Radiation therapy (RT) plus castration-inducing hormonal therapy (HT) is widely accepted as a standard treatment approach for localized prostate cancer (PCa). However, use of HT with definitive RT is highly variable in real-world practice, given its significant adverse impacts on quality of life.¹ Thus, the selection of appropriate patients and the appropriate duration for HT remains controversial. Herein, we discuss the role of HT as a component of the up-front treatment of intact PCa with RT.

The MARCAP meta-analysis pooled data from 10,853 patients at 12 centers and found that adding HT to RT in the form of androgen deprivation therapy (ADT) improved metastasis-free survival (HR: 0.83 [0.77-0.89]) in men undergoing definitive RT for PCa, as did prolongation of adjuvant ADT (HR: 0.84 [0.78-0.91]) irrespective of RT dose, patient age, or National Comprehensive Cancer Network (NCCN) risk group.² This suggests that even in the modern era of RT dose intensification, there appears to be a relative benefit to adding any duration of ADT to RT for most men with localized PCa. However, the absolute benefit of ADT diverges for intermediate-risk (IR) vs high-risk patients, with a calculated number needed to treat in order to avert 1 distant metastasis (DM) event at 10 years of 8.4 (95% CI: 6.0-13.8) for high-risk patients compared to 18.0 (95% CI: 12.7-30.7) for IR patients.

Among IR patients, ADT may be most beneficial for patients with unfavorable IR (UIR) disease, whereas men with favorable IR (FIR) disease might reasonably be spared ADT given the potentially minimal absolute benefit.³ If ADT is chosen for IR disease, multiple studies have demonstrated that the ideal duration of ADT that balances oncologic outcomes and quality of life in IR patients is between 4-6 months, with longer durations failing to improve biochemical progression and event-free survival.^4,5 RTOG 9408 was the only study to demonstrate an overall survival (OS) advantage for IR patients (HR: 1.17, P = .03, 62% vs 57%)⁶, but this study employed a lower dose of RT (66.6 Gy) than would be standardly utilized today, potentially inflating the benefits of ADT in their cohort.

The timing of short-term ADT also remains an important question, with recent data favoring a greater proportion of ADT in the adjuvant vs the neoadjuvant setting. In the SANDSTORM analysis,⁷ when comparing concurrent/adjuvant ADT to neoadjuvant/concurrent ADT, metastasis-free survival (MFS; HR 0.65 [0.54-0.79], corresponding to a 10-year benefit of 8%), DM (HR 0.52 [0.33-0.82]), prostate cancer–specific mortality (HR 0.3 [0.16-0.54]), and OS (HR 0.69 [0.57-0.83]) were all improved with a concurrent/adjuvant approach, though these benefits were reserved for men receiving prostate-only RT and not recapitulated in men who also received whole pelvis RT.

Ongoing clinical trials seek to harness precision medicine platforms to identify IR patients who may benefit from de-escalation to RT alone vs those who benefit from treatment escalation with intensified ADT. For example, NRG GU010/GUIDANCE (NCT05050084) will risk-stratify 2,050 UIR patients using The Decipher Prostate Cancer Test. Patients with a Decipher score <0.4 are randomized to RT alone or RT with 6 months of ADT with a primary endpoint of DM. A separate randomization for men with Decipher score >0.4 will determine if patients should undergo an intensified regimen of RT plus 6 months of ADT along with a second-generation antiandrogen, darotulamide, or standard-of-care RT with 6 months of ADT alone, with MFS as the primary endpoint. An artificial-intelligence–derived digital pathology-based biomarker has also garnered recent excitement following validation of its ability to predict the benefit of ADT in cohort of IR patients enrolled on RTOG 9408.⁸ However, until such biomarkers can be prospectively validated, candidates for omission of ADT without significant compromise in oncologic outcomes are likely best identified by NCCN risk group classification, with omission preferred for FIR patients and 4-6 months of concurrent/adjuvant ADT preferred for UIR patients.

The value of ADT plus RT in high-risk and very high-risk patients has been well-studied. Long-term ADT (LTADT) has consistently improved OS in multiple large, randomized trials,^9-12 with RTOG 9202¹³ and DART 01/05⁵ both finding that 28 months of ADT was more effective than 4 months of ADT, particularly in men with Gleason 8 disease and other high-risk factors. Several studies have also suggested that intermediate-term ADT (ITADT) is also superior to short-term ADT and may even be comparable to LTADT. PCS IV was designed as a superiority trial and specifically sought to compare ITADT (18 months) vs LTADT (36 months) in high-risk patients and failed to demonstrate superior OS outcomes in the LTADT arm (86% vs 91% P = .07) with quality of life analysis favoring ITADT.¹⁴ However, it is worth noting that lack of superiority is distinct from non-inferiority and that ADT compliance was poor in the 36-month arm, which may have driven the similar comparison. The addition of a brachytherapy boost may also factor into the calculation of ADT duration, with favorable progression-free survival rates on the ASCENDE-RT trial¹⁶ driving the recommendation for just 12 months of ADT in men who receive a brachytherapy boost as part of their high-risk RT approach. A recent retrospective analysis that incorporated data from the TROG RADAR trial and the DART 01/05 trial suggested that 12 months of ADT might be optimal for patients receiving a brachytherapy boost, while durations longer than 18 months may still offer an oncologic benefit even with dose-escalated external beam radiotherapy.¹⁵ Taken together, these data suggest patients receiving dose-escalated external beam radiotherapy should receive a minimum of 18 months of ADT (supported by high-level data), while those receiving a brachytherapy boost might be able to shorten ADT duration to 12 months (supported by lower-level data).

Finally, recent attention has also focused on the benefits of adding advanced second-generation antiandrogen therapies to standard ADT in the highest-risk patients. In a recent meta-analysis of 2 phase 3 trials from the STAMPEDE platform protocol, 1,974 high-risk patients (defined as node positive disease or the presence of two-thirds of the following features: T3/T4 disease, Gleason score 8-10, or PSA ≥40) undergoing local therapy (predominately with RT) were randomized to either ADT alone (control group), ADT with abiraterone and prednisolone (intervention arm of the first trial), or ADT with abiraterone, prednisolone, and enzalutamide (intervention arm of the second trial).²⁵ At 6 years, the combination arms demonstrated improved MFS (HR: 0.53 [95% CI: 0.44-0.64 P = .0001], 82% vs 69%) along with improved OS, prostate cancer–specific mortality, biochemical recurrence, and progression-free survival when compared to ADT alone. Thus, HT intensification for these high-risk patients is now a category I recommendation in NCCN guidelines (see Figure).

In summary, as RT technology has improved, so too has our understanding of the appropriate patient selection, duration, and timing of HT. Genomic classifiers and digital histopathologic-based artificial intelligence platforms are poised to improve patient selection for the addition of HT to RT in the near future.