Version July 2025
INTRODUCTION —
Serial measurements of prostate-specific antigen (PSA) are routinely obtained to detect early disease recurrence in males who had definitive treatment for localized disease. When increases in PSA are not accompanied by signs, symptoms, or radiographic evidence of disease, this is termed a biochemical recurrence. Most of these individuals have testosterone levels that are >50 ng/mL, and their prostate cancer is described as castration-sensitive. However, some will have rising PSA despite suppressed testosterone levels, and such patients are said to have a castration-resistant biochemical recurrence.
For males with a biochemical recurrence, local salvage therapy may result in prolonged disease-free survival, particularly if there are no high-risk features. However, systemic treatment is indicated when local salvage therapy is not an option.
The role of systemic therapy in the treatment of patients with a biochemical recurrence after definitive local therapy will be reviewed here. The evaluation of a rising serum PSA and definition of biochemical recurrence is discussed elsewhere.
●(See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)
The role of salvage therapy for a biochemical recurrence is discussed separately.
●(See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
The management of patients with locoregionally advanced or metastatic prostate cancer is also discussed separately.
●(See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)
●(See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
ESTABLISHING BIOCHEMICAL RECURRENCE AND NEED FOR SYSTEMIC THERAPY —
For males with rising or persistently elevated prostate-specific antigen (PSA), imaging is first obtained to evaluate for local or metastatic recurrence. There is no consensus on the best imaging modality to detect distant disease. Next generation imaging techniques and whole-body magnetic resonance imaging are appropriate in select patients. This is discussed in detail elsewhere. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer", section on 'Evaluating disease extent'.)
If no evidence of disease is present, it is considered a biochemical recurrence. Systemic therapy is indicated as the primary treatment modality in patients who cannot receive salvage local therapy for biochemical recurrence, specifically:
●Patients have already had local therapy following their initial definitive treatment and subsequently have an ongoing or recurrent isolated biochemical recurrence, or
●Patients are unable to receive additional local therapy (contraindications to surgery or no additional radiation therapy can be safely administered).
BIOCHEMICALLY RECURRENT CASTRATION-SENSITIVE DISEASE
Identifying high-risk features — The choice of systemic therapy depends on whether a patient has high- or low-risk features.
We use the American Society of Clinical Oncology (ASCO) guidelines, which define high-risk features as:
•For those who underwent radical prostatectomy (RP): A PSA doubling time <1 year or a Gleason score of 8 to 10; or
•For those who underwent radiation therapy (RT): An interval to biochemical recurrence <18 months or a Gleason score of 8 to 10 [1].
However, the definition of high risk varies among trials and society guidelines. Other definitions of high risk use either ≤9 months or ≤10 months as the interval to biochemical recurrence [2,3].
Approach to patients with high-risk features
Androgen receptor pathway inhibitors (ARPI) plus ADT (preferred) — In patients with a high-risk biochemical recurrence in whom local salvage therapy is not feasible, we suggest enzalutamide and androgen deprivation therapy (ADT), given that these males have a higher chance of developing metastatic disease. The use of enzalutamide alone may be an option for select patients who do not wish to receive ADT due to concerns of toxicity. ADT alone is also an acceptable alternative, particularly in males with a higher risk for toxicity with enzalutamide such as individuals with uncontrolled hypertension, seizure disorder, or frailty.
The addition of enzalutamide to ADT has shown improvements in metastasis-free survival compared with ADT alone in males with a high-risk biochemical recurrence [2]. In a randomized trial including 1068 males with high-risk biochemical recurrence, five-year outcomes were as follows:
●Enzalutamide and ADT versus ADT alone.
•Metastasis-free survival: 87 versus 71 percent (hazard ratio [HR] 0.42, 95% CI 0.3-0.61)
•Overall survival (OS): 92 versus 87 percent (HR 0.59, 95% CI 0.38-0.91)
•Treatment-related adverse events: 86 versus 80 percent
•Rate of discontinuation due to adverse events: 21 versus 10 percent
●Enzalutamide and ADT versus enzalutamide alone – The comparison of enzalutamide and ADT to enzalutamide alone was a secondary outcome, and hazard ratios were not provided.
•Metastasis-free survival: 87 versus 80 percent
•OS: 92 versus 90 percent
•Treatment-related adverse events: 86 versus 88 percent
•Rate of discontinuation due to adverse events: 21 versus 18 percent
●Enzalutamide alone versus ADT alone are discussed below. (See 'Enzalutamide monotherapy' below.)
High risk in this trial included males with a PSA doubling time of ≤9 months and a PSA level ≥2 ng/mL above nadir after RT or ≥1 ng/mL after RP. Males were excluded from this trial if they had a RP and were considered to be a candidate for salvage RT. Treatment with enzalutamide and ADT stopped at week 37 if the PSA was ≤0.2 ng/mL. Treatment was then restarted if the PSA level increased to ≥5 ng/mL in patients who did not have a history of a RP, or ≥2 ng/mL in patients with a RP.
Hot flashes, fatigue, and arthralgias were common toxicities occurring in >20 percent of all patients.
This trial supports our suggestion for enzalutamide and ADT for patients with a high-risk biochemical recurrence, because of an improvement in metastasis-free survival and OS and a manageable toxicity profile compared with ADT alone.
Alternatives
Enzalutamide monotherapy — In males who need systemic therapy but wish to potentially avoid some of the toxicity of ADT, enzalutamide monotherapy is an acceptable option with regulatory approval in the United States [4].
As discussed above enzalutamide and ADT improved five-year metastasis-free survival compared with ADT alone in patients with a high-risk biochemical recurrence (see 'Androgen receptor pathway inhibitors (ARPI) plus ADT (preferred)' above). This trial also examined the benefit of enzalutamide monotherapy in comparison to ADT alone [2].
Five-year metastasis-free survival was 80 percent in the enzalutamide-alone group versus 71 percent in the ADT group (HR 0.63, 95% CI 0.46-0.87). The five-year OS was similar (90 percent in the enzalutamide-alone group versus 87 percent in the ADT group [HR 0.78, 95% CI 0.52-1.17]). Based on this data enzalutamide alone is an acceptable option.
Enzalutamide alone can cause toxicity such as hot flashes, arthralgias, and fatigue. In addition, gynecomastia was more common in the enzalutamide-alone group (45 percent) compared with 8 percent in the combination group and 9 percent in the ADT group.
ADT monotherapy — Select males with high-risk features may elect for ADT monotherapy as an alternative to enzalutamide and ADT, because of differences in side effect profiles. ADT options include using a gonadotropin-releasing hormone (GnRH) agonist, GnRH antagonist (injectable or oral), or orchiectomy.
The rationale and efficacy of ADT for advanced disseminated prostate cancer, including the various forms of ADT, is presented elsewhere. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Benefits and methods for androgen deprivation therapy'.)
●When to initiate ADT based therapy – In high-risk males who have decided against enzalutamide and have a life expectancy of at least 10 years, we suggest early rather than late initiation of ADT, although the optimal timing is debated [5]. A practical target is a PSA <5 ng/mL (or perhaps <10 ng/mL for older individuals). This approach is consistent with updated guidelines from ASCO [1].
Observational data suggest the benefit gained from early initiation of ADT is limited to high-risk groups [3,6-9]. An observational study in over 5000 males who had a biochemical recurrence after definitive therapy found only those patients who had a doubling time <9 months had an association with improved OS and prostate cancer-specific survival with ADT [10].
●Continuous versus intermittent ADT – ADT therapy can be given intermittently or continuously. We typically use intermittent for most males with a biochemical recurrence. Intermittent ADT (IADT) is a reasonable option for patients who wish to have periods off of treatment. IADT is associated with better physical function and quality of life. However, the impact on OS with intermittent treatment remains unclear. For these reasons, either option is reasonable based on individual patient preferences. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Intermittent versus continuous ADT'.)
IADT typically involves treatment for either a fixed interval of time or until a maximal response is achieved based upon serum PSA levels. ADT is then withdrawn, and patients are followed for evidence of recurrence. The goal of IADT is to minimize the adverse effects of medical castration. Males managed with IADT can be expected to be off therapy approximately 35 to 50 percent of the time. Time off treatment in the first cycle ranges from 6 to 15 months and is often shorter in subsequent cycles. The off-treatment period is generally associated with an improvement in the sense of wellbeing, and recovery of libido and potency in those who report normal or near-normal sexual function before the start of IADT.
Multiple randomized trials and meta-analyses have addressed the benefit of IADT in patients with a biochemical recurrence [11-16]. For example, a meta-analysis found similar survival outcomes with IADT compared with continuous ADT for prostate cancer of any stage (HR for OS 1.02, 95% CI 0.87-1.19; HR for cancer-specific survival 1.02, 95% CI 0.87-1.19; HR for progression-free survival 0.94, 95% CI 0.84-1.05) although the studies all had an unclear or high risk of bias [16]. Notably, there was a minimal difference in patients' self-reported quality of life between the two interventions, but most trials observed an improvement in physical and sexual functioning with IADT.
Treatments not used — Several other systemic options have been considered for males with a biochemical recurrence. However, none of these are recommended for biochemical recurrence, given other more preferable options.
●ADT plus docetaxel – We do not add docetaxel to ADT in patients with a biochemical recurrence, given a lack of demonstrated survival benefit. In a randomized trial that enrolled 254 patients with high-risk prostate cancer and a rising PSA level after primary local therapy, PSA progression-free survival was similar between docetaxel and ADT and ADT alone (20.3 versus 19.3 months) [17]. OS data were not mature.
In addition, a subgroup analysis in males with M0 disease from the STAMPEDE trial did not demonstrate a statistically significant OS benefit with the addition of docetaxel to standard of care therapy (HR 0.98, 95% CI 0.63-1.52).
●ADT plus abiraterone or apalutamide – There are no data to support a survival benefit from the addition of either abiraterone or apalutamide to ADT in males with isolated biochemical recurrence of prostate cancer. The PRESTO trial randomly assigned patients with biochemically-relapsed prostate cancer and a PSA doubling time ≤9 months to 12 months of ADT alone, ADT plus apalutamide, or ADT plus abiraterone plus prednisone [18]. In a preliminary report, compared with ADT alone, two-year biochemical progression-free survival (the primary endpoint) was significantly better with both ADT plus apalutamide (24.9 versus 20.3 months; HR 0.52, 95% CI 0.35-0.77) and ADT plus abiraterone (26.0 versus 20.3 months; HR 0.48, 95% CI 0.32-0.71). However, this is a nonvalidated endpoint, and data on OS or metastasis-free survival were not mature. Following completion of therapy, testosterone recovery times were similar across the three treatment arms.
●Other agents – We do not recommend the use of other agents such as noncastrating hormonal therapy with first generation compounds (bicalutamide, finasteride) or 5-alpha reductase inhibitors. These agents have not shown a benefit compared with other therapies that are recommended [19-28]. (See 'Biochemically recurrent castration-sensitive disease' above.)
Approach to patients without high-risk features
Surveillance — In males with no high-risk features present, surveillance alone is preferred. Surveillance typically includes monitoring of the serum PSA level every three to six months. ADT therapy can cause significant side effects without a clear benefit in low-risk patients. However, in those patients who want to start treatment sooner rather than later, ADT is an option after a detailed discussion about potential toxicity and lack of demonstrated benefit.
In patients with a biochemical recurrence after initial treatment, metastatic disease may not become evident for many years. As an example, one trial estimated the median time from detection of a biochemical recurrence to development of metastatic disease at eight years [3]. ADT causes side effects that can significantly lower the quality of life. These adverse effects are particularly important in otherwise asymptomatic individuals whose only manifestation of disease is a rising serum PSA. The potential development of hot flashes, fatigue, loss of libido, decreased muscle mass, mild anemia, cognitive changes, and osteoporosis is a significant concern with ADT. Furthermore, there are concerns about ADT-induced weight gain and an increased risk for diabetes mellitus, cardiac disease, and metabolic syndrome. (See "Side effects of androgen deprivation therapy".)
If systemic therapy is started, we use conventional ADT monotherapy (a GnRH agonist or GnRH antagonist). In this setting, our preference is to use IADT. (See 'ADT monotherapy' above.)
There is a lack of data from randomized trials comparing the role of ADT with observation in patients with biochemical recurrence. Most of the data is extrapolated from patients with more advanced disease. However, one retrospective series of over 2000 patients with a PSA-only relapse found a similar survival in patients who deferred ADT compared with those who started therapy immediately [29]. Other observational data suggest the benefit gained from early initiation of ADT is limited to high-risk groups [3,6-9]. (See 'ADT monotherapy' above and "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Risk of metastases or death'.)
BIOCHEMICALLY RECURRENT CASTRATION-RESISTANT DISEASE —
Some patients will progress to castration-resistant disease manifested by continued increases in serum prostate-specific antigen (PSA) without clinical evidence of metastases, although this situation is becoming less common with the wider use of next generation imaging. The type of therapy for these patients will depend on prior treatments.
●No prior ARPI – For males who have not yet received an androgen receptor pathway inhibitor (ARPI) we suggest starting therapy along with ADT. Randomized trials have demonstrated that treatment with an ARPI (enzalutamide, apalutamide, darolutamide) can significantly delay the onset of clinical evidence of metastatic disease and improve overall survival. All three drugs have been approved for nonmetastatic castration-resistant prostate cancer in the United States. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Enzalutamide, apalutamide, and darolutamide'.)
●Prior use of enzalutamide and ADT – The approach to males who received enzalutamide and ADT for a high-risk biochemical recurrence and then develop a castration-resistant biochemical recurrence is evolving. In this setting options include switching to an alternative ARPI (while continuing ADT), enrollment in a clinical trial, metastasis-directed therapy, or ongoing surveillance with repeat imaging at a short interval. A choice among these options is based on patient preference. The use of chemotherapy and radiopharmaceuticals is not approved for use in patients with biochemical recurrence only. The approach to patients who have developed metastases is found elsewhere. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
MONITORING —
While patients are actively on treatment or being monitored on surveillance, we obtain a prostate-specific antigen (PSA) every three to four months. Imaging can be considered in the context of rapid PSA rises or symptoms.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of prostate cancer".)
SUMMARY AND RECOMMENDATIONS
●General approach – Systemic therapy is the primary therapeutic option for patients who are unable to receive local salvage therapy or have had local salvage therapy following definitive treatment and who subsequently have an ongoing or recurrent isolated biochemical recurrence. (See 'Establishing biochemical recurrence and need for systemic therapy' above.)
●Patients with high-risk features – When systemic therapy is appropriate, the presence of high-risk features affects the selection of agents. High-risk features are: a prostate-specific antigen doubling time <12 months or pathologic Gleason score 8 to 10 after radical prostatectomy, or interval to biochemical recurrence <18 months, or a clinical Gleason score 8 to 10 after radiation therapy.
•If high-risk features are present, we suggest the addition of enzalutamide to androgen deprivation therapy (ADT) in males with a high-risk biochemical recurrence (Grade 2B). This approach has shown improvements in metastasis-free and overall survival compared with ADT alone. (See 'Androgen receptor pathway inhibitors (ARPI) plus ADT (preferred)' above.)
•Enzalutamide alone or ADT alone are reasonable alternatives if there is concern about toxicity of the combination. If ADT alone is chosen, we typically use intermittent therapy, but continuous is also an acceptable strategy. (See 'Enzalutamide monotherapy' above and 'ADT monotherapy' above.)
●Patients without high-risk features – In males with no high-risk features present, we suggest surveillance rather than early initiation of ADT (Grade 2C). (See 'Approach to patients without high-risk features' above.)
●Biochemically recurrent castration-resistant disease – The approach to males with a castration-resistant biochemical recurrence on or after enzalutamide and ADT is evolving. For males who have not yet received an androgen receptor pathway inhibitor (ARPI) we suggest starting an ARPI, along with ADT (Grade 2C). For males who have already received enzalutamide appropriate options include switching to an alternative ARPI, enrollment in a clinical trial, or ongoing surveillance with repeat imaging at a short interval. (See 'Biochemically recurrent castration-resistant disease' above.)
ACKNOWLEDGMENTS —
The UpToDate editorial staff acknowledges Judd W Moul, MD, FACS, who contributed to earlier versions of this topic review.
We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.
