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Clinical Trial
. 2023 Jun 1;9(6):825-834.
doi: 10.1001/jamaoncol.2023.0161.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial

Chad Tang  1   2   3 , Alexander D Sherry  1 , Cara Haymaker  2 , Tharakeswara Bathala  4 , Suyu Liu  5 , Bryan Fellman  5 , Lorenzo Cohen  6 , Ana Aparicio  7 , Amado J Zurita  7 , Alexandre Reuben  8 , Enrica Marmonti  2 , Stephen G Chun  1 , Jay P Reddy  1 , Amol Ghia  1 , Sean McGuire  1 , Eleni Efstathiou  7 , Jennifer Wang  7 , Jianbo Wang  7 , Patrick Pilie  7 , Craig Kovitz  7 , Weiliang Du  9 , Samantha J Simiele  9 , Rachit Kumar  10 , Yerko Borghero  10 , Zheng Shi  11 , Brian Chapin  12 , Daniel Gomez  13 , Ignacio Wistuba  2 , Paul G Corn  7
Affiliations
Clinical Trial

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial

Chad Tang et al. JAMA Oncol. .

Abstract

Importance: Despite 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.

Objective: To 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, participants: The 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.

Interventions: Patients 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 measures: The 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.

Results: The 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 < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; 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 relevance: In 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 registration: ClinicalTrials.gov Identifier: NCT03599765.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Tang reported receiving grants from the Cancer Prevention & Research Institute of Texas (CPRIT) and the Andrew Sabin Family Foundation and being an Andrew Sabin Scholar during the conduct of the study and receiving royalties from Wolters Kluwer and consulting fees and honoraria from Bayer, Diffusion Pharmaceuticals, and The Osler Institute Lecture Series outside the submitted work. Dr Haymaker reported receiving grants from Avenge Bio, Sanofi, Dragonfly, BTG, Iovance Biotherapeutics, and TriSalus Life Sciences; receiving personal fees from Nanobiotix; receiving speaker honoraria from the Southwest Oncology Group and the Society for Immunotherapy of Cancer; and receiving stock options from BriaCell as a member of the scientific advisory board outside the submitted work. Mr Fellman reported receiving grants from the National Institutes of Health (NIH) to The University of Texas MD Anderson Cancer Center during the conduct of the study. Dr Aparicio reported receiving consulting fees and honoraria from Janssen and AstraZeneca outside the submitted work. Dr Zurita reported receiving grants from Infinity Pharmaceuticals and Pfizer and receiving consulting fees and honoraria from Amedco, AstraZeneca, Bayer, Biocept, Cancer.Net, Pfizer, Janssen, and McKesson outside the submitted work. Dr Reuben reported receiving consulting fees and honoraria from Adaptive Biotechnologies outside the submitted work. Dr Chun reported receiving personal fees from AstraZeneca, Norton Healthcare, Curio Science, the Japanese Society for Radiation Oncology, ViewRay, Inc, and Henry Ford Health during the conduct of the study and receiving consulting fees and honoraria from AstraZeneca and Norton Healthcare outside the submitted work. Dr Ghia reported receiving consulting fees and honoraria from Brainlab outside the submitted work. Dr Efstathiou reported receiving grants from Janssen, Sanofi, Bayer, Merck, AstraZeneca, Nuvation, and Eli Lilly & Company and receiving consulting fees and honoraria from Janssen, Sanofi, Bayer, Merck, AstraZeneca, Nuvation, Eli Lilly & Company, Myovant Sciences, Astellas Pharma, and Pfizer outside the submitted work. Dr Pilie reported receiving personal fees from the Bayer advisory board outside the submitted work. Dr Kovitz reported receiving grants from CPRIT/National Cancer Institute (NCI) during the conduct of the study. Dr Chapin reported receiving grants from Blue Earth Diagnostics, Regeneron Pharmaceuticals, and Janssen and receiving consulting fees and honoraria from Blue Earth Diagnostics, Regeneron, Janssen, and Pfizer outside the submitted work. Dr Gomez reported receiving grants from AstraZeneca, Merck, Varian, and Bristol Myers Squibb and receiving consulting fees and honoraria from Grail, AstraZeneca, Olympus, Johnson & Johnson, Varian, Medtronic, and Med Learning Group outside the submitted work. Dr Wistuba reported receiving personal fees from Genentech/Roche, Bayer, Bristol Myers Squibb, Astra Zeneca, Pfizer, HTG Molecular, Merck, GlaxoSmithKline, Guardant Health, Flame Biosciences, Novartis, Sanofi, Daiichi Sankyo, Amgen, Oncocyte, Janssen, Medscape, MSD, Regeneron, and Platform Health and receiving grants from Adaptive Biotechnologies, 4D Molecular Therapeutics, Adaptimmune, EMD Serono, Takeda, Karus Therapeutics, Iovance Biotherapeutics, Johnson & Johnson, Akoya Biosciences, Merck, Pfizer, Bayer, Amgen, Genentech/Roche, AstraZeneca, EMD Serono, Medimmune, and Precision Oncology outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Figure 2.
Figure 2.. Primary and Key Secondary End Points
B, Eugonadal progression-free survival (testosterone level ≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) was defined as the time from eugonadal status to disease progression. HR indicates hazard ratio; PD, progressive disease.
Figure 3.
Figure 3.. Analysis of Progression-Free Survival According to Key Patient Subgroups
Data are from an exploratory, unstratified Cox proportional hazards regression. Stages are according to American Joint Committee on Cancer criteria. To convert prostate-specific antigen (PSA) level to micrograms per liter, multiply by 1.0. Squares indicate hazard ratios, with horizontal lines indicating 95% CIs.
Figure 4.
Figure 4.. Immune Cell Subsets and T-Cell Receptor (TCR) Sequencing
Peripheral blood samples were obtained at baseline and at first follow-up (3 months). A, For flow cytometry gating, parent populations are the CD3+ population for both CD4+ and CD8+, the CD4+ population for all markers on CD4+ cells including T-regulatory cells (Tregs), the CD8+ population for all markers on CD8+ cells, and the Treg population for the Treg CD73+ population. Asterisks indicate P < .05 for the W-score comparing the population between the 3-month follow-up timepoint and the baseline timepoint. CTLA-4 indicates cytotoxic T-lymphocyte associated protein 4; ICOS, inducible costimulator; LAG-3, lymphocyte activation gene 3; MDT, metastasis-directed therapy; PD-1, programmed cell death protein 1; TIGIT, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM3, T-cell immunoglobulin and mucin domain 3.
See this image and copyright information in PMC

Comment in

  • Urologic Oncology: Prostate Cancer.
    Taneja SS. Taneja SS. J Urol. 2023 Nov;210(5):822-824. doi: 10.1097/JU.0000000000003675. Epub 2023 Aug 25. J Urol. 2023. PMID: 37622534 No abstract available.

References

    1. Duchesne GM, Woo HH, Bassett JK, et al. . Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016;17(6):727-737. doi:10.1016/S1470-2045(16)00107-8 - DOI - PubMed
    1. Studer UE, Whelan P, Albrecht W, et al. . Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) trial 30891. J Clin Oncol. 2006;24(12):1868-1876. doi:10.1200/JCO.2005.04.7423 - DOI - PubMed
    1. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341(24):1781-1788. doi:10.1056/NEJM199912093412401 - DOI - PubMed
    1. James ND, Sydes MR, Clarke NW, et al. ; STAMPEDE investigators . Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. doi:10.1016/S0140-6736(15)01037-5 - DOI - PMC - PubMed
    1. Fizazi K, Foulon S, Carles J, et al. ; PEACE-1 investigators . Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1 - DOI - PubMed

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