Ultra-hypofractionated radiotherapy and concomitant oral relugolix for treatment of intermediate risk prostate cancer (ULTRA-HERO)

Radiotherapy (RT) and concomitant short course androgen deprivation therapy (ADT) is one of the standard approaches for patients affected by localized intermediate risk prostate cancer. However, effects of testosterone depletion may have a significant impact on bone mineral density, metabolic changes, increased insulin resistance, sexual dysfunction, hot flashes. Moreover, many men undergoing ADT may fail to recover their mean baseline eugonadal testosterone level even after long term from ADT cessation. Relugolix is an oral, highly selective, GnRH antagonist recently tested in a randomized phase III trial showing reduced risk in terms of cardiovascular events and rapid testosterone recovery if compared to Leuprolide. Given its rapid testosterone recovery, relugolix may significantly reduce the long term negative impact of ADT in the specific setting of a short term duration treatment. However, prospective evidence is needed in order to assess if concomitant treatment with short course ADT with relugolix and RT may obtain the same disease control benefit if compared to historical data related to standard ADT with LH- RH analogues. With this purpose, we designed an interventional trial aimed to evaluate rate of complete biochemical response in an homogeneous cohort of patients affected by intermediate risk localized prostate cancer undergoing prostate radiotherapy+short course oral relugolix. Methods: ULTRA-HERO is a Prospective, no-profit, single arm phase II, interventional multicentric trial aimed to evaluate the effectiveness of concomitant prostate RT and short course oral relugolix. In brief, patients affected by unfavouralbe intermediate risk prostate carcinoma (Gleason 4+3 and or>50% of biopsy cores positive and or >2 intermediate risk factors), who are deemed suitable for ultrahypofractionated treatment on prostate (IPSS < 15, prostate volume <90 cc) will undergo definitive treatment consisting in ultrahypofractionated prostate radiotherapy for a total dose of 36.25 Gy in 5 fractions, 7.25 Gy each, every other day and concomitant treatment with oral relugolix administered with an attack dose of 360 mg (3 tablets) the first day, followed by a daily dose of 120 mg for a total duration of 6 months. All patients with neuroendocrine differentiation, metastatic disease at diagnosis or any high risk features are excluded from the trial. Primary endpoint of the study will be rate of patients with complete biochemical response (nadir < 0.5 ng/ml) at 6 months after end of radiotherapy. Enrollment started in May 2025 and 20 patients have been enrolled up to date. A final sample size of sample size of 73 patients will be needed to estimate the expected proportion of patients with complete biochemical response with a 5% precision margin and a 95% confidence interval. Clinical trial information: CTIS ID: 36502.