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ImportanceDespite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial.ObjectiveTo determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone.Design, Setting, ParticipantsThe External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022.InterventionsPatients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression.Main Outcomes and MeasuresThe primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing.ResultsThe study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm.Conclusions and RelevanceIn this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals.Trial RegistrationClinicalTrials.gov Identifier: NCT03599765

Ductal adenocarcinoma (DAC) is the most common variant histological subtype of prostate carcinoma and has an aggressive clinical course. DAC is usually characterized and treated as high-risk prostatic acinar adenocarcinoma (PAC). However, DAC has a different biology to that of acinar disease, which often poses a challenge for both diagnosis and management. DAC can be difficult to identify using conventional diagnostic modalities such as serum PSA levels and multiparametric MRI, and the optimal management for localized DAC is unknown owing to the rarity of the disease. Following definitive therapy for localized disease with radical prostatectomy or radiotherapy, the majority of DACs recur with visceral metastases at low PSA levels. Various systemic therapies that have been shown to be effective in high-risk PAC have limited use in treating DAC. Although current understanding of the biology of DAC is limited, genomic analyses have provided insights into the pathology behind its aggressive behaviour and potential future therapeutic targets.

351 Background: S/R mRCC is an aggressive disease that is associated with improved response to ICT. Studies performed prior to the approval of ICT demonstrated poor outcomes of S/R RCC with VEGF targeted therapies (TT). Here, we report outcomes of pts with S/R mRCC treated with VEGF TT after PD on ICT. Methods: We retrospectively reviewed the records of pts with mRCC with sarcomatoid (S), rhabdoid (R), or sarcomatoid plus rhabdoid (S+R) features who received VEGF TT after PD on ICT. Clinical endpoints of interest were time on VEGF TT and OS from treatment initiation. Directed acyclic graphs were used to identify confounders for adjustment in regression models. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using multivariable Cox regression. Multivariable models adjusted for epithelial histology, IMDC risk, prior VEGF TT, and inclusion of cabozantinib in the post-ICT VEGF TT regimen. Results: 57 pts with metastatic S/R RCC (52 with clear cell and 5 with non-clear cell histology) received a VEGF TT after PD on ICT. 46% of pts received a VEGF TT prior to ICT. After PD on ICT, 67% of pts had IMDC intermediate-risk disease; the most commonly used VEGF TT were cabozantinib (44%), either sunitinib, pazopanib, or axitinib (24%), and a VEGF TT in combination with an ICT (21%). Pts with R RCC had significantly longer time on VEGF TT compared with S RCC (adjusted HR = 0.45, 95% CI 0.21-0.94, p = 0.034), whereas the OS comparison was inconclusive (adjusted HR = 0.77, 95% CI 0.36-1.62, p = 0.486). IMDC risk classification following ICT progression was predictive of OS (adjusted HR = 2.22, 95% CI 1.07-4.61, p = 0.032), whereas, its association with time on VEGF TT was less conclusive (adjusted HR = 1.78, 95% CI 0.88-3.60, p = 0.107). Conclusions: Patients with S/R mRCC derive clinical benefit from VEGF TT after progression on ICT, and it is similar to the benefit previously described for patients without S/R features. Our findings suggest that the type of S/R features present and IMDC risk score inform the clinical benefit that VEGF TT will produce in this setting.[Table: see text]