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A Phase 2, Randomized, Controlled Trial of Best Systemic Therapy versus Best Systemic Therapy with Definitive Treatment of the Primary Tumor in Metastatic Prostate Cancer - Beyond the Abstract

Systemic therapy for metastatic hormone-sensitive prostate cancer has advanced rapidly over the past decade with the integration of androgen receptor pathway inhibitors and chemotherapy into androgen deprivation therapy. As these treatments extend survival and change the natural history of the disease, interest has grown in whether treatment of the primary tumor meaningfully alters outcomes for men who present with metastatic disease.

In this randomized phase 2 study, adding definitive treatment of the primary tumor to the best systemic therapy did not improve overall survival. Findings like this are important. In a field where there is enthusiasm to intensify treatment, prospective data that question the incremental value of additional therapy provide a needed perspective.

Several randomized trials have explored treatment of the primary tumor in metastatic disease with mixed results. The HORRAD trial did not demonstrate a survival advantage with prostate radiotherapy.1 STAMPEDE Arm H later reported improved survival with prostate radiotherapy in men with low-volume metastatic disease but not in those with high-volume disease.2 A subsequent meta-analysis combining STAMPEDE and HORRAD suggested benefit in low-volume disease, although that signal was largely driven by the STAMPEDE cohort.3 More recently, PEACE-1 evaluated prostate radiotherapy in the setting of intensified systemic therapy and showed improvement in progression-related endpoints in low-volume disease without a clear overall survival benefit. 4

Other randomized studies have taken a broader approach to local therapy. The trial by Dai and colleagues, similar in design to this phase 2 study, allowed treatment of the primary tumor with either surgery or radiotherapy and suggested improved outcomes with local therapy.5 The G-RAMPP trial later evaluated radical prostatectomy specifically and reported an improvement in cancer-specific mortality but did not demonstrate a statistically significant improvement in overall survival.6

Taken together, these studies illustrate that the role of treating the primary tumor in metastatic prostate cancer remains uncertain. Ongoing trials aim to provide greater clarity. The SWOG S1802 trial is evaluating whether definitive treatment of the primary tumor, added to the best systemic therapy, improves survival in men with metastatic hormone-sensitive prostate cancer, allowing treatment of the primary tumor with either surgery or radiation.7 The PRESIDENT trial in the United Kingdom is evaluating radical prostatectomy added to systemic therapy in men with low-volume metastatic disease identified using PSMA PET imaging.8

Across these studies, one theme continues to emerge: metastatic prostate cancer is biologically heterogeneous. Some patients experience durable disease control with systemic therapy alone, while others develop progressive local disease despite adequate systemic treatment. Whether the primary tumor continues to influence disease progression likely varies between patients.

For that reason, the next step is not simply determining whether local therapy works, but identifying which patients benefit and why. Integrating meaningful correlative science into these trials will be critical. Molecular characterization, advanced imaging, and clinical phenotypes such as aggressive variant prostate cancer may help clarify which tumors remain biologically linked to the primary site and which represent disease that is already fully systemic.

Until those signals are better defined, decisions regarding local therapy will continue to occur in areas of uncertainty. Shared decision making remains essential when considering treatments that carry potential morbidity in patients already receiving increasingly effective systemic therapy. Ultimately, combining carefully conducted trials with deeper biologic insight will determine when treatment of the primary tumor meaningfully improves outcomes for men with metastatic prostate cancer.

Written by: Brian F. Chapin,1 Marc Smaldone,2 Amado J. Zurita,3 Jennifer Wang,3 Matthew R. Cooperberg,4 Martin Gleave,5 Scott E. Delacroix,6 John Davis,1 Curtis Pettaway,1 Louis Pisters,1 Mehrad Adibi,1 Lisly Chery,1 John Papadopoulos,1 John Ward,1 Justin Gregg,1 Neema Navai,1 Paul Corn,3 Sumit K. Subudhi,3 Christopher Logothetis,3 Deborah Kuban,7 Quynh Nguyen,7 Chad Tang,7 Seungtaek Choi,7 Karen Hoffman,7 Marisa Lozano,1 Mohamed Elsheftawi,1 Mary Achim,1 Yuehui Zhao,8 Naveen Ramesh,8 Emi Sei,8 Nicholas Navin,8 Graciela M Nogueras Gonzalez,9 Xuemei Wang,9 Keyi Zhu,10 Patricia Troncoso,10 Miao Zhang,10 Sean McGuire,7 Ana M. Aparicio,3

  1. Department of Urology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  2. Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA.
  3. Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  4. Department of Urology, University of California San Francisco, San Francisco, CA, USA.
  5. Department of Urology, University of British Columbia, Vancouver, BC, Canada.
  6. Department of Urology, The Louisiana State University, Baton Rouge, LA, USA.
  7. Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  8. Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  9. Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  10. Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
References:

  1. Boevé LMS, Hulshof MCCM, Vis AN, Zwinderman AH, Twisk JWR, Witjes WPJ, Delaere KPJ, Moorselaar RJAV, Verhagen PCMS, van Andel G. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019 Mar;75(3):410-418. doi: 10.1016/j.eururo.2018.09.008. Epub 2018 Sep 25. PMID: 30266309.
  2. Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, Ritchie AWS, Attard G, Chowdhury S, Cross W, Dearnaley DP, Gillessen S, Gilson C, Jones RJ, Langley RE, Malik ZI, Mason MD, Matheson D, Millman R, Russell JM, Thalmann GN, Amos CL, Alonzi R, Bahl A, Birtle A, Din O, Douis H, Eswar C, Gale J, Gannon MR, Jonnada S, Khaksar S, Lester JF, O'Sullivan JM, Parikh OA, Pedley ID, Pudney DM, Sheehan DJ, Srihari NN, Tran ATH, Parmar MKB, Sydes MR; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018 Dec 1;392(10162):2353-2366. doi: 10.1016/S0140-6736(18)32486-3. Epub 2018 Oct 21. PMID: 30355464; PMCID: PMC6269599.
  3. Burdett S, Boevé LM, Ingleby FC, Fisher DJ, Rydzewska LH, Vale CL, van Andel G, Clarke NW, Hulshof MC, James ND, Parker CC, Parmar MK, Sweeney CJ, Sydes MR, Tombal B, Verhagen PC, Tierney JF; STOPCAP M1 Radiotherapy Collaborators. Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol. 2019 Jul;76(1):115-124. doi: 10.1016/j.eururo.2019.02.003. Epub 2019 Feb 28. PMID: 30826218; PMCID: PMC6575150.
  4. Bossi A, Foulon S, Maldonado X, Sargos P, MacDermott R, Kelly P, Fléchon A, Tombal B, Supiot S, Berthold D, Ronchin P, Kacso G, Salem N, Calabro F, Berdah JF, Hasbini A, Silva M, Boustani J, Ribault H, Fizazi K; PEACE-1 investigators. Efficacy and safety of prostate radiotherapy 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. 2024 Nov 23;404(10467):2065-2076. doi: 10.1016/S0140-6736(24)01865-8. Erratum in: Lancet. 2025 May 10;405(10490):1665. doi: 10.1016/S0140-6736(25)00903-1. PMID: 39580202.
  5. Dai B, Zhang S, Wan FN, Wang HK, Zhang JY, Wang QF, Kong YY, Ma XJ, Mo M, Zhu Y, Qin XJ, Lin GW, Ye DW. Combination of Androgen Deprivation Therapy with Radical Local Therapy Versus Androgen Deprivation Therapy Alone for Newly Diagnosed Oligometastatic Prostate Cancer: A Phase II Randomized Controlled Trial. Eur Urol Oncol. 2022 Oct;5(5):519-525. doi: 10.1016/j.euo.2022.06.001. Epub 2022 Jun 29. PMID: 35780048.
  6. Sooriakumaran P, Haendler L, Nyberg T, Gronberg H, Nilsson A, Carlsson S, Hosseini A, Adding C, Jonsson M, Ploumidis A, Egevad L, Steineck G, Wiklund P. Biochemical recurrence after robot-assisted radical prostatectomy in a European single-centre cohort with a minimum follow-up time of 5 years. Eur Urol. 2012 Nov;62(5):768-74. doi: 10.1016/j.eururo.2012.05.024. Epub 2012 May 18. PMID: 22633365.
  7. SWOG Cancer Research Network. Standard systemic therapy with or without definitive treatment in treating participants with metastatic prostate cancer. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2018 Sep 19 [cited 2026 Apr 16].
  8. Sooriakumaran P, Klaassen Z. PRESIDENT: Prostatectomy surgery in disseminated low-volume metastatic hormone-sensitive prostate cancer with endpoint assessment using nuclear imaging technology using PSMA PET/CT imaging: a definitive randomized controlled trial. UroToday [Internet]. 2026 Mar [cited 2026 Apr 16].
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