evaluate MDT with HT in oligometastatic prostate cancer and demonstrated improvement in PFS and eugonad PFS. Combination of MDT with intermittent HT may allow for both excellent disease control while facilitating prolonged eugonad testosterone intervals.