The optimal indication for ADT has long been a point of controversy, at least until the results of randomised trials comparing RT with and without ADT were published. NCCN guidelines and most retrospective series and left the decision to prescribe ADT in combination with RT to the discretion of the treating physician, despite a lack of clear scientific evidence to support this recommendation. The percentage of patients in those retrospective series who received hormone therapy ranged from 33% to 71%, but generally involved patients with adverse prognostic factors (Gleason score > 7, stage pT3-T4, PSA > 1 ng/mL in cases with biochemical recurrence [BCR], and PSA doubling time [PSA-DT] < 6 months). Despite the heterogeneity in those studies in terms of treatment duration, RT dose, and treatment volumes, most of the studies found that ADT significantly prolonged biochemical relapse-free survival (BRFS), especially in patients with PSA levels > 1 ng/mL at recurrence.

The results of two randomised trials evaluating SRT with or without ADT were published in 2017, with both trials demonstrating a benefit for ADT in this clinical setting. A follow-up study confirmed the value of ADT in combination with SRT in terms of better PFS and, in the RTOG study, an improvement in overall survival (OS). Despite the lack of data from phase III trials regarding the influence of PSA-DT, the BRFS interval, and the Gleason score in terms of their effects on the clinical course of patients who develop BCR, there is strong evidence from other studies to support the use of these variables (together with age and comorbidities). Given the available evidence, we believe that these variables should be considered when determining the indications for ADT.

In line with the philosophy underlying the approach used by D'Amico to develop a risk classification system for prostate cancer patients at diagnosis, we propose three risk groups. According to Pollack et al. and Spratt et al., low-risk patients would not benefit from hormone therapy, especially long-term ADT, due to the deleterious effects of such treatment. By contrast, intermediate and high risk patients would be candidates for ADT combined with RT. However, the optimal duration of ADT in these patients (6 months vs. 2 years) remains undefined and needs to be determined prospectively in a randomised trial, similar to the approach used in the DART 05.01 trial.

SRT and ADT are widely used in routine clinical practice to treat patients who develop BCR after prostatectomy. In this context, we intend to perform a multicentre, phase III trial to define the optimal duration of ADT (6 vs. 24 months).

Inclusion Criteria:

1. Patients with histologically-confirmed prostate cancer treated with radical prostatectomy. Patients who have not undergone lymph node dissection are eligible for inclusion.

2. Biochemical recurrence after prostatectomy: BCR is defined as a PSA value ≥ 0.2 ng/mL, with at least one confirmatory PSA determination ≥ two weeks after the first test (the confirmatory PSA level must be higher than the initial value). Patients with Gleason 8-10, pT3b or R1 are eligible for inclusion in the trial with PSA ≥ 0.15 ng/mL; however, in patients with PSA > 0.4 ng/mL, imaging tests (conventional CT and bone scans or advanced imaging techniques such as PSMA or choline PET/CT) should be performed to check for metastases. In patients with PSA levels between 0.15 and 0.4 ng/mL, no further tests are required to check for distant metastases prior to inclusion.

3. Intermediate and high-risk patients according to the classification criteria proposed by González San Segundo et al. (18):

   CHARACTERISTICS INTERMEDIATE RISK (≥ 2) HIGH RISK(≥ 1)

   PSA at diagnosis, ng/mL 0.6-1.0 ≥1.0 PSA doubling time, months 6-12 < 6 GLEASON / ISUP 7/3 ≥8/≥4 TNM (prostatectomy specimen) pT2-3a pN0-Mx pT3b pN0-Mx Time to biochemical recurrence, months >18 <18 Margins Positive Positive

4. Testosterone level > 150 ng/dL at inclusion

5. ECOG 0-1

6. Life expectancy > 5 years

7. Signed informed consent

Exclusion Criteria:

1. Presence of pN1 disease in the original surgical specimen
2. Presence of macroscopic disease on imaging tests. If the PSA at diagnosis is > 0.4 ng/mL, then imaging tests (CT and bone scan and/or PET/CT or body magnetic resonance imaging [MRI]) are required.
3. PSA <0.2 or <0.15 ng/mL (if Gleason score=10, pT3b, or R1 in the radical prostatectomy specimen).
4. Previous pelvic radiotherapy
5. Radiotherapy contraindicated
6. Ongoing treatment with ADT or PSA-modulating drugs (e.g., finasteride, dutasteride, high dose steroids)
7. Inability to understand the treatment protocol or sign informed consent