For patients with localized prostate cancer, definitive therapies cure most cases; however, those with high-risk features can still face a > 50% chance of recurrence or metastasis. While adjuvant radiotherapy (RT) was once a common consideration for patients at high risk of local recurrence, data from key clinical trials, such as RADICALS and RAVES, indicate that the vast majority of these patients can be closely observed until they have a measurable PSA recurrence.^1,2 Importantly, there has been long-standing variability in practice patterns among urologists surrounding use of adjuvant and salvage therapies, with broad underutilization when looking broadly at postoperative treatment rates.³ The recent AUA/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO) salvage therapy guidelines aim to tackle these core issues, addressing appropriate risk stratification, imaging, and therapy selection in patients with a PSA recurrence following initial treatment.

The salvage therapy guidelines provide a key list of patient and disease factors that may be used to risk stratify patients to better guide management of biochemical recurrence (BCR; Table). For example, grade group, pathologic stage, shorter interval to BCR after primary therapy, PSA doubling time (PSADT), and tissue-based genomic classifier scores are all strongly associated with risk of metastasis. In 1 retrospective analysis of risk factors predicting oncologic outcomes in over 5500 patients with BCR after radical prostatectomy (RP), short (<12-month) interval to BCR, Gleason score, and PSADT were all found to independently strongly predict worse phenotypes, including metastatic progression and prostate cancer mortality.⁴

Table. High-Risk Features Associated With Worse Oncologic Outcomes in the Setting of Biochemical Recurrence Highlighted in the 2024 AUA/ASTRO/SUO Guidelines

A central component of the guidelines surrounds the use of salvage radiation therapy (SRT) in patients with a post-RP BCR. One of the most important principles of postoperative treatment in this setting is the early initiation of SRT. Multiple studies have demonstrated that the efficacy of SRT decreases with increased presalvage therapy PSA, and the new guidelines recommend that clinicians provide SRT when the PSA is ≤ 0.5 ng/mL. Importantly, not only is there a decreased risk of secondary (post-SRT) BCR among patients treated with SRT at a PSA ≤ 0.5 ng/mL,⁵ but a number of studies have demonstrated a decreased risk of metastatic progression-free survival with early rather than late SRT. Furthermore, the 2 largest studies showed that presalvage RT PSA level ≤ 0.5 ng/mL was associated with a lower risk of prostate cancer–specific mortality compared to presalvage RT PSA level of > 0.5 ng/mL. Additional data have suggested potential differences in efficacy at even lower thresholds; for example, with Tilki and colleagues demonstrating that patients receiving SRT at a PSA ≤ 0.25 ng/mL had reduced all-cause mortality compared to those receiving later SRT.⁶ Thus, for patients at particularly high risk of progression, SRT may be initiated at PSA < 0.2 ng/mL.

In terms of imaging, the guidelines highlight the role of advanced positron-emission tomography (PET) imaging with prostate-specific membrane antigen (PSMA) and non–PSMA-based tracers (eg, ¹⁸F-fluciclovine, ¹¹C-choline) in patients being considered for SRT. PSMA-PET is the most sensitive and specific for prostate cancer detection at low PSA levels and is the preferred imaging modality in this setting. Important information can be gleaned from prior studies using non–PSMA-based tracers, including the EMPIRE-1 trial, which randomized patients to ¹⁸F-fluciclovine PET in order to assess the value of integrating molecular imaging into salvage therapy decisions.⁷ Incorporating molecular imaging into treatment planning significantly reduced progression rates compared to using conventional imaging alone, highlighting the utility of advanced imaging in guiding RT fields. Notably, a negative PSMA-PET result should not be an indication to delay SRT given the importance of treating most patients at a PSA ≤ 0.5 ng/mL.

Another key area these guidelines address is the role of systemic therapy in patients undergoing SRT. While androgen deprivation therapy (ADT) may be omitted in patients without high-risk features, patients with any high-risk features who are undergoing SRT should be offered ADT as well. These high-risk features include post-RP PSA ≥ 0.7 ng/mL, grade groups 4 to 5, PSADT ≤ 6 months, persistently detectable postoperative PSA, and/or seminal vesicle involvement. There is high-level evidence to support this recommendation. For example, GETUG-AFU 16 compared short-term ADT plus prostate bed SRT ± pelvic lymph node RT vs salvage RT alone and found improved 10-year progression-free and metastasis-free survival in the intervention arm.⁸ RTOG 9601 compared long-term bicalutamide plus SRT vs SRT alone and found that ADT improved numerous outcomes, including overall survival, prostate cancer–related mortality, and metastasis.⁹ In a post hoc analysis, stratification by presalvage PSA suggested an improved overall survival with the addition of ADT in patients with a PSA ≥ 0.7 ng/mL but not in patients with PSA < 0.7 ng/mL.¹⁰

For patients with a suspected local recurrence following primary prostate RT, prostate biopsy is critical for confirmation. Salvage therapy options in this setting include salvage RP, ablation, or reirradiation, all of which show similar efficacy but with few high-quality data. Clinicians may offer these therapies in a shared-decision approach, and patients should be counseled on the risk of adverse effects. For patients with oligometastatic disease identified on PET imaging, metastasis-directed therapy may be appropriate. This is one setting where salvage therapy to the prostate may be omitted.

While multimodal treatment offers clear oncologic benefits, its impact on quality of life must also be considered. For example, SRT following RP can impact urinary, bowel, and sexual function. Adding ADT increases risks of cardiac, metabolic, and skeletal complications, along with causing hot flashes. These potential risks as well as patient comorbidities should be carefully incorporated into shared decision-making, taking care to balance oncologic benefit with quality of life and patient preferences.