INTRODUCTION — The critical role of androgens in stimulating prostate cancer growth was established in 1941 by Charles Huggins [1,2]. These findings led to the development of androgen deprivation therapy (ADT) as the treatment for patients with advanced prostate cancer. Although ADT is palliative, it can normalize serum levels of prostate-specific antigen in over 90 percent of patients and can produce objective tumor responses in 80 to 90 percent. This antitumor activity can improve quality of life by reducing bone pain as well as the rates of complications (eg, pathologic fracture, spinal cord compression, ureteral obstruction).

The duration of response to ADT for patients with metastatic prostate cancer is highly variable, and most males eventually experience disease progression despite treatment. Patients who have progressed while receiving ADT typically have castrate testosterone levels (defined as <50 ng/dL) and are said to have castration-resistant disease, although such tumors may remain responsive to additional therapies directed against androgenic stimulation of the prostate cancer. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)

Many males will develop advanced, recurrent, or metastatic prostate cancer at a time when they have never received, or are no longer receiving ADT for localized disease in the adjuvant setting. In most of these cases, testosterone levels are higher than 50 ng/dL, and these males are described as having noncastrate or castration-sensitive prostate cancer (CSPC).

Historically, ADT was initially used as monotherapy for the treatment of males with advanced CSPC. More recently, the development of additional effective therapies such as abiraterone, docetaxel, and second-generation antiandrogens such as enzalutamide and apalutamide has led to their use in combination with ADT for initial therapy of advanced CSPC.

This topic will discuss initial systemic therapy options for management of advanced recurrent and metastatic CSPC. The role and timing of systemic therapy for males with an isolated biochemical recurrence after local definitive prostate cancer are discussed elsewhere, as is an overview of treatment for CSPC that includes a discussion of prostate-directed therapy in those with metastatic disease and of metastasis-directed therapy in those with oligometastatic disease. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer" and "Overview of systemic treatment for advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for patients with metastatic disease".)

DISEASE EXTENT AND THE APPROACH TO THERAPY — Males with advanced, recurrent, or metastatic CSPC encompass a broad spectrum of disease presentations, including individuals with a rising serum prostate-specific antigen [PSA] level after definitive local therapy and no demonstrable local or metastatic disease (termed a biochemical recurrence), those with locally recurrent nonmetastatic tumors, and those with demonstrable metastases, in bone, viscera, or both.

Issues involved with evaluating the extent of disease are discussed elsewhere. (See "Overview of systemic treatment for advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for patients with metastatic disease", section on 'Evaluating disease extent' and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)

The role and timing of systemic therapy in the setting of an isolated biochemical recurrence is addressed elsewhere. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)

Local therapy options for males with an isolated local recurrence after radical prostatectomy or definitive radiation therapy are also addressed elsewhere. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management" and "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)

For males with advanced castration-sensitive, locally advanced, nonmetastatic, and metastatic prostate cancer, androgen deprivation therapy (ADT; ie, lowering the serum testosterone level to castrate levels) is the mainstay of initial treatment. (See 'Historical evolution' below.)

More recently, the development of additional effective systemic therapies has led to their use in combination with ADT for initial therapy of males with more advanced disease:

●Abiraterone/prednisone plus ADT – Abiraterone acts by blocking the intracellular conversion of androgen precursors in the testes, adrenal glands, and prostate tumor tissue. It initially was shown to prolong overall survival in castration-resistant disease. More recently, randomized trials showed that combining ADT with abiraterone plus prednisone in patients with very high-risk localized nonmetastatic or metastatic castration-sensitive disease prolongs overall survival compared with ADT alone. (See 'ADT plus abiraterone' below.)

●Docetaxel plus ADT – Docetaxel prolongs survival in males with metastatic castration-resistant prostate cancer. Subsequently, randomized trials have demonstrated that combining docetaxel with ADT offers a clinically meaningful survival advantage for patients with high-volume castration-sensitive metastatic disease. (See 'ADT plus docetaxel' below.)

●Enzalutamide or apalutamide plus ADT – Both enzalutamide and apalutamide bind to the androgen binding site in the androgen receptor and function as androgen receptor inhibitors. Both drugs have significant activity in males with castration-resistant prostate cancer. More recently, three randomized trials (ENZAMET [Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) 1304], TITAN, and ARCHES) showed benefit over ADT alone for metastatic CSPC. Both apalutamide and enzalutamide are now approved for use in this setting. (See 'ADT plus second-generation antiandrogens' below.)

Importantly, there are only limited clinical trial data comparing the combination of ADT plus abiraterone versus ADT plus docetaxel, and there are no data comparing either of these approaches with ADT plus either apalutamide or enzalutamide. (See 'ADT plus other agents' below.)

Given the lack of comparative data supporting one approach over any other, the choice of the specific regimen is usually based on disease extent, and a discussion with the patient about potential toxicities associated with abiraterone, docetaxel, apalutamide, and enzalutamide, as well as the expected duration and cost of treatment. An example of an approach to initial systemic therapy that is derived from an American Society of Clinical Oncology guideline [3], and based upon disease extent at the time of presentation is presented in the algorithm (algorithm 1). Our suggested approach largely parallels these guidelines. This guidance is consistent with updated European guidelines for treatment of relapsing and metastatic prostate cancer [4].

OPTIONS FOR SYSTEMIC THERAPY

Androgen deprivation therapy — Androgen deprivation therapy (ADT) with lowering of serum testosterone levels to castrate levels is an integral component of the primary approach to the systemic treatment of castration-sensitive advanced prostate cancer. ADT can be accomplished either by surgical orchiectomy (castration) or medical castration (using either a gonadotropin-releasing hormone [GnRH] agonist or a GnRH antagonist). Both medical castration and surgical orchiectomy are effective methods for lowering serum testosterone levels in males with advanced CSPC. The decision between medical and surgical treatment is based on a variety of factors, including patient preference, cost, and treatment availability. (See 'Surgical orchiectomy' below and 'Medical castration' below and 'ADT plus first-generation antiandrogens' below.)

This recommendation is consistent with guidelines from major groups, including the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), the European Association of Urology, and the American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology, which all recommend initial ADT using either medical castration or surgical orchiectomy for initial systemic therapy of males with advanced prostate cancer [4-7].

Historical evolution — Historically, the use of estrogens to suppress serum testosterone was studied as an alternative to surgical or medical castration. Estrogens inhibit the release of GnRH from the hypothalamus, thus suppressing pituitary luteinizing hormone (LH) release and thereby reducing testicular production of testosterone. Diethylstilbestrol (DES) was extensively studied as an alternative to surgical orchiectomy for the initial management of metastatic prostate cancer prior to the development of GnRH agonists. However, two large randomized trials conducted by the Veterans Administration Cooperative Urological Research Group found that DES at a dose of 5 mg per day significantly increased the risk of dying from heart disease or stroke and that DES did not provide any advantage compared with surgical orchiectomy in terms of overall survival [8,9].

Surgical orchiectomy — Bilateral orchiectomy is a relatively simple, cost-effective procedure [10]. Following surgery, serum testosterone levels rapidly decrease to castrate levels [11], and this is usually associated with improvements in bone pain and other disease-related symptoms [2].

Although orchiectomy is used much less frequently than medical castration in North America and Europe, it remains a useful alternative when an immediate decrease in testosterone is necessary (eg, impending spinal cord compression) or when costs or adherence to medical therapy are an issue. In many countries, bilateral orchiectomy remains the standard of care for initial hormone therapy of metastatic prostate cancer.

The psychological impact of surgical castration is also an important factor for males choosing between surgery and medical treatment. In a study of 159 males with metastatic prostate cancer who were provided with standard information regarding the costs, benefits, and risks of orchiectomy, only 22 percent chose orchiectomy [12]. However, the benefits of lower overall cost, avoidance of injections for continued medical castration, and potentially fewer clinic visits may make orchiectomy more appealing in the current era of escalating health care costs.

The psychological effects of orchiectomy may be ameliorated with placement of testicular prostheses or with modification of the total orchiectomy to a subcapsular orchiectomy, in which the tunica albuginea and epididymis remain intact, providing a cosmetic effect in the scrotum [13,14].

Medical castration — Medical castration can be accomplished using either a GnRH agonist (eg, leuprolide) or a GnRH antagonist (eg, degarelix or relugolix). In our view, either approach is acceptable.

GnRH agonists — Synthetic gonadotropin-releasing hormone (GnRH) analogs have greater receptor affinity, have reduced susceptibility to enzymatic degradation, and are approximately 100-fold more potent than the natural GnRH molecule [15]. GnRH agonists bind to the GnRH receptors on pituitary gonadotropin-producing cells, causing an initial release of both LH and follicle-stimulating hormone (FSH), which causes a subsequent increase in testosterone production from testicular Leydig cells (figure 1). After approximately one week of therapy, GnRH receptors are downregulated on the gonadotropin-producing cells, with a decline in the pituitary production of LH and FSH [16]. The fall in serum LH leads to a decrease in serum testosterone to castrate levels within three to four weeks after the start of treatment [17]. Continued treatment maintains serum testosterone at castrate levels.

The decrease in testosterone production is generally reversible upon cessation of GnRH agonist therapy. However, testosterone production does not always return to baseline levels and may be related to the duration of GnRH agonist therapy, patient age, and other factors [18,19].

●Flare phenomenon – The transient rise in LH when GnRH therapy is initiated can cause a surge in serum testosterone, which may stimulate prostate cancer growth. Although relatively uncommon, this "flare" may cause an increase in bone pain, bladder obstruction, or other symptoms due to prostate cancer [20]. Thus, initial treatment with GnRH alone is contraindicated in males with severe urinary tract obstruction or painful bone metastases. The flare phenomenon in males with metastatic disease can be effectively prevented using a short duration (ie, two weeks) of antiandrogen therapy, which blocks the effect of the increased serum testosterone [10]. (See 'ADT plus first-generation antiandrogens' below.)

Formulations — GnRH agonists approved for parenteral administration include leuprolide, goserelin, triptorelin, buserelin, and histrelin. Buserelin is available in both a parenteral and nasal formulation. Depot formulations are widely used. These initially were available to suppress testosterone levels for approximately one month; even-longer-acting formulations are now available that are administered every three months, and are commonly used. A subcutaneous form of leuprolide is also now approved, which is administered once every six months.

Serum testosterone level — The objective of ADT is to lower the serum testosterone level at least to the same extent as that achieved with surgical orchiectomy [21]. Historically, this has correlated with a level of 1.7 nmol/L (<50 ng/dL), although contemporary laboratory testing indicates that in most cases, testosterone levels decline to 0.7 nmol/L (<20 ng/dL) after orchiectomy [11].

The potential relationship between suppression of serum testosterone and clinical outcome is illustrated by a secondary analysis of the JPR.7 trial, in which 626 evaluable males were treated with continuous ADT for a rising prostate-specific antigen (PSA) and were followed for a median of eight years [22,23]. The risk of dying was lowest in those with the greatest suppression of serum testosterone in the first year. Compared with a first-year minimum testosterone nadir <0.7 nmol/L, those with a nadir testosterone of 0.7 to 1.7 nmol/L had an increased risk of dying (hazard ratio [HR] 2.08, 95% CI 1.28-3.38), as did those with a nadir >1.7 nmol/L (HR 2.93, 95% CI 0.77-4.70). However, it is unclear whether further hormonal manipulation to achieve a deeper suppression of serum testosterone would result in improved outcomes [24].

Our practice is consistent with the current guidelines from the NCCN, which use a serum testosterone level of 1.7 nmol/L (<50 ng/dL) [25]. Additional hormonal maneuvers can be considered if this level of suppression of serum testosterone cannot be achieved with initial treatment.

Rechecking the serum testosterone level is especially important if the anticipated clinical or biochemical response to treatment has not been achieved. Some patients have serum testosterone levels >50 ng/dL even when rechecked. For those patients, serum testosterone level should be repeated using mass spectroscopy because testosterone levels performed by radioimmunoassay may crossreact with closely related androgens.

GnRH agonists versus orchiectomy — Unlike orchiectomy, medical castration with gonadotropin-releasing hormone (GnRH) agonists offers the potential to reverse hypogonadal symptoms upon cessation of therapy. In addition, GnRH agonists avoid the psychological issues associated with surgical castration.

A meta-analysis of 10 trials involving 1908 patients comparing a GnRH agonist with orchiectomy found equivalence in overall survival, progression-related outcomes, and time to treatment failure [26]. At two years, survival with a GnRH agonist was not statistically worse (HR for death 1.13, 95% CI 0.92-1.39, compared with orchiectomy). In this meta-analysis, there were no significant differences in efficacy between leuprolide, goserelin, and buserelin.

GnRH agonists are frequently used with antiandrogens to produce a combined androgen blockade (CAB) during the initial period of treatment to prevent a disease flare; they also may be used in conjunction with antiandrogens for long-term therapy. (See 'ADT plus first-generation antiandrogens' below.)

GnRH antagonists — Pure GnRH antagonists were developed to suppress testosterone while avoiding the flare phenomenon observed with GnRH agonists. GnRH antagonists bind to the GnRH receptors on pituitary gonadotropin-producing cells but do not stimulate an initial release of LH or FSH.

Degarelix — The efficacy of degarelix was established in a phase III trial in which 610 males with prostate cancer were randomly assigned to degarelix (240 mg for one month followed by monthly maintenance with doses of either 80 mg [n = 207] or 160 mg [n = 201]) or to leuprolide (7.5 mg per month) [27]:

●Degarelix suppressed testosterone levels within three days in 96 percent of patients, an outcome not achieved in patients treated with leuprolide. Suppression of serum testosterone levels was maintained for the duration of the 12-month trial.

●The incidence of PSA failure during the study on the degarelix 240/80 schedule was significantly lower than in the leuprolide arm (7.7 versus 12.9 percent, p = 0.05). However, the incidence of PSA failure during the study on the degarelix 240/160 schedule was 12.9 percent [28].

●Secondary analyses from the phase III trial reported a greater suppression of serum alkaline phosphatase with degarelix compared with leuprolide. However, the mean baseline serum alkaline phosphatase was lower in the leuprolide arm in all three of the subgroups that were examined, with small numbers of patients per subgroup. Furthermore, whether greater control of serum alkaline phosphatase translates into better control of skeletal metastasis is not known [28,29].

●Local injection site reactions were more frequent with degarelix than with leuprolide (40 versus <1 percent), although no systemic allergic reactions were reported. A secondary analysis of cardiovascular complications in the phase III trial found a similar cardiovascular safety profile for both agents [30].

●In a follow-up study, patients initially assigned to degarelix were continued on maintenance therapy for up to five years, and those originally assigned to leuprolide were given the opportunity to cross over to degarelix [31]. Treatment with degarelix was well tolerated during this maintenance phase, and testosterone suppression was sustained throughout this period.

At least two meta-analyses have explored the relative efficacy and safety of GnRH antagonists versus GnRH agonists:

●An individual patient meta-analysis of five randomized trials totaling 1925 males compared degarelix with either leuprolide or goserelin [32]. Progression-free survival (PFS) was longer in those treated with degarelix (18 versus 25 percent with progression, p = 0.04). However, treatment in these trials was limited to either 3 or 12 months, and there were only four deaths due to prostate cancer.

●In another meta-analysis of eight randomized trials totaling 2632 men, GnRH antagonists were associated with more injection site reactions (38 versus 5 percent) but fewer cardiovascular events (relative risk [RR] 0.52, 95% CI 0.34-0.80) [33]. While PSA progression rates were similar, GnRH antagonists were associated with lower overall mortality rates (RR 0.48, 95% CI 0.26-0.90).

Despite these data, the need for monthly degarelix injections, the high frequency of injection site reactions (approaching 40 percent) [27], and the long-term experience and safety of GnRH agonists has made GnRH agonists the preferred approach in many practices. On the other hand, the available data suggest that the risk for cardiovascular disease may be lower in patients treated with GnRH antagonists like degarelix rather than GnRH agonists [34], although this is still an unsettled issue [35,36]. (See "Side effects of androgen deprivation therapy", section on 'GnRH antagonists'.)

Relugolix — Relugolix is an oral, highly selective GnRH antagonist that is administered once daily that rapidly lower testosterone levels [37,38]. The superiority of relugolix over leuprolide was shown in the phase III HERO study, which randomly assigned 934 males with advanced prostate cancer to relugolix (120 mg orally once daily) or leuprolide injections every three months [39]. Relugolix achieved more rapid suppression of testosterone levels (<50 ng/dL in 56 percent on day 4 versus none of the leuprolide patients), and the likelihood of maintaining castrate levels from week 29 through 48 was significantly higher with relugolix (96.7 versus 88.8 percent, p <0.001). In the subgroup of 184 males followed for testosterone recovery, mean testosterone levels 99 days after discontinuation of ADT were higher with relugolix (288 versus 59 ng/dL).

The incidence of major cardiovascular events was 54 percent lower with relugolix (2.9 versus 6.2 percent, HR 0.46, 95% CI 0.24-0.88), and the difference was even more marked in the subgroup of males with a history of cardiovascular events. (See "Side effects of androgen deprivation therapy", section on 'GnRH antagonists'.)

Largely based upon this study, relugolix was approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with advanced prostate cancer [40]. Despite the advantages over leuprolide shown in the HERO study, we consider relugolix to be an alternative to GnRH agonists or degarelix.

Timing of treatment initiation

Symptomatic metastases — For patients with symptomatic metastases, we recommend prompt initiation of ADT, both to palliate symptoms and to prevent severe complications (eg, pathologic fractures, spinal cord compression).

There are no randomized trials of early versus deferred ADT in males with symptomatic metastatic disease that indicate a survival benefit from this approach for this population. However, there is clear benefit for prompt initiation of ADT in terms of quality of life, and reduction of disease-associated morbidity and disease progression [41]. Analysis of clinical trials which included mainly patients with asymptomatic metastases or an isolated biochemical recurrence after initial local therapy suggest that early as compared with deferred ADT also modestly improves survival in these populations, and it significantly reduces disease progression and associated complications [42-44]. These data are discussed in the following section. However, patients with symptomatic metastases are at greatest risk of these complications, a fact that off-sets the uncertainty of a survival benefit from early initiation of ADT, and the adverse effects of immediate as compared with delayed treatment in this setting.

Asymptomatic metastases — Even for asymptomatic patients, we suggest early rather than delayed ADT to improve survival and reduce the morbidity from potential complications of untreated disease (eg, ureteral obstruction, pathologic fractures, spinal cord compression, urethral obstruction, extraskeletal metastases).

Treatment for metastatic prostate cancer is not curative, and treatment-related side effects can adversely affect quality of life. Therefore, a question remains for asymptomatic patients as to whether to start therapy as soon as metastatic disease is diagnosed or whether to delay treatment until significant symptoms are present. (See 'Preventing the side effects of ADT' below.)

The optimal timing for therapeutic intervention has been addressed in a number of randomized trials. However, the interpretation of these trials is limited by their heterogeneous patient populations, which often included large numbers of patients with locally advanced disease but without evidence of disseminated metastases. Furthermore, some of the patients in these trials did not receive deferred treatment as originally planned.

A year 2019 Cochrane review included 10 randomized trials of early versus deferred ADT in advanced CSPC, with the majority of trials enrolling males with asymptomatic disease, often with a rising PSA as the only evidence of advanced disease [43]. Compared with deferred treatment until disease progression, early ADT modestly but significantly reduced the time to death of any cause (HR 0.82, 95% CI 0.75-0.98; moderate-quality evidence from 10 trials) and time to death from prostate cancer (HR 0.69, 95% CI 0.57-0.84; moderate-quality evidence from seven trials), and it reduced the risk of skeletal events (HR 0.37, 95% CI 0.17-0.80; low-quality evidence from three randomized trials). However, early ADT also increase the risk of fatigue (RR 1.41, 95% CI 1.23-1.62; low-quality evidence from two trials), and heart failure (RR 1.90, 95% CI 1.09-3.33; low-quality evidence from one trial), although the impact on global quality of life was equivocal, as assessed by the EORTC QLQ-C30 scale (mean difference 1.56 points lower, range 4.5 lower to 1.38 higher; low quality evidence from one trial).

Isolated biochemical recurrence — The factors affecting the optimal timing of treatment for males whose only manifestation of disseminated prostate cancer is an elevated serum PSA are discussed separately. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'When to initiate ADT-based therapy'.)

Locoregional nonmetastatic disease — For males with locoregionally advanced nonmetastatic CSPC who have not undergone previous local treatment and are willing and able to undergo RT, we also suggest early initiation of ADT with abiraterone. This recommendation is based upon the results of the STAMPEDE trial, discussed below. (See 'ADT plus abiraterone' below.)

For males with locoregionally advanced nonmetastatic CSPC who have not undergone previous local treatment and are unwilling or unable to undergo RT, we also suggest early initiation of ADT monotherapy. Another option is deferred therapy until progression.

For males with recurrent disease after local treatment, who do not have a local therapy option, the best approach is not clear. Deferred ADT is often preferred by patients who desire to avoid or at least delay potential ADT side effects. However, we restrict this practice to asymptomatic individuals, and give early ADT to symptomatic individuals. Discussions with the patient about the timing of ADT should include consideration of underlying comorbidities and the level of patient anxiety regarding their prostate cancer and the potential side effects of ADT.

For males who have locoregionally advanced disease who have not undergone previous local treatment, early ADT may prolong overall and cause-specific survival, although the data are less than robust:

•A meta-analysis included five randomized trials involving approximately 3300 males with locally advanced or metastatic disease as well as those with disease at any stage who were unwilling or unable to undergo curative local treatment [45]. In the absence of local treatment, early ADT provided a modest but significant improvement in overall survival (HR 0.90, 95% CI 0.83-0.97) and cause-specific survival (HR 0.79, 95% CI 0.71-0.89).

•A later multicenter multinational trial that randomly assigned 293 males with PSA relapse or de novo incurable disease to early versus delayed ADT found that five-year median overall survival was numerically higher with early treatment (91 versus 86 percent), but because of insufficient sample size, neither the unadjusted (HR 0.55, 0.5-1.00) nor the adjusted analysis (HR 0.54, 95% CI 0.27-1.06) demonstrated a significant improvement with early ADT.

Intermittent versus continuous ADT — For most males with metastatic disease, continuous ADT represents the standard approach.

Intermittent androgen deprivation (IAD) attempts to minimize the adverse effects of medical castration by withdrawing treatment in patients who have responded to ADT, and then reinstituting ADT when there is evidence of recurrent or progressive disease. IAD 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. As testosterone production resumes, the side effects of ADT are mitigated, but the risk of disease progression also increases. The patient is followed with PSA measurements, and ADT is reinitiated based on a predefined threshold level of serum PSA (which varies with different practices but is often between 10 and 20 ng/mL) or with evidence of new metastatic disease.

The biological rationale for IAD is twofold. First, prolonged ADT theoretically may facilitate progression from androgen dependence to androgen independence. In addition, many of the acute and chronic side effects of ADT are due to castrate levels of testosterone. Periods of time when males are off therapy may be associated with decreases in these side effects, thereby improving quality of life.

●Metastatic and locally advanced disease – Data on the superiority of continuous rather than intermittent ADT are available from at least two trials:

•The Intergroup trial INT 0162 (S9346, NCT00002651) compared IAD with continuous ADT for its impact on overall survival and quality of life in patients with metastatic CSPC and a serum PSA ≥5 ng/mL [46]. Patients were treated with a combination of a GnRH analog and an antiandrogen for seven months. Patients who achieved a PSA ≤4 ng/mL were then randomly assigned to either continuous ADT or IAD. Patients assigned to IAD remained off therapy until they met a prespecified criterion (serum PSA either ≥20 ng/mL or back to original baseline), at which point ADT was resumed. Patients who responded to resumption of ADT could be managed with additional cycles off therapy. Notably, INT 0162 was designed as a noninferiority trial based upon overall survival. Survival with IAD was to be considered noninferior if the 95 percent confidence interval for the HR excluded 1.20 (ie, a 20 percent difference roughly equal to one year).

Of the 3040 patients who were enrolled, 1749 patients were randomized and 1535 patients were available for analysis at a median follow-up of 9.8 years:

-Overall survival measured from the time of randomization was longer with continuous ADT than with IAD (median 5.8 versus 5.1 years, HR 1.10, 95% CI 0.99-1.23). Based upon these results, IAD could not be considered noninferior compared with continuous ADT. In unplanned subset analyses, results were consistent across all subgroups except for those with extensive metastatic disease, where IAD did meet the criteria for noninferiority.

-Quality of life parameters (erectile function, libido, vitality, physical functioning, mental health) were assessed at baseline and 3, 9, and 15 months after randomization. There were statistically significant improvements in erectile function and mental health at three months with IAD but not at later time points.

•IAD was also compared with continuous ADT in a smaller phase III trial from the South European Uroncological Group [47]. Although this trial demonstrated noninferiority of intermittent treatment in terms of overall survival, only 11 percent of patients had metastatic disease, while the remainder had clinical T3 or T4 disease and were not candidates for definitive therapy.

●Rising PSA after local therapy – IAD is a more accepted option for males with an isolated biochemical recurrence after definitive local therapy, although questions remain as to whether survival is adversely impacted as compared with continuous ADT. This subject is addressed in detail elsewhere. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'Continuous versus intermittent ADT'.)

Preventing the side effects of ADT

●Prevention of bone loss and fracture – ADT increases bone turnover, decreases bone mineral density, and increases the risk of clinical bone fractures in males with prostate cancer. (See "Side effects of androgen deprivation therapy", section on 'Osteoporosis and bone fractures'.)

Dietary calcium intake (food and supplements) of 1000 to 1200 mg daily, supplemental vitamin D 800 to 1000 international units daily, and lifestyle modifications (weight-bearing exercise, decreased alcohol consumption, smoking discontinuation) are indicated for all males beginning ADT. (See "Side effects of androgen deprivation therapy", section on 'Lifestyle modification'.)

Consistent with guidelines from the ASCO and Cancer Care Ontario (CCO) [48-50], estimates of fracture risk using the FRAX algorithm, or another tool such as the Canadian Association of Radiologists and Osteoporosis Canada tool [51], with or without bone density measurements, can be used to provide guidance in the consideration of medical therapies to prevent fracture, although none of these tools have been validated in patients with secondary osteoporosis caused by hormonal deprivation therapies. Baseline and periodic assessment of bone density may also be useful in detecting early evidence of osteoporosis. Males receiving ADT who are at high risk for fracture are appropriate candidates for preventive therapy with a bone-modifying agent (denosumab or a bisphosphonate) [48-50]. However, the CCO and ASCO panels both noted that the evidence of benefit in fracture prevention from starting or continuing denosumab at the osteoporosis-indicated dose (60 mg once every six months) or a bisphosphonate at the osteoporosis indicated dose (4 mg every 6 to 12 months) in males with CSPC and bone metastases is less compelling than for those without metastatic disease. This subject is discussed in detail elsewhere. (See "Side effects of androgen deprivation therapy", section on 'Osteoporosis and bone fractures'.)

The use of higher-dose bone-modifying agents to reduce skeletal-related events in males with prostate cancer bone metastases is addressed elsewhere. (See "Bone metastases in advanced prostate cancer: Management", section on 'Prevention of bone metastasis complications'.)

●Other side effects – A broad discussion of the range of side effects from ADT, including prevention and management, is provided separately. (See "Side effects of androgen deprivation therapy".)

Alternative hormonal approaches — Other hormonal approaches such as antiandrogen monotherapy have been studied as a means to achieve similar antitumor efficacy in castration-sensitive patients without the toxicities associated with ADT. These approaches have not proven equivalent to ADT, and ADT remains a component of the standard of care.

As an example, a meta-analysis of eight trials that compared first-generation antiandrogens alone with medical or surgical castration found a trend toward shorter overall survival with antiandrogen monotherapy compared with castration that approached, but did not reach, statistical significance (HR 1.22, 95% CI 0.99-1.40) [26].

ADT plus other agents — For males with castration-sensitive, high-risk or high-volume, metastatic prostate cancer, we recommend that androgen deprivation therapy (ADT) be combined with abiraterone, docetaxel, apalutamide, or enzalutamide, rather than using ADT alone. We also suggest the combination of ADT plus either abiraterone, apalutamide, or enzalutamide for patients with low-risk or low-volume metastatic prostate cancer. Combining ADT with these therapies offers significant advantages in appropriately selected patients and is incorporated into guidelines from the ASCO (algorithm 1), as well as combined guidelines from the American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology [3,7].

The optimal selection of males for this approach is not established. Our approach, which is consistent with ASCO guidelines, is as follows:

●The combination of ADT and abiraterone is indicated in males with high-risk de novo metastatic prostate cancer. High-risk disease is defined by the presence of at least two of three factors: Gleason score ≥8, at least three bone lesions, and measurable visceral disease. The combination of ADT and abiraterone may also be considered for patients with low-risk metastatic disease, and for those with locoregional nonmetastatic disease. (See 'ADT plus abiraterone' below.)

●We reserve the combination of ADT and docetaxel for males with high-volume metastatic disease (ie, visceral metastases and/or four bone metastases, including at least one outside the vertebral bodies and pelvis). (See 'ADT plus docetaxel' below.)

●The combination of ADT and either apalutamide or enzalutamide is indicated in males with de novo metastatic prostate cancer, regardless of disease extent. The addition of apalutamide has been associated with improvement in progression-free and overall survival in males with high-volume metastatic disease, and improvement in PFS in those with low-volume metastatic disease. The benefits of adding enzalutamide to ADT have also been shown in males with both high- and low-volume metastatic disease. (See 'ADT plus second-generation antiandrogens' below.)

ADT plus abiraterone — Loss of efficacy of ADT in controlling prostate cancer may be mediated by the intracellular conversion of steroid precursors to androgenic steroids within adrenal or prostate cancer cells. The rationale for combining ADT with abiraterone is based upon the ability of abiraterone to block this conversion.

Two large randomized clinical trials (and a meta-analysis of both [52]) have demonstrated that the combination of abiraterone plus ADT significantly prolongs overall survival and other disease-related secondary endpoints in patients with CSPC [53-56]:

●LATITUDE trial – In the LATITUDE trial, 1199 males with newly diagnosed castration-sensitive metastatic prostate cancer were randomly assigned to ADT plus abiraterone and prednisone or to ADT plus matching placebos [53,55]. All males had high-risk disease with the presence of at least two of three high-risk parameters: Gleason score ≥8, at least three bone lesions, and the presence of measurable visceral metastasis.

The trial was terminated after a planned interim analysis with a median follow-up of 30 months, after 406 deaths; patients assigned to ADT plus placebo were crossed over to receive ADT plus abiraterone. In the final analysis, the following were noted [56]:

•At a median follow-up of 52 months, overall survival, the primary endpoint of the study, was significantly increased with the addition of abiraterone plus prednisone (median survival 53.3 versus 36.5 months, HR 0.66, 95% CI 0.56-0.78).

•A similar degree of benefit was seen in all secondary endpoints, including time to pain progression, time to PSA progression, time to symptomatic skeletal event, time to chemotherapy, and time to subsequent prostate cancer therapy, and this was reflected in patient-reported outcomes showing clinical benefit in terms of symptoms and health-related quality of life.

•The addition of abiraterone increased the rates of grade 3 or higher hypertension (21 versus 10 percent) and hypokalemia (12 versus 2 percent).

●STAMPEDE trial – In the STAMPEDE trial, 1917 males not previously treated with ADT were randomly assigned to ADT plus abiraterone and prednisolone or to ADT alone [54]. The patient population was heterogeneous and included the following groups:

•Newly diagnosed patients constituted 94.9 percent of the study population. These included high-risk prostate cancer (stage T3-T4N0M0 disease with either PSA ≥40 ng/mL or Gleason sum 8 to 10) in 26.6 percent, node-positive nonmetastatic disease (N1M0) in 19.2 percent, and metastatic disease (M1) in 49.1 percent. Prostate radiation therapy (RT) was mandated for males with newly diagnosed node-negative nonmetastatic disease, and encouraged in those with newly diagnosed node-positive nonmetastatic disease.

•Previously treated patients relapsing after radical prostatectomy or RT accounted for only 5.1 percent of the study population and included those with a rising serum PSA only (1.9 percent) or metastatic disease (3.2 percent).

The primary endpoint of the trial was overall survival, and the coprimary endpoint was failure-free survival. Results were presented at a median follow-up of 14 months.

•Overall survival was significantly increased with the addition of abiraterone (three-year survival 83 versus 76 percent with ADT alone, HR 0.63, 95% CI 0.52-0.76). Results were similar for those with nonmetastatic and metastatic disease (HR 0.75 and 0.61, respectively).

•Failure-free survival was also significantly increased in the ADT plus abiraterone arm of the trial (three-year failure-free survival rate 75 versus 45 percent for ADT alone, HR 0.29, 95% CI 0.25-0.34). Improvement in failure-free survival was noted in males with metastatic disease and those with locally advanced nonmetastatic disease.

In later analyses of males with metastatic (M1) disease, coadministration of abiraterone with ADT was beneficial irrespective of risk stratification for high- versus low-risk status or disease volume [57,58].

Dosing of abiraterone — The approved dose of abiraterone is 1000 mg orally, once daily, on an empty stomach, either one hour before or two hours after a meal. A randomized phase II trial comparing the effects of 1000 mg per day fasting versus 250 mg per day given after a low-fat breakfast demonstrated similar PSA response, PFS, and pharmacodynamic effects with the lower dose, despite higher trough levels in the higher dose arm. Given the high cost of this agent, we (and others [59,60]) support the use of the lower abiraterone dose administered with a low-fat breakfast as an alternative to the higher dose given on an empty stomach, especially for males with a high copay, as it might improve adherence. However, there are at least some data linking low trough levels with poorer outcomes in males with metastatic castration-resistant prostate cancer [61], and larger studies are needed in this important area.

Dosing of steroids with abiraterone — The concurrent use of glucocorticoids is important to mitigate the secondary mineralocorticoid excess caused by abiraterone. For metastatic CSPC, prednisone (5 mg daily) and prednisolone (5 mg daily) were used in the LATITUDE and STAMPEDE studies, respectively. For metastatic castration-resistant prostate cancer, a higher dose of prednisone (5 mg twice daily) has been used. Dexamethasone at 0.5 mg daily has also been used with abiraterone in patients with metastatic castration-resistant prostate cancer that progressed despite abiraterone with prednisone (5 mg twice daily) [62]. This retrospective analysis of 30 patients described a PSA decline of ≥30 percent in 39 percent of subjects.

The optimal choice and dose of glucocorticoid have not been defined in either metastatic castration-sensitive or castration-resistant prostate cancer, and in our view, any of these approaches is acceptable. A randomized phase 2 study compared abiraterone plus different glucocorticoid regimens (prednisone 5 mg twice daily, 5 mg once daily, or 2.5 mg twice daily, or dexamethasone 0.5 mg once daily) in males with metastatic castration-resistant prostate cancer with the primary endpoint of no evidence of mineralocorticoid excess (grade ≥1 hypokalemia or grade ≥2 hypertension) through 24 weeks of therapy [63]. Both prednisone at 5 mg twice daily and dexamethasone at 0.5 mg daily met the threshold for the primary endpoint.

United States Prescribing Information for abiraterone recommends prednisone 5 mg once daily for males with CSPC.

ADT plus docetaxel — In three randomized trials, the combination of ADT and docetaxel increased overall survival compared with ADT alone [64]. The benefit has been most clearly demonstrated for males with high-volume metastatic disease as defined in the CHAARTED trial (the presence of visceral metastases and/or four bone metastases, including at least one outside the vertebral bodies and pelvis), and this was confirmed in a later combined analysis of the CHAARTED and GETUG-AFU 15 trials [65].

●CHAARTED trial – In the CHAARTED trial, 790 males with previously untreated CSPC and radiologic evidence of bone metastases were randomly assigned to ADT plus 18 weeks of docetaxel (75 mg/m² every three weeks) or to ADT alone [66-68].

In an initial analysis with a median follow-up of 29 months, the median time to biochemical, symptomatic, or radiographic progression was longer with chemohormonal therapy (20 versus 12 months, HR 0.61, 95% CI 0.52-0.72) [66].

In a subsequent report at a median follow-up of 54 months, overall survival was significantly increased (median 58 versus 47 months, HR 0.72, 95% CI 0.59-0.89) [67]. Benefit was most convincingly shown for males with high-volume metastatic disease (ie, visceral metastases or at least four bone lesions with at least one outside the vertebral bodies and pelvis). For the 513 patients with high-volume disease, overall survival was significantly increased (median 51 versus 34 months, HR 0.63, 95% CI 0.50-0.79). By contrast, for the 277 males with low-volume disease, there was no significant difference in overall survival (median 64 months versus not reached, HR 1.04, 95% CI 0.70-1.55).

The use of docetaxel-based chemotherapy in conjunction with ADT is associated with a significant increase in the incidence of serious (grade 3 to 5) toxicity. A preliminary report of patients in the CHAARTED trial found that the use of docetaxel in conjunction with ADT resulted in a transient impairment in quality of life at three months, but that patients who received ADT plus chemotherapy had an equal or better quality of life with subsequent follow-up [68].

●STAMPEDE trial – The STAMPEDE trial randomly assigned males to one of multiple regimens as a means of improving outcomes in the setting of castration-sensitive disease [69]. In an initial report of this trial, 2962 males were randomly assigned to one of four different treatment regimens: standard of care only (long-term ADT), standard of care plus docetaxel (75 mg/m² every three weeks for six cycles plus prednisolone 10 mg daily), standard of care plus docetaxel and zoledronic acid (for up to two years), or standard of care plus zoledronic acid only.

The patient population included in this analysis included those with high-risk disease but without nodal or disseminated metastases (localized disease), as well as those with metastases (39 and 61 percent, respectively). Bone metastases were present in 52 percent of the study population. ADT consisted of a GnRH agonist or antagonist in 98 percent of cases. The primary endpoint of the trial was overall survival, and the intermediate primary endpoint of the trial was failure-free survival.

At a median follow-up of 43 months, results included the following:

•Overall survival – Docetaxel plus ADT significantly improved overall survival compared with ADT alone (median 81 versus 71 months, HR 0.78, 95% CI 0.66-0.93). There was no further improvement with the addition of zoledronic acid to docetaxel plus ADT (median 76 versus 71 months with ADT alone, HR 0.82, 95% CI 0.69-0.97). There was no significant difference in overall survival with ADT alone compared with ADT plus zoledronic acid.

•Failure-free survival – Docetaxel plus ADT significantly increased the duration of failure-free survival compared with ADT alone (median 37 versus 20 months, five-year rate 38 versus 31 percent, HR 0.61, 95% CI 0.53-0.70). Similar results were seen with the combination of docetaxel, zoledronic acid, and ADT (median 36 versus 20 months, five-year rate 34 versus 31 percent, HR 0.62, 95% CI 0.54-0.70). There was no significant difference between ADT plus zoledronic acid and ADT alone.

•Patient subsets – There was no heterogeneity in treatment effect in any of the patient subsets, including metastasis status or lymph node status.

•Serious (grade 3 to 5) toxicity was significantly increased in patients receiving docetaxel compared with those treated with ADT alone (52 versus 32 percent).

●GETUG-AFU 15 trial – In the GETUG-AFU 15 trial, 385 males with metastatic prostate cancer were randomly assigned to ADT (either a GnRH agonist or orchiectomy) plus docetaxel (75 mg/m² every three weeks for up to nine cycles) or to ADT alone [70,71]. At a median follow-up of 84 months, overall survival was increased with chemohormonal therapy compared with ADT alone, but the difference did not reach statistical significance (median 62 versus 49 months, HR 0.88, 95% CI 0.68-1.14). There was a statistically significant increase in biochemical PFS with the addition of chemotherapy to ADT (median 22.9 versus 12.9 months, HR 0.67, 95% CI 0.54-0.84). In an unplanned subset analysis, the difference in PFS was noted in both those with low- and high-volume disease.

Additional information from these trials will be required to fully interpret the role of chemohormonal therapy, including longer follow-up to assess the potential delayed toxicity associated with this approach. Furthermore, these trials were conducted prior to the availability of some of the newer therapeutic approaches, and the relative value of aggressive initial therapy in this context will require ongoing evaluation.

Toxicity — The combination of ADT plus docetaxel was associated with a significant increase in serious toxicity in all three trials [64,66,69,70]. In the STAMPEDE trial, the overall incidence of grade 3, 4, or 5 adverse events with the docetaxel-containing regimens was 52 versus 32 percent in those managed with ADT alone [69].

Severe myelosuppression was a particular issue. In the three trials, the incidence of febrile neutropenia ranged from 6 to 15 percent. In the STAMPEDE trial, there were eight deaths probably or possibly associated with docetaxel, including five from neutropenic sepsis and three from pneumonia [69]. In the GETUG-AFU 15 trial, there were two deaths associated with docetaxel-related neutropenia before the protocol was amended to include prophylactic granulocyte colony stimulating factor (G-CSF) [70].

ADT plus second-generation antiandrogens — Enzalutamide and apalutamide bind to the androgen binding site in the androgen receptor and function as androgen receptor inhibitors. Both drugs have significant activity in males with castration-resistant prostate cancer, and more recently, three randomized trials (ENZAMET [Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) 1304], TITAN, and ARCHES) showed benefit for ADT plus either enzalutamide or apalutamide over ADT alone for metastatic CSPC. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide'.)

The activity of apalutamide and enzalutamide as initial therapy for earlier castration-sensitive disease has been addressed in the following studies:

●Apalutamide has a similar mechanism of action to enzalutamide but less reported central nervous system toxicity. The efficacy of apalutamide in conjunction with ADT was addressed in the TITAN trial, in which 1052 males with metastatic CSPC were randomly assigned to ADT plus either apalutamide (240 mg daily) or placebo [72]. Approximately 11 percent had received prior docetaxel chemotherapy, but concurrent use of docetaxel was not permitted. At a median follow-up of 23 months, overall survival was greater with apalutamide (two-year overall survival 82 versus 74 percent, HR 0.67, 95% CI 0.51-0.89), as was radiographic PFS (68 versus 48 percent; median had not been reached). Benefit was seen both in males with high-volume (defined as visceral metastases and at least one bone lesion, or at least four bone lesions with at least one outside the axial skeleton) and with low-volume metastatic disease. The side effect profile did not differ substantially between the two groups, and health-related quality of life was maintained in the apalutamide group despite the additive androgen blockade [73].

In the latest analysis, at a median follow-up of 44 months, overall survival continued to be significantly greater with apalutamide (four-year overall survival 65 versus 52 percent, median not reached versus 52.5 months, HR for death 0.65, 95% CI 0.53-0.79) [74]. Long-term benefit for males previously treated with docetaxel could not be established due to the small numbers of patients previously exposed to docetaxel in both groups.

Largely based on this study, apalutamide was approved by the FDA for males with metastatic CSPC in September 2019.

●The ENZAMET (ANZUP 1304) trial randomly assigned 1125 males with metastatic CSPC to ADT plus either enzalutamide (160 mg daily) or a standard nonsteroidal antiandrogen (bicalutamide, nilutamide, or flutamide) until clinical disease progression or prohibitive toxic effects [75]. Notably, after enrollment of the first 88 patients, a protocol amendment permitted initiation of early treatment with 18 weeks of docetaxel at the discretion of the treating clinician. Early docetaxel was planned for a similar minority of males in either group (45 versus 44 percent in the enzalutamide and standard care arms, respectively). At a median follow-up of 34 months, enzalutamide was associated with significantly better overall survival (three-year overall survival 80 versus 72 percent) and longer biochemical and clinical PFS compared with the nonsteroidal antiandrogen. The overall survival benefit disappeared when the analysis was restricted to those who had planned early docetaxel (three-year overall survival 73 versus 74 percent). Concurrent enzalutamide was associated with more docetaxel toxicity, and fewer subjects completed the planned course of six cycles of docetaxel (65 percent in the enzalutamide group compared with 76 percent in the standard care group).

The enzalutamide group had a higher incidence of seizures (seven patients [1 percent] versus none with standard care) and other toxic effects, especially among those treated with early docetaxel. Nevertheless, despite the greater treatment-related toxicity and early deterioration in several aspects of self-reported health-related quality of life (HRQOL; including fatigue, cognitive and physical function) in males assigned to enzalutamide, three-year deterioration-free survival was actually better with enzalutamide because delays in disease progression in this group outweighed early deterioration in these aspects of HRQOL [76].

●Benefit for combined therapy with enzalutamide plus ADT was also suggested in the multicenter phase III ARCHES trial, in which 1150 males with metastatic CSPC were randomly assigned to ADT plus either enzalutamide 160 mg daily or placebo [77]. At a median follow-up of 14.4 months, combined therapy was associated with a significant improvement in radiographic disease-free progression (the primary endpoint, HR 0.39, 95% CI 0.30-0.50), time to PSA progression (HR 0.19, 95% CI 0.13-0.26), and time to initiation of a new antineoplastic therapy (HR 0.28, 95% CI 0.20-0.40); benefit was observed in both high-volume and low-volume disease, and in males with and without prior docetaxel therapy. The median treatment duration was 12.8 months (range 0.2 to 24.6 months). Overall survival data were not yet mature. There were no significant differences in the frequency of grade 3 or 4 adverse events between the groups.

Largely based on these data, in December 2019, enzalutamide was approved for males with metastatic CSPC [78].

In a later analysis, the addition of enzalutamide to ADT delayed deterioration in several health-related quality-of-life subscales and pain severity in high-volume disease [79].

ADT plus two other agents — In our view, concurrent use of enzalutamide, apalutamide, or abiraterone with docetaxel, or abiraterone plus apalutamide for castration-sensitive disease remains outside of the FDA approval for these either drugs in males with prostate cancer.

●Docetaxel plus abiraterone, enzalutamide, or apalutamide – There are conflicting data on the benefit of combining docetaxel plus either abiraterone or enzalutamide:

•The ENZAMET trial described no additional benefit when enzalutamide was added to docetaxel and ADT, and it was associated with more docetaxel toxicity [75]. (See 'ADT plus second-generation antiandrogens' above.)

•The PEACE-1 trial used a 2x2 factorial design to test the value of prostate RT, abiraterone, or both, plus standard of care (ADT monotherapy) compared with standard of care alone in males with newly diagnosed de novo metastatic CSPC. The trial was initiated before the publication of the LATITUDE and STAMPEDE trials, described above, which changed the standard of care in metastatic CSPC to include six cycles of docetaxel in conjunction with ADT. (See 'ADT plus docetaxel' above.)

As a result, the standard of care arm was amended to include, and subsequently mandate, the use of six cycles of docetaxel in addition to ADT in the standard of care arm. The trial had two co-primary endpoints, radiographic PFS and overall survival.

Preliminary data on the groups receiving or not receiving abiraterone were presented at the 2021 annual ASCO meeting, and both groups with or without RT were combined for the analysis, after a lack of interaction was shown between abiraterone and RT [80]. Approximately 60 percent of the enrolled patients had received docetaxel. In the overall population, the addition of abiraterone to standard of care +/- RT significantly improved median radiographic PFS (rPFS; 4.5 versus 2.2 years, HR 0.54, 95% CI 0.46-0.64); a similar benefit was reported when the analysis was limited to those also receiving docetaxel plus ADT (median rPFS 4.5 versus 2.0 years, HR 0.50, 95% CI 0.40-0.62). Benefits were seen in all subgroups, including those with low- and high-metastatic disease burden. Overall survival data were not mature. In contrast to ENZAMET, combined therapy with docetaxel plus abiraterone did not significantly worsen treatment-related toxicity.

There are no data for combined therapy with apalutamide plus docetaxel in conjunction with ADT for CSPC.

●Abiraterone plus a second-generation antiandrogen – Only limited data have evaluated combinations of abiraterone with a second-generation antiandrogen as an ADT-free alternative:

•The phase II randomized LACOG-0415 trial directly compared ADT plus abiraterone plus prednisone (AAP) versus apalutamide alone (APA) versus the combination of abiraterone, prednisone, and apalutamide (AAP + APA) in 128 males with noncastrate advanced prostate cancer [81]. In a preliminary report, both the AAP plus ADT and AAP + APA groups had high effectiveness (as defined by PSA ≤0.2 or a PSA drop ≥50 percent at week 25), as well as a significant decline in serum testosterone, but side effects and rates of treatment withdrawal were more common with APA + AAP than with AAP.

•In the setting of castration-resistant disease, a preliminary report of the phase III ACIS trial also suggested modest benefit for combined therapy with apalutamide plus abiraterone, albeit with more treatment-related toxicity. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Combining abiraterone and an AR antagonist'.)

ADT plus first-generation antiandrogens — Combining ADT with first-generation antiandrogens (so-called "combined androgen blockade" [CAB]) does not have an established role in the modern treatment of advanced CSPC other than for the prevention of a GnRH flare. However, for patients in resource-constrained settings, where drugs like abiraterone may not be available, CAB using ADT plus a first-generation nonsteroidal antiandrogen (ie, bicalutamide, flutamide, nilutamide) may be offered to males with locally advanced nonmetastatic prostate cancer as an alternative to ADT monotherapy alone [3].

First-generation antiandrogens (eg, flutamide, bicalutamide, nilutamide) bind to androgen receptors and competitively inhibit their interaction with testosterone and dihydrotestosterone. Antiandrogens alone do not block the hypothalamic-pituitary axis; testosterone levels are normal or increased.

CAB has been extensively studied but does not have an established role in the treatment of advanced CSPC. The available antiandrogens and their use as second-line endocrine therapies are discussed separately. (See "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Older antiandrogens'.)

First-generation antiandrogens are not indicated for monotherapy in previously untreated patients with advanced prostate cancer. The use of first-generation antiandrogens with ADT ("combined androgen blockade" [CAB]) has largely been replaced by the development of more effective combination regimens.

Short-term use to prevent flare — We use antiandrogens in the management of males with disseminated prostate cancer during the initiation of treatment with a GnRH agonist in order to prevent a disease flare due to the transient increase in testosterone levels [10]. (See 'GnRH agonists' above.)

A placebo-controlled trial demonstrated that antiandrogens decrease bone pain at the initiation of GnRH agonists for patients with metastatic prostate cancer [82]. In practice, antiandrogen therapy is often started seven days prior to GnRH agonist initiation for males at high risk of flare symptoms or concurrently for asymptomatic patients. Antiandrogen therapy is then continued for two to four weeks.

Long-term combined androgen blockade — In contrast to short-term use of an antiandrogen to block the "flare phenomenon" from initial GNRH agonist therapy, long-term administration of a first-generation antiandrogen has been combined with medical or surgical castration to block the effects of adrenal testosterone in an approach referred to as CAB. (See 'GnRH agonists' above.)

However, the use of CAB as a therapeutic alternative to ADT monotherapy cannot be recommended as a standard approach. Numerous randomized trials and meta-analyses comparing ADT alone versus ADT plus a first-generation antiandrogen for initial therapy of advanced disease have concluded that this approach is associated with inferior outcomes [83,84]. As an example, one meta-analysis conducted by the Prostate Cancer Trialists' Collaborative Group analyzed individual patient data from 27 randomized trials, totaling 8275 males (88 percent with metastatic disease) [83]. CAB was associated with a trend toward decreased five-year mortality (70.4 versus 72.4 percent, HR 0.96, 95% CI 0.91-1.01). When the seven studies using the steroidal antiandrogen cyproterone acetate were excluded, the reduction in mortality with CAB was statistically significant (72.4 versus 75.3 percent, HR 0.92).

However, when compared with more modern approaches for metastatic disease, such as combined ADT plus enzalutamide, at least one randomized trial demonstrated inferior outcomes with ADT plus bicalutamide [85].

Choice of approach

●Metastatic disease – For males with metastatic disease, there are only limited clinical trial data comparing the combination of ADT plus abiraterone versus ADT plus docetaxel, and there are no data comparing either of these approaches with ADT plus either apalutamide or enzalutamide:

•In a subset analysis of the STAMPEDE trial [86] and in two meta-analyses [87,88], the magnitude of survival benefit was similar with ADT plus either abiraterone or docetaxel. However, patient-reported quality of life analysis from the STAMPEDE trial favored abiraterone [89]. (See 'ADT plus docetaxel' above.)

•At least three network analyses comparing these combined approaches have come to disparate conclusions:

-One network meta-analysis of seven trials of ADT plus abiraterone, docetaxel, apalutamide, or enzalutamide concluded that, in indirect comparisons, enzalutamide appeared to have a better overall survival compared with docetaxel in males with low-volume metastatic disease, but there was no difference in any other comparison [90].

-Another network analysis of 13 studies concluded that, compared with docetaxel plus ADT, treatment with androgen receptor axis-targeted therapies (enzalutamide, apalutamide, abiraterone) combined with conventional ADT did not offer a significant survival benefit, but all were associated with a lower disease progression rate [91]. Apalutamide and enzalutamide (but not abiraterone) were also associated with lower rates of high-grade adverse events compared with docetaxel.

-A third analyses of seven trials enrolling 7287 patients concluded that when all agents were compared both directly and indirectly, combinations of ADT plus abiraterone and apalutamide appeared to provide the largest overall survival benefit with relatively lowest incidence of serious adverse effects; docetaxel was associated with a 23-fold higher rate of serious adverse effects, and, while enzalutamide was associated with the longest extent of radiographic PFS, an overall survival benefit could not be shown [92].

Given the lack of head-to-head comparative data supporting one approach over any other, the choice of the specific regimen is usually based on a discussion with the patient about disease extent, potential toxicities associated with abiraterone, docetaxel, apalutamide, and enzalutamide, as well as the expected duration and cost of treatment. A suggested approach that is derived from an ASCO guideline [3], and based strictly upon disease extent at the time of presentation is presented in the algorithm (algorithm 1).

For males with metastatic disease, given the lack of comparative data, the choice of the specific regimen (ADT plus either abiraterone, docetaxel, apalutamide, or enzalutamide) should be based not only on disease extent, but also needs to include a discussion with the patient about the potential toxicities associated with abiraterone (hypokalemia, hypertension, edema, hepatotoxicity), docetaxel (myelosuppression, febrile infections, nail changes, neuropathy), apalutamide (rash, diarrhea, arthralgias), and enzalutamide (edema, fatigue, hypertension, hyperglycemia, seizures), as well as the expected duration of treatment (approximately 33 months for abiraterone versus 18 weeks for docetaxel).

For apalutamide and enzalutamide, the optimal duration of treatment is not established. The median PFS had not been met for apalutamide as of 23 months in the TITAN trial, and the median duration of enzalutamide in the ARCHES trial was 12.8 months (range 0.2 to 24.6 months). Cost may also be an issue [3]. (See 'ADT plus abiraterone' above and 'ADT plus docetaxel' above and 'ADT plus second-generation antiandrogens' above.)

●Patients previously treated with docetaxel – For patients with metastatic disease who have completed six cycles of docetaxel with ADT, apalutamide or enzalutamide may be subsequently added to ADT, although there are scant data supporting these approaches:

•The ARCHES trial demonstrated a PFS benefit when enzalutamide was added after docetaxel, compared with placebo [77]. (See 'ADT plus second-generation antiandrogens' above.)

•In the TITAN trial of ADT with or without apalutamide, approximately 11 percent of patients had received prior docetaxel, although that study was not designed to study the effect of this sequence of therapies [72]. (See 'ADT plus second-generation antiandrogens' above.)

•There are no similar data to support the addition of abiraterone to ADT after completion of docetaxel.

●Locoregionally advanced nonmetastatic disease

•The benefit of adding abiraterone plus prednisone to ADT in conjunction with prostate RT was shown in the STAMPEDE trial, and we prefer this approach over ADT alone for males who are willing and able to undergo prostate RT, which was mandated in the STAMPEDE trial. (See 'ADT plus abiraterone' above.)

•For males with recurrent disease after local treatment, who do not have a local therapy option, the best approach is not clear. Deferred ADT is often preferred by patients who desire to avoid or at least delay potential ADT side effects. However, we restrict this practice to asymptomatic individuals. Discussions with the patient about the timing of ADT should include consideration of underlying comorbidities and the level of patient anxiety regarding their prostate cancer and the potential side effects of ADT. (See "Side effects of androgen deprivation therapy".)

RESPONSE ASSESSMENT DURING TREATMENT — For males with CSPC who are undergoing systemic therapy, periodic assessment should be geared toward identifying signs and symptoms of disease progression.

Serial evaluation of serum prostate-specific antigen (PSA) is the mainstay of testing. Consensus-based guidelines from the National Comprehensive Cancer Network recommend testing PSA every three to six months during treatment for advanced prostate cancer [93]. Most clinicians make decisions about the need for radiographic evaluation based on changes in PSA values and/or the development of new symptoms. Therapeutic changes are usually not made based on a rising PSA alone.

Assessment strategies during treatment for CSPC are the same as for castration-resistant prostate cancer and are discussed in more detail separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Assessment during treatment'.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment versus harm from COVID-19, ways to minimize immune suppression during cancer treatment (eg, using abiraterone, apalutamide, or enzalutamide rather than the more myelosuppressive agent docetaxel in combination with androgen deprivation therapy in the setting of advanced CSPC), ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. (See 'ADT plus other agents' above.)

These issues and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Patients with advanced recurrent or metastatic noncastrate (castration-sensitive) prostate cancer (CSPC) encompass a broad spectrum of disease presentations, including a rising serum prostate-specific antigen [PSA] level after definitive local therapy with no demonstrable local or metastatic disease (ie, isolated biochemical recurrence); locoregionally advanced nonmetastatic disease; and overt metastatic disease in bone, viscera, or both. Androgen deprivation therapy (ADT; ie, lowering the serum testosterone level to castrate levels) is the mainstay of initial systemic treatment for males with advanced CSPC. But the approach differs by disease extent. (See 'Androgen deprivation therapy' above.)

Our recommended approach to initial systemic therapy, which parallels the approach suggested by the American Society of Clinical Oncology (ASCO, (algorithm 1)), is outlined in the following bullets:

●ADT

•For patients with symptomatic metastases, we recommend prompt initiation of ADT to palliate symptoms and to prevent severe complications (eg, pathologic fractures, spinal cord compression) (Grade 1B). (See 'Symptomatic metastases' above.)

For patients with asymptomatic metastatic disease, we also suggest early rather than delayed ADT (Grade 2B). Early treatment modestly improves survival and delays skeletal-related events. (See 'Timing of treatment initiation' above.)

•For males with locoregionally advanced nonmetastatic CSPC who have not undergone previous local treatment and are willing and able to undergo RT, we suggest early ADT in conjunction with abiraterone and prostate RT. (See 'Locoregional nonmetastatic disease' above.)

For males with locoregionally advanced nonmetastatic CSPC who have not undergone previous local treatment and are unwilling or unable to undergo RT, we suggest early ADT monotherapy (Grade 2C). Another option is deferred therapy until progression. (See 'Locoregional nonmetastatic disease' above.)

•For males with recurrent disease after local treatment, who do not have a local therapy option, the best approach is not clear. Deferred ADT is often preferred by patients who desire to avoid or at least delay potential ADT side effects. However, we restrict this practice to asymptomatic individuals, and we prefer early ADT for those with symptomatic disease. Discussions with the patient about the timing of ADT should include consideration of underlying comorbidities and the level of patient anxiety regarding their prostate cancer and the potential side effects of ADT. (See 'Locoregional nonmetastatic disease' above.)

•For most males with either metastatic or locoregionally advanced CSPC, we suggest continuous rather than intermittent ADT (Grade 2B). (See 'Intermittent versus continuous ADT' above.)

•For males whose only evidence of disseminated disease is an elevated or rising serum PSA, issues regarding the role and integration of systemic and local therapy are discussed separately. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)

•ADT can be accomplished by surgical orchiectomy (castration) or medical castration (using either a gonadotropin-releasing hormone [GnRH] agonist or a GnRH antagonist). The choice is driven by patient preference and other circumstances.

If medical castration is chosen, the most commonly used form of treatment is depot injection of a GnRH agonist every three months. However, use of a GnRH antagonist (eg, degarelix, relugolix) is an acceptable alternative. (See 'Medical castration' above.)

If a GnRH agonist is chosen for initial therapy, many but not all clinicians prescribe an antiandrogen for the first two to four weeks to prevent a disease flare due to the transient increase in testosterone levels. (See 'GnRH agonists' above and 'Short-term use to prevent flare' above.)

●Contribution of other agents

•For males with high-risk or high-volume metastatic CSPC, we recommend ADT combined with abiraterone, docetaxel, apalutamide, or enzalutamide, rather than ADT alone (Grade 1A).

For patients with low-risk or low-volume metastatic CSPC, we also suggest the combination of ADT plus either abiraterone, apalutamide, or enzalutamide rather than ADT alone (Grade 2B). (See 'ADT plus other agents' above.)

For males with metastatic disease, the choice of the specific regimen (ADT plus abiraterone, docetaxel, apalutamide, or enzalutamide) should be based on disease extent and potential toxicities of the various agents, as well as the expected duration and cost of treatment. (See 'Choice of approach' above.)

For males with locoregionally advanced nonmetastatic CSPC without prior treatment who are able and willing to undergo prostate radiation therapy (RT) we suggest ADT plus abiraterone and prednisone rather than ADT alone (Grade 2B). This recommendation is largely based on the STAMPEDE trial which mandated the use of prostate RT in these patients. (See 'ADT plus abiraterone' above.)

•We suggest against combining docetaxel with abiraterone or one of the second-generation antiandrogens for locoregionally advanced or metastatic prostate cancer outside of the context of a clinical trial (Grade 2C). (See 'ADT plus two other agents' above.)

●Response assessment

•For males with CSPC who are undergoing systemic therapy, periodic assessment should be geared toward identifying signs and symptoms of disease progression, as well as the side effects of treatment.

Serial evaluation of serum PSA is the mainstay of testing for disease response and progression. (See 'Response assessment during treatment' above.)