Androgen Deprivation Therapy and Salvage Radiotherapy in Post-Radical Prostatectomy Biochemical Recurrence of Prostate Cancer: Current Evidence

Abstract

Background/Objectives: Biochemical recurrence (BCR) occurs in 15–40% of men within five years of radical prostatectomy (RP), presenting a major challenge for long-term disease control. While salvage radiotherapy (SRT) and androgen deprivation therapy (ADT) are established post-RP interventions, the optimal integration of ADT with SRT—regarding timing, duration, and patient selection—remains unclear. We aimed to synthesize current clinical evidence on the efficacy and safety of combining ADT with SRT in patients experiencing BCR after RP. Methods: A narrative review was conducted, encompassing retrospective cohort studies, prospective randomized controlled trials (notably RTOG 9601, GETUG-AFU 16, RADICALS-HD, and SPPORT), and meta-analyses. Studies were selected based on relevance to combined ADT + SRT versus SRT alone, with outcomes of interest including biochemical progression-free survival (bPFS), metastasis-free survival (MFS), and overall survival (OS). Trial characteristics, ADT duration (short-term [4–6 months] versus long-term [≥24 months]), radiation scheme, and prostate specific antigen (PSA) thresholds at SRT initiation were extracted and compared. Results: The combination of ADT and SRT represents a promising strategy for the treatment of prostate cancer with BCR after RP. Current evidence supports its benefit in terms of disease control and survival, particularly in high-risk patients. Conclusions: Differences in inclusion criteria, ADT duration, and the heterogeneous quality of the available studies limit the formulation of universal recommendations. Well-designed prospective trials are needed to optimize therapeutic approaches and personalize treatment based on each patient’s risk profile.

1. Introduction

Prostate cancer is one of the most common types of cancer among men, and its recurrence after primary treatment represents a significant challenge in clinical practice [1]. Recurrence can present in various forms, with the most frequent and earliest being biochemical recurrence (BCR), characterized by a rise in prostate-specific antigen (PSA) levels without clinical or radiological evidence of progression. BCR occurs in approximately 15–40% of patients within five years after radical prostatectomy (RP), with rates varying according to patient and disease risk factors [1,2]. However, prostate cancer recurrence can also present as local recurrence (involving the prostate bed), metastatic disease (mainly to bone or lymph nodes), or clinical progression (with symptoms such as bone pain, weight loss, or urinary symptoms) [1,3].

In this context, androgen deprivation therapy (ADT) has emerged as a fundamental pillar in the management of prostate cancer with BCR after RP, by reducing androgen levels that stimulate tumor growth [4]. ADT can be implemented either surgically (orchiectomy) or medically, with the latter being more commonly used, through the administration of gonadotropin-releasing hormone (GnRH) agonists or antagonists [1,3,4]. The effectiveness of ADT has been extensively documented in the scientific literature. Several clinical trials have shown that the addition of ADT to radiotherapy (RT) significantly improves overall survival (OS) and cancer-specific survival (CSS) compared to RT alone, especially in the context of localized and locally advanced prostate cancer [5,6].

On the other hand, salvage radiotherapy (SRT) has been established as a potentially curative therapeutic option for patients with BCR after an initial radical treatment such as RP. Its goal is to eradicate residual tumor tissue, and it has shown favorable outcomes in terms of disease control and survival [7]. However, the combination of ADT with SRT is not yet clearly established and is generating increasing interest. Despite advances in both strategies, questions remain regarding the optimal sequencing of treatments, the ideal duration of ADT, and the identification of patients who may benefit most from a combined approach [1,6].

This narrative review aims to synthesize the current clinical evidence and offer therapeutic recommendations for integrating ADT with SRT in BCR.

2. Methods

This article was conceived as a narrative review aimed at synthesizing current evidence on the integration of androgen deprivation therapy (ADT) and salvage radiotherapy (SRT) in patients with biochemical recurrence (BCR) after radical prostatectomy. Although it is not a systematic review, we applied predefined steps to increase transparency and reproducibility.

A comprehensive search of PubMed/MEDLINE, Embase, and the Cochrane Library was performed for publications from January 2000 to January 2025. The search strategy combined the following terms: “prostate cancer”, “biochemical recurrence”, “salvage radiotherapy”, “androgen deprivation therapy”, “randomized controlled trial”, and “meta-analysis”. Additional studies were identified through manual screening of references from relevant reviews and clinical practice guidelines (EAU, NCCN, ESMO).

Inclusion criteria were: (i) studies addressing the combination of ADT with SRT in patients with BCR after radical prostatectomy, (ii) randomized clinical trials, prospective cohort studies, retrospective series, and meta-analyses, and (iii) reporting on oncological outcomes [biochemical progression-free survival (bPFS), metastasis-free survival (MFS), overall survival (OS)], safety, or quality of life (QoL). Exclusion criteria were: (i) case reports or series with <10 patients, (ii) non-English language publications, and (iii) conference abstracts without full-text availability.

Given the narrative design, no formal risk of bias assessment was performed. However, priority was given to high-quality randomized trials and recent meta-analyses. Evidence was synthesized descriptively, highlighting consistencies and discrepancies between studies, and emphasizing clinical applicability. In addition, Figure 1 was partially generated using ChatGPT (GPT-4o, OpenAI, July 2025) to create illustrative graphic elements. The final figure was assembled and manually edited by the authors in Microsoft PowerPoint.

3. Androgen Physiology and Mechanism of Action of ADT

Androgens, primarily testosterone and its derivative dihydrotestosterone (DHT), are male sex hormones that play a fundamental role in the development and maintenance of male sexual characteristics, as well as in the regulation of prostate growth [8,9]. Testosterone is mainly produced by Leydig cells in the testes, with a smaller amount originating from the adrenal glands, under the control of luteinizing hormone (LH), whose secretion is regulated by gonadotropin-releasing hormone or Luteinizing Hormone-Releasing Hormone (GnRH or LHRH) from the hypothalamus [8].

In prostate cancer, androgen signaling through the androgen receptor promotes cell proliferation and tumor progression. ADT aims to disrupt this pathway by suppressing testosterone production [10].

GnRH agonists induce an initial stimulation of the hypothalamic-pituitary-gonadal axis (known as flare effect), followed by sustained desensitization of pituitary receptors and a subsequent decrease in LH, Follicle-Stimulating Hormone (FSH), and testosterone. GnRH antagonists, on the other hand, bind competitively and reversibly to pituitary receptors, suppressing gonadotropin secretion without causing a flare effect. This leads to a reduction in serum testosterone levels, which can be beneficial in prostate cancer in the context of localized disease, advanced disease, or BCR [11,12] (see Figure 1).

4. Clinical Evidence of ADT Plus SRT in Biochemical Recurrence

4.1. Retrospective Studies

The combination of ADT and SRT after RP has been evaluated in various retrospective studies aiming to assess the oncological impact of adding ADT to RT. These studies have reported outcomes in terms of biochemical progression-free survival (bPFS), metastasis-free survival (MFS), and OS.

Retrospective studies have been available since the early 2000s. One such study by King et al. evaluated 53 patients treated with RT + ADT and 69 patients treated with RT alone. The study demonstrated improved 5-year bPFS (57% vs. 31%, p = 0.0012) as well as OS (100% vs. 87%, p = 0.0155) in favor of the RT + ADT group [13].

In 2012, two retrospective studies were published evaluating the addition of ADT to SRT following RP. In the first, by Soto et al., no difference in PFS was observed in the overall population; however, the combination of RT + ADT showed improved PFS in patients with Gleason > 7 (HR 2.65, 95% CI 1.69–4.13; p < 0.001) and in those with pre-RT PSA levels > 2 ng/mL (HR 1.62, 95% CI 1.09–2.40; p = 0.03) [14].

Another study by Jang et al. showed that although patients treated with RT + ADT had worse baseline prognostic features than those treated with RT alone, they experienced a modest improvement in bPFS (54.2% vs. 28.5%, p = 0.048). However, when stratified by Gleason score (<8 or ≥8), the benefit of RT + ADT was only seen in the <8 group (35.3% vs. 27.0%, p = 0.006), prompting the authors to recommend prospective studies to confirm these findings [15].

In 2018, Gandaglia et al. published a study including 525 patients with BCR evaluating the role of ADT combined with early salvage RT—a common approach in current clinical practice shown to be non-inferior to adjuvant RT [16]. This study included patients with PSA < 2 ng/mL (median 0.42 ng/mL). Patients with aggressive features such as Gleason ≥ 8, pT3b/pT4 stage, and pre-RT PSA ≥ 0.4 ng/mL benefited more from RT + ADT versus RT alone:

• Gleason ≥ 8 (HR: 1.66; 95% CI: 1.01–3.30)
• pT3b/pT4 (HR: 2.61; 95% CI: 1.51–4.52)
• Pre-RT PSA (HR: 0.82; 95% CI: 0.76–0.89)

Regarding ADT duration, Jackson et al. evaluated its impact when combined with either adjuvant or salvage RT in mostly high-risk patients (pT3b, pathological Gleason ≥ 8, and pre-RT PSA > 1 ng/mL). They observed higher rates of biochemical failure (HR: 0.39; 95% CI: 0.20–0.74; p = 0.004) and distant metastases (HR: 0.21; 95% CI: 0.06–0.76; p = 0.017) in patients who received <12 months of ADT compared to those with ≥12 months [17].

In a multi-institutional study by Fossati et al. (2019), the role and optimal duration of hormone therapy combined with salvage RT were evaluated in 1264 patients from eight centers—1125 (89%) received RT for recurrence, and 139 (11%) for persistent PSA [18]. They assessed several risk factors: stage ≥ pT3b, Gleason ≥ 8, and pre-RT PSA > 0.5 ng/mL. Results showed that patients with one or more risk factors benefited from the addition of ADT to RT for both clinical recurrence (HR: 0.95; 95% CI: 0.93–0.98; p = 0.001) and BCR (HR: 0.90; 95% CI: 0.87–0.94; p < 0.0001). In patients with a single risk factor, short-term ADT was beneficial; those with two or more benefited from long-term ADT.

Thus, according to these studies, patients with poor prognostic features such as ≥pT3b stage, pathological Gleason ≥ 8, and pre-RT PSA > 0.4–0.5 ng/mL seem to benefit from ADT combined with RT compared to RT alone. It is also advisable to consider the number of high-risk features to determine whether the patient should receive short- or long-term: ADT.

4.2. Prospective Studies

Several prospective and randomized clinical trials have assessed the impact of adding androgen deprivation therapy (ADT) to external beam radiotherapy (RT) in patients with prostate cancer experiencing biochemical recurrence (BCR) following radical prostatectomy (RP). These studies have helped better define which patient subgroups benefit from this combination and what might be the optimal duration of hormonal therapy.

The RTOG 9601 trial was a pioneer in this area. This study included patients with PSA levels between 0.2 and 4.0 ng/mL and randomized them to receive RT alone or combined with bicalutamide for 24 months. A significant improvement in overall survival (OS) at 12 years (76% vs. 71%) was observed in the ADT group, although this benefit was mainly evident in patients with PSA > 0.7 ng/mL. This finding led to a critical re-evaluation of the role of ADT in patients with low PSA levels, in whom the risk of toxicity might outweigh the oncologic benefits. Regarding safety, no relevant differences were observed in early urinary, bowel, or hematologic reactions. Late grade 3 GU events occurred in 7.9% vs. 7.5% and grade 4 events in 0.3% vs. 0.8% (ADT vs. placebo). Hepatic late toxic effects were rare (grade 2: 1.6% vs. 0.8%; grade 3: 0.8% vs. 0.3%). Hot flashes were comparable between arms (grade 1: 16.5% vs. 15.2%; grade 2: 4.5% vs. 3.2%; grade 3: 0.8% vs. 0%), while gynecomastia was markedly more frequent with bicalutamide (any grade: 69.6% vs. 11.2%; p < 0.01). Cardiovascular deaths did not significantly differ between groups [19].

The GETUG-AFU 16 study evaluated the addition of six months of goserelin to RT in patients with PSA levels between 0.2 and 2.0 ng/mL. The results showed an improvement in biochemical progression-free survival (bPFS) at five years (80% vs. 62%), supporting the use of ADT even in patients with relatively low PSA levels, although the study lacked power to accurately discriminate according to risk subgroups. In terms of safety, no excess of late adverse events was observed between groups. The most frequent acute ADT-related toxicities were hot flushes and sweating: 8% of patients experienced grade ≥ 2 hot flushes, and 1% grade ≥ 2 sweating, with four patients developing grade ≥ 3 events; none were reported in the RT-alone group. The most common late grade ≥ 3 events were GU complications (8% vs. 7%) and sexual disorders (8% vs. 5%). No treatment-related deaths were reported [6].

More recently, the RADICALS-HD trial specifically addressed the optimal duration of ADT, comparing 6 versus 24 months of treatment in patients eligible for salvage radiotherapy (SRT). Specifically, metastasis-free survival (MFS) at 10 years was 78.1% in the long-course ADT group compared to 71.9% in the short-course ADT group (HR 0.773; p = 0.029). However, this benefit in MFS did not translate into an improvement in OS with a median follow-up of 8.9 years. Two pre-specified subgroup analyses were planned: based on PSA level before radiotherapy and Charlson Comorbidity Index score. The treatment effect on MFS did not differ significantly in either of these subgroups (interaction p-values were 0.99 for pre-radiotherapy PSA and 0.67 for the Charlson index). Exploratory subgroup analyses were also performed according to randomization stratification factors, and no evidence of differential treatment effect was found. Although an interaction p-value of 0.032 was observed for Gleason score, this was not considered statistically significant after adjustment for multiple testing. During follow-up, grade ≥ 3 RTOG toxicities were reported in 14% of the short-course group and 19% of the long-course group. The most frequent severe events were urethral stricture and hematuria. In total, 24 serious adverse events occurred in the short-course arm (five treatment-related) and 49 in the long-course arm (13 treatment-related). Three fatal serious adverse events were reported, none judged related to trial treatment. These results highlight the higher toxicity burden of extended ADT [20].

Finally, the NRG/RTOG 0534 (SPPORT) study evaluated the efficacy of adding short-term ADT (4–6 months) and elective pelvic nodal radiotherapy (WPRT) to conventional SRT to the prostate bed in patients with cN0 disease. A significant improvement in bPFS was observed with the triple combination (SRT + ADT + WPRT) compared to prostate bed RT alone. Acute grade ≥ 2 events occurred in 19.7%, 37.7%, and 44.6% of patients in Arms 1, 2, and 3, respectively (p < 0.001), with diarrhea and lymphopenia being the most common. In terms of late toxicity, no significant differences were seen in grade ≥ 3 GU or GI events across arms (≈3–5%), though Arm 3 showed more late hematologic events, mostly leukopenia/lymphopenia (OR 2.60 vs. Arm 2; p = 0.006). Overall, treatment intensification increased acute toxicity but maintained acceptable late safety [21].

Overall, these studies confirm that adding ADT to SRT improves oncological outcomes in patients with biochemical recurrence post-prostatectomy. However, the benefit may vary depending on pre-SRT PSA, pathological profile, and duration of hormonal treatment. Potential long-term risks of ADT must also be considered, and therefore, patient selection should be performed cautiously, weighing the risk/benefit ratio of its use. A comparative overview of these trials is presented in

Table 1. Key Randomized Trials of ADT and RT Combination in Biochemical Recurrence.

Study [Ref]	N	Design/Setting	ADT Duration	Main Results	Toxicity
RTOG 9601 [19]	760	Phase III, N0 or Nx, PSA 0.2–4.0 ng/mL	24 months (bicalutamide 150 mg/day)	18-year 53% vs. 43% (HR 0.82; p = 0.025); benefit if PSA > 0.6 ng/mL	Late GU grade ≥ 3 around 8%. Gynecomastia 70% vs. 11%. No increase in cardiovascular deaths
GETUG-AFU 16 [6]	743	Phase III, N0 or Nx, PSA 0.2–2.0 ng/mL	6 months (goserelin)	5-year bPFS: 80% vs. 62% (ADT+ vs. RT alone)	Hot flushes 8%. GU grade ≥ 3: 8% vs. 7%. Sexual disorders 8% vs. 5%. No treatment-related deaths
RADICALS-HD [20]	1523	Phase III, N0 or Nx, PSA <0.2–<1.5 ng/mL	6 vs. 24 months (GnRH agonists)	10-year MFS: 71.9% short-course ADT group vs. 78.1% long-course ADT group (HR 0.77; p = 0.029)	Grade ≥ 3 AEs 19% vs. 14%. More fatigue, genitourinary, metabolic and sexual effects with long ADT
NRG/RTOG 0534 (SPPORT) [21]	1792	Phase III, N0 or Nx, detectable PSA post-RP	4–6 months (GnRH agonists)	Improved bPFS with RT + ADT + nodal irradiation vs. RT alone	Acute grade ≥ 2 events in 20–45%. Late GU/GI grade ≥ 3 about 3–5%. More late hematologic events with pelvic RT

Main randomized clinical trials evaluating the addition of ADT to salvage radiotherapy after radical prostatectomy, summarizing inclusion criteria and oncological outcome. Abbreviations: Ref: reference; ADT: androgen deprivation therapy; PSA: prostate-specific antigen; RT: radiotherapy; OS: overall survival; MFS: metastasis-free survival; bPFS: biochemical progression-free survival; post-RP: post-radical prostatectomy.

, highlighting differences in ADT duration and survival benefits.

4.3. Systematic Reviews and Meta-Analyses

Finally, several systematic reviews and meta-analyses have also been conducted to evaluate the efficacy of SRT (SRT) following BCR after surgery, in combination with androgen deprivation therapy (ADT). Two systematic reviews published in 2018 reached the same conclusions. The studies conducted by Spratt et al. and Kishan et al. found that the benefit of ADT varies according to prognostic factors, such as higher pre-RT PSA levels, high Gleason score, or positive surgical margins [22,23].

In 2021, Yuan et al. published a meta-analysis of 11 studies, 9 of which were retrospective and only 2 were randomized clinical trials. The aim was to compare the safety and efficacy of SRT combined with ADT versus SRT alone in patients with BCR after RP. The analysis showed that, compared to SRT alone, the combined treatment with ADT provides a benefit in bPFS (HR: 0.57; 95% CI: 0.52–0.63; p < 0.001), and this benefit was more pronounced in the high-risk patient group. However, the benefit was not statistically significant in patients with Gleason score >8. Regarding OS, the authors found a slight improvement with the combined treatment (HR: 0.73; 95% CI: 0.57–0.93; p = 0.01), although only 2 of the studies analyzed the impact of the combination on OS. The authors concluded that more randomized trials are needed to validate and improve the findings of this review [24].

In 2023, Liang et al. published a meta-analysis of four randomized clinical trials with the aim of assessing the safety and efficacy of SRT combined with ADT in patients with BCR after RP. This meta-analysis found that the combined treatment of SRT with ADT showed a benefit in bPFS (HR: 0.52; 95% CI: 0.46–0.59; p < 0.00001). Subgroup analysis by PSA level showed that if SRT was given early, at PSA levels of 0.2 ng/mL or lower, the combined treatment was favorable in terms of bPFS compared to SRT alone. A benefit in MFS was also observed with the combined treatment (HR: 0.75; 95% CI: 0.64–0.88; p = 0.0004). Regarding OS, a favorable trend toward improvement was found with the combined treatment, but it was not statistically significant (HR: 0.83; 95% CI: 0.69–1.01; p = 0.06). As for acute and late genitourinary and gastrointestinal toxicity, no significant differences were found between the combined treatment and SRT alone [25].

A systematic review by Karim et al. of studies analyzing the optimal timing to initiate ADT with SRT concluded that the ideal time to start ADT in prostate cancer BCR remains unclear. However, as in the previous studies, it is recommended not to delay ADT in patients with high-risk features [26].

The DADSPORT meta-analysis, published very recently, included data from five randomized clinical trials with 4411 patients, evaluating the addition of ADT to SRT. The study found that ADT significantly improved MFS (HR: 0.78; 95% CI: 0.69–0.88; p < 0.001) and CSS (HR: 0.61; 95% CI: 0.47–0.79; p < 0.001), with modest absolute benefits at 8 years. While the improvement in OS did not reach statistical significance (HR: 0.86; p = 0.057), a trend toward benefit was observed, particularly among patients with higher pre-RT PSA levels (HR: 0.97 for 0.3 ng/mL vs. 0.58 for 1.5 ng/mL; absolute OS difference of 1.5% vs. 4%) and those classified as high-risk with a CAPRA-S score ≥ 6. The analysis also suggested greater benefits in terms of MFS and CSS with prolonged ADT to short-term treatment, although this did not translate into significant OS differences. These findings reinforce the role of ADT combined with SRT, especially in patients with high-risk features [27].

4.4. Ongoing Trials and Future Directions

Numerous randomized clinical trials are currently underway evaluating the use and duration of GnRH analogs, second-generation antiandrogens, and other agents in combination with SRT following RP (e.g., FORMULA-509, RTOG 3506, CARLHA-2, LOBSTER, and the Spanish multicenter URONCOR 06-24 trial [NCT05781217]). The results of these trials will provide more information about the benefit of hormonal treatment in this group of patients (

Table 2. Ongoing studies on the combination of hormonal treatment and RT.

Study	Study Design	Primary Endpoint	Radiotherapy Scheme	Intervention/Treatment	Status and Estimated Completion Date
NCT03371719 (BALANCE Trial)	Phase II	bPFS	Not specified	SRT +/− Apalutamide	Active, not recruiting Estimated completion: 3 January 2026
NCT03809000 (RTOG 3506)	Phase II	PFS	Prostate bed: 66.6–70.2 Gy in 37–39 fractions or 66.0–70.0 Gy in 33–35 fractions Optional: nodal boost	SRT + ADT + Enzalutamide vs. SRT + ADT	Active, not recruiting Estimated completion: 15 September 2029
NCT03141671 (FORMULA-509 Trial)	Phase II	bPFS	Not specified	SRT associated with: GnRH analog + Bicalutamide GnRH analog + Abiraterone + Apalutamide + Prednisone	Active, not recruiting Estimated completion: 31 December 2025
NCT02203695	Phase II	bPFS	Prostate bed: 66.6–70.2 Gy in 37–39 fractions	Experimental arm: SRT + Enzalutamide (6 months) Control arm: SRT + placebo (6 months)	Completed Completion date: 31 December 2024
NCT03899077 (SAVE Trial)	Phase II	Compare sexual function 9 months after starting treatment	Not specified	Control arm: SRT + GnRH agonist or antagonist Experimental arm: SRT + Apalutamide	Recruiting Estimated completion: 31 December 2025
NCT04181203 (CARLHA-2)	Phase III	PFS	Prostate bed: 66 Gy in 33 fractions. Pelvis: 51.6 Gy in 33 fractions Simultaneous integrated boost: 69.3 Gy, 33 fractions (if local recurrence on PET-CT/MRI)	Control arm: SRT + GnRH agonist Experimental arm: SRT + GnRH agonist + Apalutamide	Recruiting Estimated completion: 28 December 2033
NCT05794906 (ARASTEP)	Phase III	rPFS	Not specified	Control arm: GnRH agonist/antagonist + Placebo Experimental arm: GnRH agonist + Darolutamide	Recruiting Estimated completion: 29 March 2030
NCT06305832	Phase II	3-year bPFS	Prostate bed: 66.6–72 Gy Pelvis (if candidate): 50.4 Gy	Control arm: SRT + GnRH agonist Experimental arm: SRT + GnRH agonist + Rezvilutamide	Recruiting Estimated completion: March 2030
NCT05781217 (URONCOR 06-24)	Phase III	5-year MFS	Prostate bed: 66–70 Gy in 33–35 fractions or moderate hypofractionation in 20–26 fractions. Pelvis: considered in high-risk patients	SRT associated with: Arm 1: Bicalutamide 50 mg (30 days) + GnRH analog 6 months Arm 2: Bicalutamide 50 mg (30 days) + GnRH analog 24 months	Recruiting Estimated completion: December 2032
NCT01994239	Phase II	OS	Prostate bed: 66 Gy Pelvis: 46 Gy in 23 fractions	Control arm: SRT Experimental arm: SRT + Degarelix	Active, not recruiting Estimated completion: March 2025
NCT04931979 (Pembro-SRT)	Phase II	BCR	Prostate bed: at least 66 Gy	Experimental arm: SRT + Pembrolizumab IV every 3 weeks	Recruiting Estimated completion: 4 January 2026
NCT04242017 (LOBSTER)	Phase II/III	MFS	Prostate bed: 70 Gy in 35 fractions	Control arm: SRT + 6 months ADT (Triptorelin) Experimental arm: SRT + 24 months ADT (Triptorelin)	Recruiting Estimated completion: 2 January 2031

Ongoing randomized clinical trials evaluating the role of ADT combined with salvage radiotherapy are summarized. Abbreviations. SRT: Salvage Radiotherapy; bPFS: biochemical progression-free survival; PFS: progression-free survival; rPFS: radiological progression-free survival; BCR: biochemical complete response; MFS: metastasis-free survival.

).

5. Discussion

This narrative review focused on analyzing the available evidence regarding the use of ADT in patients with BCR after RP, both in combination with SRT and across different duration schemes. As this is a non-systematic review, there is a risk of selection bias and the unintentional exclusion of relevant studies. Biomarker-guided trials are needed to better stratify patients based on molecular recurrence risk.

Although high-quality randomized clinical trials have been included, a significant portion of the evidence still comes from retrospective studies, which have inherent limitations such as heterogeneity in inclusion criteria, patient characteristics, and evaluated outcomes. Additionally, the studies vary in baseline PSA levels, definitions of risk, and ADT duration, making it difficult to establish universal recommendations. Finally, while results consistently support the addition of ADT in certain high-risk subgroups, questions remain regarding its usefulness in patients with low-risk BCR and the optimal timing for initiating hormonal therapy.

These uncertainties highlight the importance of carefully weighing not only oncological benefit but also the potential harms of ADT. In addition to oncological outcomes, the potential adverse effects of ADT must also be considered when selecting patients and determining treatment duration. Adverse effects of ADT include metabolic alterations (such as insulin resistance and weight gain) increased cardiovascular risk, and loss of bone mineral density with higher fracture risk are well recognized. Furthermore, ADT frequently impacts quality of life through hot flashes, sexual dysfunction, fatigue, and sarcopenia. Therefore, it is essential to take into account the individual patient profile and the potential adverse effects when deciding on the initiation and optimal duration of ADT, reinforcing the rationale for a risk-adapted approach that balances therapeutic benefit with toxicity [28].

Another relevant aspect in the contemporary management of BCR is the role of PSMA-PET imaging, which enables earlier and more accurate detection of recurrence at low PSA levels, improving patient selection for SRT and guiding target volumes, particularly in nodal disease. Its higher sensitivity may also prompt intensification of systemic therapies, including ADT, in selected patients. The incorporation of PSMA-PET into clinical practice is recommended by international guidelines and supported by prospective studies, enhancing the precision of salvage treatment strategies [1,29].

In the near future, as is being studied in localized prostate cancer, Artificial Intelligence and the use of validated biomarkers could help identify which patients will benefit from the addition of ADT to salvage RT, as well as its optimal duration [30].

Based on this evidence, we provide a synthesized risk-adapted framework for clinical decision-making, as shown in

Table 3. Clinical summary with postoperative ADT recommendations.

ISUP Grade Group (Gleason)	Margin Status	CAPRA-S Score *	Pre-RT PSA	Other Adverse Factors	ADT + RT Recommendation
1 (3 + 3)	Negative	0–2	<0.2 ng/mL	pT2	No ADT or RT (selective)
2, 3 (3 + 4, 4 + 3)	Negative	3–5	0.2–0.5 ng/mL	pT3a	ADT 6 months + RT
1–3 (3 + 3, 3 + 4, 4 + 3)	Positive	<5	>0.5 ng/mL	pT2–pT3a	Consider ADT 6 or 24 months + RT (based on preference and age)
4, 5 (4 + 4, 4 + 5, 5 + 4, 5 + 5)	Positive	≥6	>0.5 ng/mL	pT3b	ADT 24 months + RT

Recommendations derived from the data found in this review. These recommendations represent a synthesis of the current evidence and should be interpreted within the context of this narrative review. * CAPRA-S (Cancer of the Prostate Risk Assessment post-Surgical) score ranges from 0 to 12: 0–2 = low risk; 3–5 = intermediate risk; ≥6 = high risk. Abbreviations. ISUP: International Society of Urological Pathology; ADT: androgen deprivation therapy; PSA: prostate-specific antigen; RT: radiotherapy.

.

6. Conclusions

The combination of ADT and SRT represents a promising strategy for the treatment of prostate cancer with BCR after RP. Current evidence supports its benefit in terms of disease control and survival, particularly in high-risk patients. However, differences in inclusion criteria, ADT duration, and the heterogeneous quality of the available studies limit the formulation of universal recommendations. Well-designed prospective trials are needed to optimize therapeutic approaches and personalize treatment based on each patient’s risk profile. In clinical practice, a risk-adapted approach may be adopted. Patients with high-risk features—e.g., Gleason ≥ 8, pT3b/pT4, PSA > 0.5 ng/mL, short PSA-doubling time, and/or CAPRA-S ≥ 6—appear most likely to derive benefit from adding ADT to SRT, often with long-term courses when appropriate. Intermediate-risk patients may be candidates for short-term ADT whereas carefully selected low-risk patients can often be managed with SRT alone, thereby avoiding hormone-related toxicities. These principles may guide treatment decisions while awaiting further high-quality evidence, with final choices individualized to comorbidity, life expectancy, and patient preferences.