INTRODUCTION — Androgen deprivation therapy (ADT) is generally the initial treatment for males with advanced prostate cancer, in combination with chemotherapy or combined with a second-generation androgen-targeted therapy or both. Standard approaches to first-line ADT include orchiectomy, a gonadotropin-releasing hormone (GnRH) agonist, or a GnRH antagonist. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)
Despite initial response rates of 80 to 90 percent, nearly all males eventually develop castration-resistant disease, which is typically metastatic. Patients who develop progressive disease after their initial ADT are considered to have castration-resistant prostate cancer (CRPC), although their disease may respond to secondary endocrine therapies. In this setting, two agents, abiraterone (an inhibitor of androgen synthesis) and enzalutamide (a potent and selective inhibitor of the androgen receptor), have been shown to prolong overall survival and are the preferred systemic therapies when endocrine therapy is indicated (table 1). (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Abiraterone' and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide'.)
Several alternative endocrine approaches (other older antiandrogens, antiandrogen withdrawal, ketoconazole, glucocorticoids, megestrol acetate, estrogens) appear to be less effective and have not been demonstrated to improve survival. However, these approaches may induce clinical responses or stable disease. These alternative endocrine therapies are often used sequentially and may be useful in postponing interventions such as chemotherapy, with its associated toxicity, or after chemotherapy when no other effective options are available.
These alternative endocrine approaches are discussed in this topic.
Overviews of the management of advanced castration-sensitive prostate cancer and CRPC are presented separately. (See "Overview of systemic treatment for advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for patients with metastatic disease" and "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
CONTINUATION OF ANDROGEN DEPRIVATION THERAPY — Androgen deprivation therapy (ADT) is generally continued in conjunction with secondary therapies after progression on the initial ADT regimen [1]. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Continuation of androgen deprivation therapy'.)
ANTIANDROGENS AND ANTIANDROGEN WITHDRAWAL — Antiandrogens are drugs that interfere with the androgen receptor (AR) signaling pathway. Antiandrogens may be used as the initial treatment in males with CRPC, or they may be used sequentially after newer agents that have been demonstrated to increase overall survival (table 1). Antiandrogens are also sometimes used as part of a combined androgen blockade for the initial treatment of males with advanced castration-sensitive prostate cancer. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Interference with androgenic stimulation' and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus first-generation antiandrogens'.)
For males with CRPC, antiandrogens are generally given in the context of continued gonadotropin-releasing hormone (GnRH) agonist therapy or in males who have undergone orchiectomy. All of the antiandrogens have side effects related to the deprivation of androgen effect. These include loss of libido, impotence, hot flashes, and breast tenderness and/or gynecomastia.
Abiraterone and enzalutamide — Abiraterone (which blocks the synthesis of androgens) and enzalutamide (which acts at multiple sites in the AR signaling pathway) generally are the initial choice for second-line endocrine therapy in males with CRPC after failure of initial androgen deprivation therapy as long as they have not already received these agents as part of initial therapy for castration-sensitive disease. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Abiraterone' and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide' and "Overview of systemic treatment for advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for patients with metastatic disease", section on 'Triplet therapy' and "Overview of systemic treatment for advanced, recurrent and metastatic castration-sensitive prostate cancer and local treatment for patients with metastatic disease", section on 'Patients with low-volume disease, or not candidates for docetaxel'.)
Older antiandrogens — Older antiandrogens primarily act by blocking the binding of dihydrotestosterone to the androgen receptor. Flutamide, bicalutamide, and nilutamide are older antiandrogens that are used less often given the availability and superior efficacy of abiraterone and enzalutamide [2,3]. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Interference with androgenic stimulation'.)
These agents are often rotated and used sequentially when progressive disease occurs, based on the assumption that specific antiandrogens interact differently with the androgen receptor. The potential utility of switching antiandrogens was illustrated by a retrospective series of 232 patients who progressed after initial treatment with combined androgen blockade [4]. After observation for an antiandrogen response, patients were treated with an alternative nonsteroidal antiandrogen. Overall, a prostate-specific antigen (PSA) decrease ≥50 percent was observed in 36 percent of patients, and a PSA decrease <50 percent was seen in another 25 percent. These results antedate the development of enzalutamide and abiraterone, and there are only very limited data on the efficacy of these agents after progression with one of these agents.
In locations where abiraterone and enzalutamide are not available and where first-generation antiandrogens are still used, bicalutamide is the preferred agent, based on a better toxicity profile and more efficacy in the large randomized trials that established its role in males with CRPC. Other antiandrogens may be used in sequential fashion after bicalutamide. Nilutamide is often the second antiandrogen used, although it can cause problems with light-dark adaptation, and there is a risk of pulmonary toxicity. Flutamide is seldom used because it has been associated with significant hepatic toxicity and deaths from liver failure.
Bicalutamide — Bicalutamide is the preferred antiandrogen based on its activity and favorable toxicity profile. It may be used immediately in males with CRPC after initial GnRH agonist therapy or orchiectomy, or it may have utility after newer agents (table 1).
Bicalutamide (50 mg/day) has a half-life of approximately five to six days and is administered orally once a day in conjunction with a GnRH agonist. In addition to the side effects due to androgen deprivation, less common side effects include transient liver function abnormalities in less than 5 percent of patients and diarrhea in 10 percent.
Although there is a biologic rationale for using higher doses of bicalutamide, results from clinical studies do not suggest that high-dose bicalutamide is more effective than standard-dose bicalutamide. In one study of 51 males receiving bicalutamide at a dose of 200 mg/day, PSA declines of 50 percent or greater were documented in 12 (24 percent) [5]. Similar results were noted in two other series using a dose of 150 mg/day [6,7].
Although bicalutamide has clinical activity and is useful in appropriate clinical settings, it is significantly less active than newer antiandrogens, such as enzalutamide. In two randomized clinical trials in chemotherapy-naïve CRPC, enzalutamide significantly prolonged progression-free survival compared with bicalutamide [2,3]. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Chemotherapy-naïve'.)
Nilutamide — Nilutamide has a half-life of approximately two days. In addition to the side effects due to its antiandrogenic properties, specific side effects include delayed adaptation to darkness in 25 percent of patients, nausea in 10 percent, reversible increases in hepatic transaminases in up to 8 percent, and alcohol intolerance in 5 percent [8]. There are also rare reports of interstitial lung disease caused by nilutamide [9].
Biochemical responses to nilutamide have been observed after progression on other antiandrogens [10,11]. Males with a prior antiandrogen withdrawal response may be significantly more likely to have a response to nilutamide than those without such a response [11]. (See 'Antiandrogen withdrawal' below.)
Flutamide — Flutamide has a low priority in sequential hormonal therapies because of its toxicity profile and limited activity. Flutamide has a half-life of approximately five hours and is almost completely excreted in the urine. In addition to its antiandrogenic side effects, diarrhea, nausea, and vomiting are relatively frequent side effects. Although hepatotoxicity is uncommon, it can be fatal; serum aminotransferases should be closely monitored during therapy [12,13].
The limited efficacy of flutamide is illustrated by a trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) in which 201 males were randomly assigned to either flutamide (250 mg three times daily) or prednisone (5 mg four times daily) [14]. There were no significant differences between the groups in the time to progression, overall survival, subjective response rate, biochemical response rate, or duration of response. However, patients receiving prednisone had less pain, fatigue, anorexia, and gastrointestinal distress, and had better quality of life.
Cyproterone acetate — Cyproterone acetate (CPA), a steroidal antiandrogen, can act both by blocking the androgen receptor and by inhibiting androgen synthesis. CPA at doses of 100 to 300 mg per day is considered to be as effective as estrogens or flutamide, with better tolerability [15]. However, CPA has some estrogenic activity, and its use has been associated with a risk of deep venous and arterial thromboses. In addition, liver toxicity can complicate long-term use. Patients with existing or previously treated meningiomas should not be prescribed CPA at doses of 25 mg per day or higher because of a reported association between long-term CPA use and multiple meningiomas [16,17]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'High-dose cyproterone'.)
CPA is not approved in the United States for the treatment of males with advanced prostate cancer.
Antiandrogen withdrawal — Discontinuation of treatment with an antiandrogen may result in a clinical or biochemical (PSA) response; antiandrogen withdrawal responses have been observed following discontinuation of the antiandrogens [4,18-20]. The mechanism of the antiandrogen withdrawal response is not known.
Alternative therapy should not be initiated until adequate time has elapsed to rule out a withdrawal response. This waiting period is based on the half-life of the drug administered. Response or a decline in serum PSA may not occur for three to six weeks after treatment with bicalutamide and nilutamide, which have half-lives of approximately one week and two days, respectively. With flutamide, which has a half-life of five hours, one to two weeks is adequate to observe for a possible withdrawal response. Antiandrogen withdrawal responses also have been reported following discontinuation of abiraterone [21].
The role of antiandrogen withdrawal was studied in males with CRPC in a multicenter phase III trial [18]. In this trial, 260 patients who had progressed on androgen deprivation therapy were randomly assigned to antiandrogen withdrawal plus simultaneous ketoconazole, or antiandrogen withdrawal alone with ketoconazole reserved for subsequent use upon progression. More patients had a PSA response or an objective tumor response when ketoconazole was initiated immediately rather than waiting to see if an antiandrogen withdrawal response occurred (27 versus 11 and 20 versus 2 percent, respectively). However, there was no statistically significant difference in overall survival with the two treatment strategies (15.3 versus 16.7 months, p = 0.94).
Two other observational series that each included over 200 patients observed antiandrogen withdrawal PSA response rates of 15 and 21 percent of cases, respectively [4,22].
OTHER AGENTS — A number of other hormonal therapies have at least some activity in males with CRPC. There are no comparator trials, and the choice of approach is empiric.
Ketoconazole — Ketoconazole is an imidazole antifungal agent that inhibits steroid hormone synthesis, and it also has a direct cytotoxic effect on prostatic cancer cells in vitro [23]. Ketoconazole is less specific than abiraterone, which is also an inhibitor of steroid hormone synthesis. However, it may retain a role in some patients given its much lower cost. Treatment with ketoconazole is generally initiated after allowing for a potential response from the withdrawal of an antiandrogen. (See 'Antiandrogen withdrawal' above.)
The usual dose of ketoconazole is 200 to 400 mg three times per day. Ketoconazole requires a low gastric pH for maximum absorption and thus should be taken on an empty stomach [24]. In addition, antacids, proton pump inhibitors, and histamine H2-receptor antagonists should be avoided, if possible. The use of ketoconazole is also complicated by multiple complex drug interactions. (For specific interactions, use the Lexicomp drug interactions program included with UpToDate.)
Adverse effects include nausea and vomiting in up to one-half of patients, skin rash in 10 percent, fatigue, nail dystrophy, asthenia, and gynecomastia. Ketoconazole can cause hepatotoxicity; liver function should be monitored at two weeks after initiating therapy and monthly thereafter. High doses of ketoconazole can cause adrenal insufficiency. Thus, ketoconazole is usually administered with concurrent hydrocortisone, which also has an antitumor effect and can complicate the interpretation of the results with ketoconazole.
The benefit of ketoconazole was addressed in a phase III trial conducted by the Cancer and Leukemia Group B (CALGB 9583), in which 260 patients with CRPC who had progressed on androgen deprivation therapy (ADT) were randomly assigned to antiandrogen withdrawal plus simultaneous ketoconazole or to antiandrogen withdrawal alone with ketoconazole reserved for subsequent use upon progression [18].
●Among 128 patients assigned to antiandrogen withdrawal plus immediate ketoconazole, a prostate-specific antigen (PSA) decline ≥50 percent was observed in 27 percent, and an objective tumor response was observed in 10 of 50 patients (20 percent) with measurable disease.
●In the group of 132 patients assigned to antiandrogen withdrawal alone, 108 were treated with ketoconazole plus hydrocortisone when PSA progression was documented. In these males, 35 of 108 (32 percent) had a PSA response, and 3 of 41 (7 percent) with measurable disease had an objective response.
Glucocorticoids — Glucocorticoids, prednisone in particular, are an integral component of many treatment regimens for metastatic CRPC, but for different reasons:
●Several studies have shown significant subjective and objective improvement in males with CRPC who receive glucocorticoids as monotherapy [14,25-28].
●A survival benefit has been shown from the addition of prednisone to both docetaxel and cabazitaxel [29,30]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Docetaxel versus mitoxantrone' and "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Cabazitaxel'.)
●Prednisone is also used to reduce side effects related to mineralocorticoid excess resulting from inhibition of 17-alpha-hydroxylase (CYP17), a key enzyme in androgen synthesis, from agents such as abiraterone [31]. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Abiraterone'.)
Several mechanisms might underlie the antitumor effect of glucocorticoids in advanced prostate cancer. Glucocorticoids (eg, prednisone, dexamethasone, hydrocortisone) reduce the pituitary production of adrenocorticotropic hormone (ACTH), resulting in suppression of adrenal steroidogenesis including adrenal androgens. Other possible mechanisms include direct inhibition of tumor growth by disruption of intracellular signaling pathways [32,33] and/or suppression of tumor lymphangiogenesis [34,35].
Some data on the activity of glucocorticoids come from trials in which steroids served as a control group [14,26,27,36-38]. As an example, in one trial, hydrocortisone (40 mg/day) was compared with hydrocortisone plus suramin in males with CRPC; 16 percent of those given cortisone alone had a decline in serum PSA >50 percent, while 28 percent had improved bone pain [26]. Similarly, in another trial comparing mitoxantrone plus hydrocortisone with hydrocortisone alone, 22 percent of males receiving hydrocortisone alone had >50 percent decline in serum PSA [27]. In a third trial of males previously treated with docetaxel who were assigned to abiraterone plus prednisone versus placebo plus prednisone, prednisone alone was associated with pain palliation in 29 percent but a >50 percent decline in PSA in only 6 percent [36,38].
There are only limited data addressing the optimal glucocorticoid regimen when used as monotherapy. In one single-center trial, 75 males were randomly assigned to either dexamethasone (0.5 mg/day) or prednisolone (5 mg twice daily) [25]. The PSA response rate was higher with dexamethasone (41 versus 22 percent), as was the median time to disease progression (10 versus 5 months), compared with prednisolone. In the absence of more robust data, dexamethasone may be the preferred glucocorticoid.
Whether there is benefit to switching to a different glucocorticoid in patients who progress while receiving a glucocorticoid for advanced disease (eg, prednisone in conjunction with docetaxel or abiraterone) is unclear. At least some data support the view that switching from prednisone to dexamethasone benefits some males who have limited progression while receiving abiraterone (ie, a rise in PSA and/or limited radiographic progression) for metastatic CRPC [39].
Megestrol acetate — Megestrol acetate is a synthetic progestin that may act through several mechanisms [40,41]. Megestrol acetate is rarely used since it has only limited activity and has been associated with tumor flare and risk of deep venous thrombosis.
The most extensive data using megestrol acetate come from a multicenter trial in which 149 males with advanced prostate cancer were randomly assigned to either low-dose (160 mg/day) or high-dose (640 mg/day) megestrol acetate. A >50 percent decrease in serum PSA was observed in 14 and 9 percent of low-dose and high-dose treatment groups. Median survival was the same in both groups (11 and 12 months, respectively).
Estrogens — Diethylstilbestrol (DES) at a dose of 1 mg/day and other estrogen preparations, such as transdermal estradiol, may have a role in some patients, where they are available.
High doses of estrogens compete with androgens for the androgen receptor and have a cytotoxic effect on human androgen-sensitive and androgen-insensitive prostate cancer cells in vitro [42].
●DES – DES formerly was widely used in the treatment of metastatic CRPC, but data supporting its use come primarily in the setting of initial hormone therapy for castration-sensitive advanced disease. The potential role of DES (1 mg daily) as a second-line agent was evaluated in a trial in which 58 males who had progressed on gonadotropin-releasing hormone (GnRH) agonist therapy were randomly assigned to either DES or bicalutamide [43]. Both the PSA response rate and median response durations were similar in the two groups (23 versus 31 percent and 9 versus 12 months, respectively). However, bicalutamide was better tolerated. Despite the prophylactic use of 75 mg of aspirin daily in the DES group, three of seven patients with adverse effects had cardiovascular toxicity (congestive heart failure, pulmonary embolism, stroke).
DES is inexpensive, but it is limited in availability worldwide; it is not commercially available in tablet or capsule form in the United States or Canada. However, at least in the United States, DES can be obtained from compounding pharmacies.
●Transdermal estrogen – Transdermal estrogen may be an option for males with CRPC, especially those with hot flashes, but the optimal dose is not established.
The transdermal route of estrogen administration avoids first pass through the liver, and the consequent hepatic overexpression of proteins, including those affecting coagulation, thereby diminishing cardiovascular toxicity associated with oral estrogens [44].
The best data on efficacy and toxicity come from the Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) study that randomly assigned males with locally advanced or metastatic prostate cancer scheduled to initiate indefinite hormone therapy to transdermal estradiol ([E2], 4 x 100 microg per 24 hours, changed twice weekly, reduced to three patches twice weekly if castrate at four weeks) or a luteinizing hormone releasing hormone agonist (LHRHa), and specifically addressed cardiovascular toxicity as a primary outcome [45-47]. Notably, the males included in this trial had castration sensitive, and not CRPC.
The initial pilot phase in 254 males showed transdermal E2 achieved equivalent castration rates to LHRHa without the early excess cardiovascular morbidity or mortality previously seen with oral estrogen [45]. Subsequent analyses of this dataset showed a number of other potential benefits of transdermal E2 compared with LHRHa, including improved bone mineral density [48], more favorable metabolic profiles, better quality of life over six months of ADT, although with increased likelihood of gynecomastia [46].
In the latest expanded analysis of 1694 males randomly assigned to transdermal E2 or LHRHa, at a median follow-up of 3.9 years, castration rates at one and three months were 65 and 93 percent for the LHRH agonist, and 83 and 93 percent for transdermal E2 [47]. Fatal cardiovascular events developed in 26 (2 percent), 15 in the LHRHa group and 11 treated with transdermal E2. The total number of cardiovascular events was not significantly higher with transdermal E2 (by 36 months, 8 versus 7.2 percent), nor was the time to first cardiovascular event significantly earlier (HR 1.11, 95% CI 0.80-1.53). Notably, however, 30 of the 89 cardiovascular events occurring in the transdermal E2 group (34 percent) occurred more than three months after transdermal E2 was stopped or changed to LHRHa.
Accrual to this trial (NCT00303784) continues, with progression-free and overall survival as endpoints.
Additional information on the efficacy of transdermal estrogen in males with castration-resistant disease was provided in a phase II trial of 24 males with prostate cancer progressing after primary ADT [49]. The dose of transdermal estrogen was 0.6 mg per 24 hours, administered as six 0.1 mg per 24-hour patches, replaced every seven days. Three of the 24 males (12.5 percent) had a confirmed PSA reduction >50 percent, and estimated median time to disease progression was 12 weeks (95% CI 4.6 to 19.4 weeks). Toxicity was modest and there were no thromboembolic complications.
ASSESSMENT DURING TREATMENT — For males with CRPC who are undergoing chemotherapy, 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 prostate-specific antigen (PSA) is the mainstay of testing. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend testing PSA every three to six months during treatment for advanced prostate cancer [50]. 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 CRPC are discussed in more detail separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Assessment during treatment'.)
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 5th to 6th 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 10th to 12th 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 topics (see "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Continuation of ADT
•Androgen deprivation therapy (ADT) is generally the initial treatment for males with advanced prostate cancer in combination with chemotherapy or combined with a second-generation androgen-targeted therapy or both. Despite high response rates to the initial hormone therapy, nearly all males eventually develop progressive castration-resistant disease. Subsequent management utilizes sequential application of various treatments. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway".)
•For patients with castration-resistant prostate cancer (CRPC) whose initial hormonal therapy included medical orchiectomy, we suggest that the gonadotropin-releasing hormone (GnRH) agonist or antagonist be continued throughout subsequent therapies so as to maintain suppression of testicular androgen production (Grade 2C). (See 'Continuation of androgen deprivation therapy' above.)
●Antiandrogen withdrawal – If a first generation antiandrogen was a component of initial ADT, discontinuation of treatment with the antiandrogen may result in a clinical or biochemical (prostate-specific antigen [PSA]) response. (See 'Antiandrogen withdrawal' above.)
●Other approaches
•A number of newer approaches have demonstrated improved overall survival in males with CRPC, but these have not been compared with each other in randomized clinical trials (table 1). The optimal sequencing of these therapies and their timing relative to older alternative endocrine approaches remain uncertain. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway" and "Chemotherapy in advanced castration-resistant prostate cancer" and "Bone metastases in advanced prostate cancer: Management".)
•Abiraterone and enzalutamide generally are the initial choice for second-line endocrine therapy in males with CRPC after failure of ADT if the patient has not already received a second generation androgen-targeted therapy for castration-sensitive disease. (See 'Abiraterone and enzalutamide' above.)
•The most common and least controversial use of alternative androgen-receptor-directed therapies is in patients with biochemical progression following first-line ADT in whom standard imaging shows minimal or no disease. While active surveillance is appropriate in such patients, many have biochemical responses to less potent androgen-receptor-directed agents (eg, bicalutamide), with unknown long-term clinical benefit. (See 'Older antiandrogens' above.)
•A number of other hormonal therapies have at least some activity in males with CRPC. There are no comparator trials, and the choice of approach is empiric. (See 'Other agents' above.)
ACKNOWLEDGMENT — 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.
