Androgen deprivation therapy and definitive radiotherapy for intact prostate cancer in the modern era: personalized medicine on the horizon

With the results of GETUG 14 (1), dose-escalated radiotherapy (RT) plus short-term androgen deprivation therapy (STADT) remains standard of care for unfavorable intermediate risk prostate cancer. Prior randomized studies demonstrated improved outcomes when escalating radiation dose from 70–70.2 to 78–80 Gy with standard fractionation RT alone: dose-escalation improved biochemical control in RTOG 9509 and GETUG 06 (2,3) and decreased death from prostate cancer in the MDACC trial (4). Seven randomized studies evaluating the addition of ADT to RT showed ADT improved metastasis-free survival (5). Combining dose-escalated RT and STADT for intermediate risk prostate cancer showed improved event- and clinical disease-free survival in EORTC 22991 (6) and decreased death from prostate cancer in PCS III and RTOG 0815 (7,8). The HEAT meta-analysis put it all together to show improved metastasis-free survival for RT plus STADT, regardless of RT dose (9). Demogeot and colleagues should be commended for their addition to the existing literature in support of dose-escalated RT plus STADT. In GETUG 14, among patients with (mostly) intermediate- or high-risk prostate cancer, 5-year disease-free survival improved from 76% with 80 Gy RT alone to 85% with 80 Gy RT plus 4-month ADT [hazard ratio (HR) 0.64]. Biochemical control improved from 79% to 90% (HR 0.45) (1). Now, after four phase 3 randomized trials have confirmed the benefit of adding STADT to dose-escalated RT, further studies need to refine ADT patient selection, duration, and drug type/combination, and to define the next steps in the evolution of prostate RT. More succinctly, our goal should be personalized ADT and RT for prostate cancer.

While GETUG 14 provides important evidence for dose-escalated RT plus STADT in the setting of unfavorable intermediate- and favorable high-risk prostate cancer, many questions remain, illustrated by the ongoing discussion in the pages of European Urology (10-12). Critics point out that although standard fractionation to 80 Gy achieves biological effective dose (BED) 187 Gy at an α/β ratio of 1.5 for prostate cancer, the Zaorsky dose-escalation meta-analysis showed the potential for moderate hypofractionation, ultrahypofractionation, or stereotactic body radiotherapy (SBRT) to increase disease control with BED >200 Gy (13). The PACE-C randomized trial comparing moderate hypofractionation plus STADT vs. SBRT plus STADT will help clarify the role of hypofractionation (14). When GETUG 14 was designed, neoadjuvant/concurrent ADT was common. However, the SANDSTORM pooled analysis has since established the modern standard of concurrent/adjuvant ADT when treating with prostate RT plus STADT (15). While GETUG 14 included mostly intermediate-risk patients, the study did include about 30% high-risk disease. These high-risk patients may benefit from longer duration ADT as shown in the DART 01/05 and TROG 03.04 RADAR randomized trials of long-term ADT (LTADT) and dose-escalated RT for high-risk prostate cancer (16,17). The points raised highlight a critical challenge in trial design—studies reflect the era in which they were designed. GETUG 14 was designed in the early 2000s, completed accrual in 2010, and reported the 5-year disease-free survival primary outcome in 2025. In the 25 years from trial design to publication, advances in radiation technology allowed higher dose per fraction to be delivered safely, radiation dose and fractionation adapted to new insights into prostate cancer radiobiology, and the timing and duration of ADT has become better defined. Especially with the pace of advancing technology, we must design studies that not only answer the important questions of the day but also are expected to retain their novelty by the time we have their results.

As we consider how to tailor care for each patient, ADT and RT may be personalized by toxicity. The seminal Dana Farber trial showed a survival benefit for the addition of STADT to RT for intermediate risk prostate cancer. However, subsequent analyses showed the benefit isolated to unfavorable intermediate risk disease and men with no or minimal comorbidity. Men with moderate or severe comorbidity had worse survival with the addition of ADT (18). The potential negative impact of ADT has been associated with excess cardiovascular death by observational studies, but pooled analysis of randomized trials did not reproduce this association (19). In response to the potential cardiovascular risk of gonadotropin-releasing hormone (GnRH) agonists (e.g., leuprolide), GnRH antagonists (e.g., relugolix) have been developed and are associated with lower cardiovascular event rates than GnRH agonists (20). As we increasingly use next-generation androgen receptor pathway inhibitors (ARPIs), we must continue to balance the risk-benefit profile of each agent. CYP17 inhibitors (e.g., abiraterone) have now been associated with cardiac events and hypertension in two meta-analyses. In contrast, studies indicate the androgen receptor antagonist enzalutamide does not increase cardiac event risk but does increase hypertension and arrhythmia due to increased QT interval (21). While the drug/combination of ADT and/or ARPI can be individualized for the patient, the MARCAP ADT duration meta-analysis moved further towards personalization by using prostate cancer risk factors. While LTADT showed a near-linear increase in other-cause mortality, prostate cancer risk factors defined optimal shorter ADT duration: no ADT for 1 intermediate-risk factor, 6 months ADT for 2 or more intermediate-risk factors, and 12 months ADT for high-risk disease (22). On the radiation side, PORTOS is an emerging gene signature to predict risk of adverse events after RT and response to dose-escalation (23,24).

We are now learning how to apply genomic analysis (Decipher), artificial intelligence digital pathology biomarker (ArteraAI), and molecular subtyping (PAM50) to personalize ADT for prostate cancer.

For intermediate-risk patients, the Decipher Genomic Classifier has been applied to data from RTOG 0126. Low Decipher intermediate-risk patients had excellent results with RT alone. High Decipher intermediate-risk patients had 16% distant metastasis (DM) at 10 years, suggesting potential benefit to intensification with STADT (25). The NRG GU010 trial (GUIDANCE, NCT05050084) is now evaluating de-intensification for low Decipher intermediate-risk patients (RT +/− STADT) and intensification for high Decipher intermediate-risk patients (RT + STADT +/− darolutamide) (26). In complement to Decipher genomic analysis, the ArteraAI digital pathology biomarker has predicted benefit of STADT vs. RT alone in datasets from multiple RTOG trials (27).

For high-risk patients, Decipher was applied to data from RTOG 9202, 9413, and 9902. Low Decipher high-risk patients had a low 10-year DM rate (6%) and derived little added benefit from LTADT vs. STADT. High Decipher high-risk patients had 26% 10-year DM rate and significant 11% reduction in DM with LTADT vs. STADT (28). The NRG GU009 trial (PREDICT-RT, NCT04513717) is now evaluating de-intensification for low Decipher high-risk patients (RT + 12- or 24-month ADT) and intensification for high Decipher high-risk patients (RT + LTADT +/− apalutamide) (29). In complement to Decipher genomic analysis, the ArteraAI digital pathology biomarker has predicted benefit of LTADT vs. STADT in datasets from multiple RTOG trials (30).

Beyond prognostic genomic signatures like Decipher, the PAM50 classifier can identify 3 distinct molecular subtypes of prostate cancer: Luminal A, Luminal B, and Basal. Patients with Luminal B tumors have demonstrated the most benefit from ADT after surgery (31). In NRG GU006, only Luminal B tumors benefited from postoperative apalutamide (32). Although PAM50 was developed and validated in the postoperative setting, the concept of molecular subtyping should hold true for the treatment of intact prostate cancer and should be evaluated in the context of ADT use/duration and RT dose-response.

Although studies suggest benefit of ADT independent of RT dose (9), modern imaging and radiation delivery technology may allow targeted dose-escalation and adaptive RT to individualize RT, improving the benefit while diminishing the toxicity. In GETUG 14, only about 40% of patients in each arm had MRI and RT dose was delivered to the whole gland (1). The FLAME trial treated the whole gland to 77 Gy in 35 fractions with or without 95 Gy focal boost to magnetic resonance (MR)-defined intraprostatic lesions. At 10 years, MR-guided boost had 15% improvement in biochemical control (33). While FLAME used MR-fusion boost on a traditional computed tomography (CT)-based linear accelerator to improve biochemical control, the MIRAGE trial used MR-linear accelerator (Linac) for real-time MR-guidance and daily adaptive RT to decrease toxicity with tighter planning margins (34). Focal boost using prostate-specific membrane antigen (PSMA) radiolabeled imaging has also shown promising results in a prospective trial at Mayo Clinic (35). By leveraging MRI, adaptive RT platforms, and PSMA imaging, future studies may be able to both boost intraprostatic lesions while simultaneously decreasing toxicity through margin reduction or even whole gland dose de-escalation.

In only 5 years since Food and Drug Administration (FDA) approval, PSMA positron emission tomography (PET)/CT has revolutionized prostate cancer imaging. Locally, PSMA PET/CT + MRI for targeted prostate biopsy increases the identification of clinically significant prostate cancer (36). For prior patients in an era of standard templated prostate biopsy, occult high Gleason score disease may have been missed, resulting in more modern patients moving into intermediate- and high-risk groups. Furthermore, the advent of MRI-based extraprostatic extension (EPE) grading vs. digital rectal exam alone has improved the prediction for pathologic EPE but at the same time increased the number of patients categorized as high-risk based on cT3a on MRI (37). For staging, 12% of traditionally intermediate-risk patients and 31% of traditionally high-risk patients have disease outside the prostate on PSMA PET/CT (38). This implies that a substantial proportion of patients on prior studies like GETUG14 were actually N1 or M1. Therefore, we should anticipate improved results on future studies simply due to better identification of high Gleason score disease on biopsy, improved grading for EPE on MRI, and more accurate nodal/distant staging. Improved results for modern intermediate risk patients have already been demonstrated by Proton Collaborative Group (PCG) GU003, Hypo-fractionated Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Prostate Cancer (NCT01492972). PCG GU003 treated patients with proton beam therapy to 70 Gy in 28 fractions with or without 6 months ADT. At 5 years, freedom from failure was 98.6% for RT + STADT vs. 97.3% for RT alone (HR 0.55, P=0.622), amounting to a statistically insignificant absolute difference in 5-year freedom from failure of 1.3% [95% confidence interval (CI): −7.2% to 9.4%] (C.E.V., personal communication, December 18, 2025). These excellent results for modern intermediate risk patients emphasize the need to select patients for treatment de-escalation and intensification in a rationale manner.

GETUG 14 cements dose-escalated RT and STADT as the current standard of care for unfavorable intermediate-risk prostate cancer. However, opportunities to individualize RT and ADT remain. As future trials are designed, we must identify the recipe for ADT optimization by considering traditional prostate cancer risk factors, comorbid conditions, cardiac risk, genomic classification (Decipher), AI digital pathology biomarker (ArteraAI), and molecular subtyping (PAM50). Similarly, RT can become more personalized through gene signature analysis for dose response and toxicity [Post-Operative Radiation Therapy Outcomes Score (PORTOS)], targeted intraprostatic boost using MRI and PSMA PET/CT, and daily adaptive RT (e.g., MR-Linac). By designing innovative studies using the tools at our disposal, we will move ever closer to truly personalized treatment for localized intact prostate cancer.

Acknowledgments

None.

Footnote

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