Impact of adding hormone therapy to postoperative radiotherapy in prostate cancer.

# Impact of adding hormone therapy to postoperative radiotherapy in prostate cancer *The Lancet 2026* Comment Impact of adding hormone therapy to postoperative radiotherapy in prostate cancer The addition of hormone therapy to radiotherapy at higher PSA levels. Beyond considerations of how so- improves overall survival in men with high-risk prostate called value might be assigned to a given intervention,11 cancer, over radiotherapy alone.1 Mechanisms proposed or how relevant biological heterogeneity (not reflected in to explain this effect include cytoreduction, the androgen PSA levels) might be diluted in these analyses, what could receptor’s regulation of key DNA damage response explain these results? pathways, and suppression of micrometastases.2,3 Perhaps the only benefit from adding hormone therapy However, randomised trials evaluating the benefit of to radiotherapy is the treatment of micro metastasis. adding hormone therapy to postoperative radiotherapy Indeed, over half of the patients with PSA greater (PORT) have yielded conflicting results.4–9 than 0·5 ng/mL post-prostatectomy have metastasis In The Lancet, Amar U Kishan and colleagues10 report detectable by prostate-specific membrane antigen on a meta-analysis of individual patient data from PET imaging.12 Furthermore, early intensified hormone 6507 participants in six randomised trials evaluating the therapy improves outcomes in patients with biochemical overall survival benefit of adding hormone therapy to recurrences (defined by conventional imaging) relative PORT: GETUG-AFU 165 (n=742 patients), RTOG 05346 to androgen deprivation therapy alone.3,13 Assuming (n=1716), RTOG-96014 (n=760), and the three-way (absent randomised trial data) that early androgen and two-way randomised arms of RADICALS-HD7–9 deprivation therapy alone also improves outcomes (n=1808 and 1480). These men had prostate- in biochemical recurrence, this could account for the specific antigen (PSA) levels up to 2–5 ng/mL4–9 benefit observed in patients with higher pre-PORT PSA following a radical prostatectomy and were recruited levels. Alternatively, since several life-prolonging drugs between 1998 and 2015 with a median follow-up of have been approved for prostate cancer in the last 9·0 years (IQR 7·2–10·7). Some differences across trials decade14 it is possible that longer follow-up would reveal are noteworthy. Previous pelvic lymphadenectomy and an overall survival advantage in patients with lower pre- pelvic radiotherapy were optional in all but RTOG-9601.4 PORT PSA levels, who probably have a more protracted Only RTOG-05346 and RTOG-96014 mandated baseline course. Or, maybe, an improvement in prostate cancer abdominopelvic CT and technetium-99m bone scan for specific survival is obscured by an increased mortality due all participants. A minimum PSA level was not required to hormone therapy related toxicities in patients at risk. for RADICALS participants, who were eligible if “due to The authors also explore the benefit of long-term receive PORT”, “early or late”.7–9 And, finally, in RTOG-9601 versus short-term hormone therapy added to PORT and hormone therapy consisted of high-dose bicalutamide4 find no significant interaction between hormone therapy (also allowed in RADICALS) versus lutenising-hormone- duration and the effect on overall survival but do find releasing hormone analogues in the remaining trials. that long-term hormone therapy results in longer MFS. In their analysis, Kishan and colleagues10 found that Given that the longer the androgen deprivation therapy adding hormone therapy resulted in a hazard ratio treatment, the more delayed and the lower the likelihood (HR) of 0·87 (95% CI 0·76–1·01, p=0·06) for overall of testosterone recovery,15 it can be hypothesised that the survival in the overall population. However, they observed difference in MFS is due to undertreatment in the short- a significant interaction with pre-PORT PSA levels greater term hormone therapy groups, if resumption of androgen than 0·5 ng/mL versus up to 0·5 ng/mL (p=0·03) and deprivation therapy were delayed on subsequent PSA conclude that there is no meaningful overall survival progression.3 If this were true, intermittent short-term benefit to adding hormone therapy to PORT for PSA of hormone therapy13 should be favoured over unnecessarily less than 0·5 ng/mL. On the other hand, adding hormone committing most men to potentially lifelong castration. therapy resulted in a HR of 0·79 (0·70–0·89, p<0·001) for A provocative question is whether PORT could be metastasis-free survival (MFS; a secondary endpoint) in omitted altogether in some patients. Several phase 2 the overall population, with greater benefit also observed randomised trials indicate that radiotherapy to metastasis 1030 segami ytteG aiv yrarbiL otohP ecneicS/renssiemhcsG evetS Published Online February 26, 2026 https://doi.org/10.1016/ S0140-6736(26)00368-5 See Articles page 1059 Comment has low toxicity and can improve progression-free Department of Genitourinary Medical Oncology, The University of Texas MD survival.16 However, the frequency and severity of toxicity Anderson Cancer Center, Houston, TX 77030, USA (AMA, PGP) from radiotherapy to the prostate fossa might be higher, 1 Kishan AU, Sun Y, Hartman H, et al, and the MARCAP Consortium group. Androgen deprivation therapy use and duration with definitive particularly in a population with a prolonged overall radiotherapy for localised prostate cancer: an individual patient data meta- analysis. Lancet Oncol 2022; 23: 304–16. survival. Although robust long-term prospective data 2 Pilié PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting reporting on delayed toxicities from PORT are lacking, the DNA damage response in cancer. Nat Rev Clin Oncol 2019; 16: 81–104. 3 Shore ND, Luz MA, De Giorgi U, et al. Improved survival with enzalutamide the cumulative incidence rates of toxicities of grade 2 in biochemically recurrent prostate cancer. N Engl J Med 2025; 394: 563–75. and higher are not negligible. Even if not of grade 3 and 4 Shipley WU, Seiferheld W, Lukka HR, et al, and the NRG Oncology RTOG. Radiation with or without antiandrogen therapy in recurrent prostate higher intensity, these toxicities are largely permanent cancer. N Engl J Med 2017; 376: 417–28. and can result in the need for invasive procedures and 5 Carrie C, Magné N, Burban-Provost P, et al. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after even hospitalisations, substantially affecting quality of radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial. Lancet Oncol 2019; 20: 1740–49. life.17 Long-term hormone therapy is, of course, fraught 6 Pollack A, Karrison TG, Balogh AG, et al. The addition of androgen deprivation with toxicities of its own.14 However, hypothetically, therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, intermittent short-term hormone therapy prescribed multicentre, randomised phase 3 trial. Lancet 2022; 399: 1886–901. with a strict regimen to counter these toxicities 7 Parker CC, Clarke NW, Cook AD, et al, and the RADICALS Investigators. Adding 6 months of androgen deprivation therapy to postoperative (eg, physical exercise programmes), could be a reasonable radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled alternative for patients who achieve prolonged trial. Lancet 2024; 403: 2405–15. eugonadal progression-free survival intervals after short 8 Parker CC, Clarke NW, Cook AD, et al, and the RADICALS Investigators. Randomised trial of no, short-term, or long-term androgen deprivation courses of hormone therapy.13 therapy with postoperative radiotherapy after radical prostatectomy: These and other questions would require additional results from the three-way comparison of RADICALS-HD (NCT00541047). Eur Urol 2024; 86: 422–30. randomised trials and decades of follow-up. Early 9 Parker CC, Kynaston H, Cook AD, et al, and the RADICALS Investigators. Duration of androgen deprivation therapy with postoperative radiotherapy endpoints such as MFS have proven useful,18 the caveat for prostate cancer: a comparison of long-course versus short-course being that MFS includes death from any cause, which androgen deprivation therapy in the RADICALS-HD randomised trial. Lancet 2024; 403: 2416–25. can be confounding. An attractive option is eugonadal 10 Kishan AU, Sun Y, Parker CC, et al. Hormone therapy use and duration with progression-free survival,13 which can be linked to patient postoperative radiotherapy for recurrent prostate cancer: an individual patient data meta-analysis. Lancet 2026; published online Feb 26. https:// benefit and directly attributed to the intervention. In doi.org/10.1016/S0140-6736(26)00137-6. addition, the emerging use of rigorous observational 11 Stewart DJ, Bradford JP, Sehdev S, et al. New anticancer drugs: reliably assessing “value” while addressing high prices. Curr Oncol 2024; 31: 2453–80. studies seeking causal inferences or in silico emulation 12 Mazzone E, Thomson A, Chen DC, et al. The role of prostate-specific membrane antigen positron emission tomography for assessment of local studies might contribute data that inform clinical care. recurrence and distant metastases in patients with biochemical recurrence This individual patient data meta-analysis underscores of prostate cancer after definitive treatment: a systematic review and meta-analysis. Eur Urol 2025; 88: 129–41. an important adage in prostate cancer that more might 13 Spetsieris N, Boukovala M, Alafis I, et al. Abiraterone acetate plus not always be better. Increasingly sensitive imaging prednisone in non-metastatic biochemically recurrent castration-naïve prostate cancer. Eur J Cancer 2021; 157: 259–67. modalities, genomic classifiers, and artificial intelligence- 14 Raychaudhuri R, Lin DW, Montgomery RB. Prostate cancer: a review. based pathology biomarkers19 have shown promise JAMA 2025; 333: 1433–46. 15 Ong WL, Romero T, Roy S, et al, and the MARCAP Consortium in guiding therapy escalation versus de-escalation Investigators. Testosterone recovery following androgen suppression and prostate radiotherapy (TRANSPORT): a pooled analysis of five randomized strategies. For now, clinicians and patients will need trials from the Meta-Analysis of Randomized Trials in Cancer of the to weigh the potential value of prolonging MFS by Prostate (MARCAP) Consortium. Eur Urol 2025; 87: 49–57. 16 Tang C, Sherry AD, Hwang H, et al. Metastasis-directed therapy and adding hormone therapy to PORT in light of Kishan and standard of care versus standard of care for oligometastatic prostate cancer colleagues’10 results signalling no overall survival benefit. (WOLVERINE): a systematic review and individual patient data meta- analysis from the X-MET collaboration. Lancet Oncol 2026; 27: 181–90. AMA declares honoraria for consulting or scientific advisor services from AbbVie, 17 Morgan TM, Boorjian SA, Buyyounouski MK, et al. Salvage therapy for Amgen, Astellas Pharma, AstraZeneca Pharmaceuticals, Bayer, Boehringer prostate cancer: AUA/ASTRO/SUO guideline part i: introduction and Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Glaxo Smith Kline, Johnson & treatment decision-making at the time of suspected biochemical Johnson–Janssen Pharmaceuticals, Novartis, Merck, Pfizer, and Sanofi/Genzyme; recurrence after radical prostatectomy. J Urol 2024; 211: 509–17. and research support from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, 18 Freedland SJ, de Almeida Luz M, De Giorgi U, et al, and the EMBARK Study. Daiichi Sankyo, Johnson & Johnson–Janssen Pharmaceuticals, Polaris Pharm a- Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med 2023; 389: 1453–65. ceuticals, and Sanofi/Genzyme. PGP declares honoraria for consulting or advisor services from AstraZeneca Pharmaceuticals, Bayer, and Johnson & Johnson–Janssen 19 National Comprehensive Cancer Network. Prostate cancer, version 5. 2026. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf Pharmaceuticals and holds a patent on a replication stress response gene signature. (accessed Feb 16, 2026). *Ana M Aparicio, Patrick G Pilié aaparicio@mdanderson.org --- [PDF原文](https://sci-net.xyz/storage/7932541/1b9a868d48c1039059cf77c8cf5034284cea0f0c78d01c11f87a418428c49b27/Impact-of-adding-hormone-therapy-to-postoperative-radiotherapy-in-prostate-cancer.pdf) DOI: 10.1016/S0140-6736(26)00368-5