Version May 2024
INTRODUCTION — Androgen deprivation therapy (ADT), either alone or in combination with chemotherapy, is generally the initial treatment for males with metastatic prostate cancer. Standard approaches to ADT include bilateral orchiectomy or medical orchiectomy using a gonadotropin releasing hormone (GnRH) agonist, which may be given alone or in combination with an antiandrogen (combined androgen blockade). (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 progressive disease following ADT; this is referred to as castration-resistant prostate cancer (CRPC). Contemporary research in males with CRPC has led to the development of multiple agents that improved overall survival in phase III trials (table 1 and table 2).
Insights into the mechanisms by which androgens stimulate growth of prostate cancer cells is leading to the development of new treatments with clinically significant activity in males with CRPC. These approaches are discussed here.
Overviews of the management of advanced castration-sensitive prostate cancer and CRPC are presented separately. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer" and "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
MOLECULAR PATHWAYS
Rationale — Contemporary research has demonstrated that androgen-based pathways have a clinically significant role in the progression of CRPC. In addition to androgen production by the adrenal gland and testis, several of the enzymes involved in the synthesis of testosterone and dihydrotestosterone, including cytochrome P450 17-alpha-hydroxysteroid dehydrogenase (CYP17), are highly expressed in tumor tissue [1].
Collectively, these findings changed the perspective on prostate cancer from what has long been considered an "endocrine" disease to one that is dependent on "autocrine/paracrine" signaling for tumor progression and survival. This understanding has led to the development of drugs that act by inhibiting the enzymes responsible for androgen production, as well as agents that inhibit the androgen receptor.
Androgen synthesis inhibitors — Abiraterone was developed through screening chemical derivatives of a parent structure of pregnenolone. The structural changes in abiraterone cause potent and irreversible inhibition of CYP17 [2-4]. In preclinical studies, abiraterone was 10 times more potent than ketoconazole as an inhibitor of CYP17 [4]. (See 'Abiraterone' below.)
Although ketoconazole is a more potent inhibitor of the side chain cleavage enzyme, which plays a critical role in adrenal steroidogenesis, patients treated with either of these agents are at risk for adrenal insufficiency and require steroid replacement therapy. The use of ketoconazole is further limited by the potential for drug-drug interactions, particularly with statins and antidepressants. (See "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Ketoconazole'.)
Androgen receptor antagonists — Some metastatic and primary prostate tumors retain activation of the androgen receptor in processes that are entirely independent of the androgen ligand. Several mechanisms, including up-regulation of androgen receptor expression through amplification of the androgen receptor gene [5-7], increased sensitivity of the androgen receptor via overexpression of nuclear coactivators [8], and splice variant mutations of the receptor [9,10], have been proposed and may coexist. Importantly, these data suggest that progression of CRPC in some patients may not be effectively treated by a focus solely on ligand-directed therapy.
Enzalutamide, a small molecule antagonist of the androgen receptor, has important clinical activity and a role in the management of patients with CRPC. (See 'Enzalutamide' below.)
Resistance — Although both androgen synthesis inhibitors and androgen receptor antagonists can significantly alter the natural history of CRPC, progressive disease and resistance to these agents will eventually develop in most cases. The mechanisms for resistance are not fully understood and are the subject of ongoing research [11,12].
One possible mechanism to explain the lack of activity of these agents in approximately one-third of patients and the presence of resistance in almost all of those who do respond is the presence of variants in the androgen receptor [13,14]. The androgen receptor isoform splice variant 7 (AR-V7) lacks the binding site for androgen while retaining the activating site that stimulates tumor growth.
Data on the importance of AR-V7 come from the following reports:
●In a single-institution study of 202 males with metastatic CRPC who were starting therapy with either enzalutamide or abiraterone, all patients were assessed for the presence or absence of circulating tumor cells (CTCs), and those with CTCs present were assessed for the presence or absence of AR-V7 in those cells [14]. Responses to hormonal therapy were observed in 40 of 53 (75 percent) of those patients without CTCs, 59 of 113 (52 percent) of those with CTCs but without AR-V7, and 5 of 36 (14 percent) of those with CTCs that contained AR-V7. Furthermore, the duration of progression-free survival (PFS) for these groups decreased with the presence of AR-V7 (11.3, 6.2, and 2.1 months for the three groups, respectively). Overall survival was significantly shorter for those with AR-V7 (28.7, 29.5, and 11.2 months, respectively).
●Additional information comes from the multicenter, prospective PROPHECY study, in which 118 males with metastatic CRPC starting therapy with abiraterone or enzalutamide were assessed for baseline CTC AR-V7 [15]. Detection of CTC AR-V7 by either of two different assays was independently associated with shorter PFS and overall survival, as well as fewer confirmed prostate-specific antigen (PSA) responses (0 to 11 percent versus 26 to 28 percent in those who were AR-V7 negative) and soft tissue responses (0 to 6 percent versus 21 to 25 percent in those who were AR-V7 negative).
Although the AR-V7 splice variant predicts relative resistance to enzalutamide and abiraterone, preliminary evidence suggests that it is not associated with resistance to docetaxel chemotherapy [16]. Standardized, validated, and commercially available assays for AR-V7 are now available. The optimal use of AR-V7 testing is not yet clear, but it is likely to be in the abiraterone- or enzalutamide-resistant setting, in which consideration is being given to the use of a second androgen-receptor-targeted drug versus proceeding with chemotherapy. However, in practice, most males prefer to try another oral agent before moving on to chemotherapy, and responses are possible even in the presence of the AR-V7 splice variant.
Clinical role — The clinical role of treatments for metastatic CRPC that target the androgen pathway is evolving. Contemporary research in males with CRPC has led to the development of multiple agents that have significantly improved overall survival in phase III trials (table 2 and table 1). These agents have not been compared with each other, and the appropriate sequencing of them in males with advanced disease is not established. The factors affecting the choice and sequence of therapies in the setting of CRPC are discussed separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
PATIENTS WITH METASTATIC CRPC
Abiraterone — Abiraterone is an orally administered small molecule that irreversibly inhibits the products of the cytochrome P450 17-alpha-hydroxysteroid dehydrogenase (CYP17) gene (including both 17,20-lyase and 17-alpha-hydroxylase). In doing so, abiraterone blocks the synthesis of androgens in the tumor, as well as in the testes and adrenal glands.
Efficacy — The activity of abiraterone was established in two phase III trials in males with metastatic CRPC, the first in patients who had received prior docetaxel [17-19] and the other in patients with chemotherapy-naïve disease [20,21].
Prior docetaxel chemotherapy — In the first phase III trial, 1195 males who had previously been treated with a docetaxel-containing chemotherapy regimen were randomly assigned in a 2:1 ratio to abiraterone (1000 mg/day) plus prednisone (5 mg twice a day) or to placebo plus prednisone [17-19]. Treatment was continued until disease progression. Disease progression was determined by a composite of worsening pain and decline in performance status, as well as objective progression on scans and by prostate-specific antigen (PSA) rises. A rise in PSA on therapy (or a lack of decline) was not the sole criterion for discontinuation of therapy. The trial was terminated based upon an interim analysis when results exceeded prespecified criteria.
The final analysis of overall survival was conducted at a median follow-up of 20 months. Overall survival, the primary endpoint of the trial, was significantly increased with abiraterone compared with placebo (median 15.8 versus 11.2 months, hazard ratio [HR] 0.74, 95% CI 0.64-0.86). Benefits were similar in all subsets based upon preplanned analyses. Statistically significant improvements were also seen in time to PSA progression, radiologic progression-free survival (PFS), and PSA response rate (8.5 versus 6.6 months, 5.6 versus 3.6 months, and 29.5 versus 6.5 percent, respectively). Although patients with liver or lung metastases had a worse prognosis than those with disease limited to bone and lymph nodes, those receiving abiraterone did have similar improvement in overall survival compared with placebo (median 12.9 versus 8.3 months) [22].
Secondary analyses from the phase III trial focused on the impact of abiraterone compared with placebo on symptoms due to bone metastases [19]:
●Overall, approximately 90 percent of patients had bone metastases, and 41 percent of patients with bone metastases had clinically significant pain secondary to these metastases.
●There was a statistically significant improvement in the percentage of patients with palliation of pain intensity due to bone metastases with abiraterone plus prednisone compared with placebo plus prednisone (45 versus 29 percent), and palliation of pain intensity was achieved more rapidly (5.6 versus 13.7 months). Similar benefits for the combination of abiraterone plus prednisone were seen when the impact of pain on activities of daily living was assessed.
●Skeletal-related events (pathologic fracture, spinal cord compression, or palliative radiation therapy and/or surgery to bone) were seen in 23 and 25 percent of all patients treated with abiraterone plus prednisone and placebo versus prednisone, respectively. However, there was a statistically significant increase in the time to first skeletal-related event (median 25 versus 20 months for the entire study population).
Increased isotope uptake on bone scan suggestive of progressive disease should be interpreted with caution when patients are started on therapy with abiraterone. In a phase II study, follow-up bone scans obtained three months after treatment initiation were interpreted as worsening in 12 of 23 patients (52 percent) with a decrease in serum PSA of 50 percent or more [23]. In 11 of these 12, subsequent bone scans showed improvement or stabilization of bone disease.
Chemotherapy-naïve patients — Abiraterone also delays disease progression and prolongs overall survival in males with CRPC who have not received chemotherapy.
In a phase III trial, 1088 males with metastatic, asymptomatic or minimally symptomatic CRPC were randomly assigned to abiraterone plus prednisone or placebo plus prednisone [20,21,24]. Patients could not have received prior chemotherapy. The coprimary endpoints of the trial were radiographic PFS assessed by independent review and overall survival.
●The final survival analysis was conducted at a mean follow-up of 49 months [21]. Overall survival was increased with abiraterone plus prednisone compared with placebo plus prednisone (median 34.7 versus 30.3 months, HR 0.81, 95% CI 0.70-0.93). Analysis of overall survival was complicated by the subsequent use of abiraterone in 44 percent of patients assigned to placebo and by the use of other additional active therapy following protocol participation.
●At the third planned interim analysis, radiographic PFS was significantly increased with abiraterone plus prednisone compared with placebo plus prednisone (median 16.5 versus 8.2 months, HR 0.52, 95% CI 0.45-0.61) [20].
●Secondary endpoints that also demonstrated a statistically significant superiority for abiraterone plus prednisone compared with placebo plus prednisone included time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, PSA progression, and decline in performance status. Pain progression and deterioration in health-related quality of life were also significantly delayed with abiraterone [25].
Prior enzalutamide therapy — Abiraterone plus prednisone has only minimal activity in patients who progressed after treatment with enzalutamide, and for most individuals we suggest not pursuing this therapy.
●The best evidence comes from the phase IV PLATO trial, in which 251 patients who had previously responded to enzalutamide and then progressed were randomly assigned to either abiraterone plus prednisone alone or abiraterone plus prednisone and continued enzalutamide [26]. PFS was 5.7 months with abiraterone plus enzalutamide and 5.6 months with abiraterone plus placebo. Overall, there were only four patients in either group with a PSA decline of greater than 50 percent. Hypertension and elevated liver enzymes were more common with combined therapy.
●Data are also available from the CARD trial, in which 255 patients with metastatic CRPC who had progressed on docetaxel and either abiraterone or enzalutamide were randomly assigned to cabazitaxel or the other antiandrogen previously received, outcomes were significantly better with cabazitaxel [27]. In the group receiving the androgen receptor inhibitor, the median PFS was only 2.7 months, a PSA response occurred in only 14 percent, and 12 percent had an objective tumor response. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Third-line cabazitaxel versus androgen signaling therapy'.)
Toxicity — The toxicity profile of abiraterone is, in part, dependent upon its mechanism of action. CYP17, the target of abiraterone, regulates the conversion of pregnenolone and related steroids into androgens and is relatively specific for androgen production. However, there is inhibition of 17-alpha hydroxylase with decreased cortisol and a compensatory rise in adrenocorticotropic hormone (ACTH), which is mediated by a hypothalamic response to partial adrenal inhibition.
The increased ACTH release can cause increased adrenal mineralocorticoid production, which can lead to hypertension and hypokalemia. When abiraterone is given without concomitant glucocorticoids, patients typically do not experience clinical adrenal insufficiency since cortisol production is preserved. The effects of mineralocorticoid excess can be attenuated by coadministration with prednisone, which reduces ACTH-mediated stimulation of the adrenal glands. However, long-term combined treatment is associated with muscle wasting and weakness.
In the phase III trial in males who had received prior docetaxel, the incidence of severe (grade 3 or 4) adverse events leading to discontinuation of treatment was similar in those treated with abiraterone and placebo (10 and 13 percent, respectively) [17,18]. Side effects that were more common with abiraterone included fluid retention and hypokalemia (33 versus 24, and 18 versus 9 percent, respectively). Nonspecific cardiac abnormalities, abnormal liver function tests, and hypertension may also be more common in patients treated with abiraterone (16 versus 12, 11 versus 9, and 11 versus 8 percent, respectively).
Monthly potassium and blood pressure monitoring are essential to the proper management of patients on abiraterone. Because the hypertension is mediated by an excess of mineralocorticoids, specific mineralocorticoid antagonists, such as eplerenone, may be useful; however, standard antihypertensive therapies are also of benefit.
Other toxicities include liver dysfunction and, in patients with pre-existing diabetes mellitus, hypoglycemia. In addition, all treatments directed at the androgen receptor have adverse effects on other critical physiologic functions, including the cardiovascular system [28,29]. The decision to use abiraterone in males with preexisting cardiovascular disease, optimizing cardiovascular risk, and monitoring for potential cardiovascular side effects should include input from cardiologists. (See "Side effects of androgen deprivation therapy", section on 'Potential cardiovascular harm'.)
Concurrent glucocorticoid therapy — All males receiving abiraterone should also receive prednisone to mitigate mineralocorticoid excess. The standard dose is 5 mg twice daily, and we do not suggest using either lower prednisone doses or substituting dexamethasone for prednisone.
The original phase III trial demonstrating the benefit of abiraterone in CRPC used prednisone 5 mg twice daily [17,18], and this is the dose that is recommended in the United States prescribing information for abiraterone. The optimal dose of glucocorticoid for use in conjunction with abiraterone was directly tested in a multicenter randomized phase II trial in which 164 males starting abiraterone for CRPC were randomly assigned to one of five glucocorticoid regimens: prednisone at 5 mg twice daily, 5 mg daily, or 2.5 mg twice daily, and dexamethasone at 0.5 mg once daily [30]. The primary endpoint, no mineralocorticoid excess (defined by no ≥grade 2 hypertension (table 3), and no ≥grade 1 hypokalemia (table 4)), was achieved by 71 percent of males receiving prednisone 5 mg twice daily, compared with 37 and 60 percent of those receiving prednisone 5 mg daily or 2.5 mg twice daily, and 70 percent of those receiving dexamethasone. The dexamethasone group had significantly higher rates of adverse metabolic consequences (decrease in bone mineral density, increase in serum insulin), and the authors concluded that the results confirmed the approved use of abiraterone with prednisone 5 mg twice daily.
Side effects attributable to prednisone are limited, as evidenced by the following data:
●A detailed analysis of 2267 patients from the two pivotal phase III trials found that the two most frequent side effects associated with prednisone were hyperglycemia and weight gain (7.4 and 4.3 percent), and the incidence of grade 3 or greater side effects was 4.5 percent [31].
●In the above mentioned randomized phase II trial comparing different doses of prednisone (2.5 mg twice daily, 5 mg once daily, or 5 mg twice daily) or dexamethasone (0.5 mg once daily) in males receiving abiraterone for metastatic CRPC, 29 percent of the 41 males receiving prednisone 5 mg twice daily developed hypertension, and it was grade 3 in 7 percent [30]. Other common side effects in this group included peripheral edema in 20 percent, hypokalemia and weight gain in 10 percent each, and elevated liver function tests in 7 percent.
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 with 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 [32]. Given the high cost of this agent, these and other data support the use of the smaller abiraterone dose administered with a low-fat breakfast as an alternative to the higher dose given on an empty stomach [33,34], especially for males with a high copay and those who live in resource-poor settings, as it might improve compliance and increase access to treatment [35]. However, there are at least some data linking low trough levels with poorer outcomes in males with metastatic CRPC [36], and larger studies are needed in this important area. Nevertheless, administration of the lower dose, administered with a low-fat breakfast, is supported in updated consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [37].
Treatment at progression — Although the practice of switching between abiraterone and enzalutamide after progression with the other is common, particularly to delay the initiation of chemotherapy, few data are available to support meaningful benefit from use of enzalutamide after failure of abiraterone, and for most individuals we suggest not pursuing this approach. (See 'Prior abiraterone therapy' below.)
Other options are as follows:
●One option for males with limited disease progression while receiving abiraterone (PSA elevation and/or limited radiographic progression) is to switch from prednisone to dexamethasone [38]. (See "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Glucocorticoids'.)
●Retreatment with abiraterone can be associated with response in some patients, although clinical benefit appears to be limited [39-42].
●Enzalutamide appears to retain some activity in patients who have been previously treated with abiraterone [27,39,42-44]. However, clinical benefit is less than in patients who have not received prior abiraterone, and less than has been seen with alternative therapies such as cabazitaxel:
•The most extensive data come from a multicenter, single-arm phase IV study in which 214 patients were treated with enzalutamide, including 145 who were chemotherapy naïve [44]. All patients had been treated with abiraterone for a minimum of 24 weeks, and all had metastatic disease. The median duration of radiographic PFS, the primary endpoint of the study, was 8.1 months and was similar in those who had received prior chemotherapy and those who were chemotherapy naïve. The overall rate of PSA decline ≥50 percent was 27 percent, and the median time to PSA progression was 5.7 months.
•Data are also available from the CARD trial, in which 255 patients with metastatic CRPC who had progressed on docetaxel and either abiraterone or enzalutamide were randomly assigned to cabazitaxel or the other antiandrogen previously received, outcomes were significantly better with cabazitaxel [27]. In the group receiving the androgen receptor inhibitor, the median PFS was only 2.7 months, a PSA response occurred in only 14 percent, and 12 percent had an objective tumor response.
●Other therapies (chemotherapy with docetaxel [if not previously received], cabazitaxel, alternative endocrine therapies, immunotherapy) may be appropriate, particularly for males with more extensive disease progression. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)" and "Chemotherapy in advanced castration-resistant prostate cancer" and "Alternative endocrine therapies for castration-resistant prostate cancer" and "Immunotherapy for castration-resistant prostate cancer".)
Enzalutamide — Enzalutamide is an alternative to abiraterone for males with metastatic CRPC. Enzalutamide binds to the androgen binding site in the androgen receptor, thereby leading to inhibition of nuclear translocation of the androgen receptor and inhibition of the association of the androgen receptor with nuclear deoxyribonucleic acid (DNA). Phase I/II studies showed that enzalutamide had significant activity in males with CRPC [45,46]. This has led to the assessment of enzalutamide in larger randomized clinical trials.
Prior docetaxel chemotherapy — In the AFFIRM trial, 1199 males with metastatic CRPC who had received prior docetaxel-based chemotherapy were randomly assigned to either enzalutamide (160 mg as a single dose, once daily) or placebo in a two to one ratio (NCT00974311) [47,48]. Concurrent therapy with glucocorticoids was permitted but not required on both treatment arms. The patient population in that trial was heavily pretreated, with approximately 50 percent of patients having received three or more prior endocrine therapies, and 25 percent had been treated with two or more chemotherapy regimens.
Based upon the results of the planned interim analysis after 520 deaths, the blind was broken, and patients were allowed to cross over from placebo to enzalutamide upon progression. Results included the following [47]:
●Overall survival was significantly increased with enzalutamide compared with placebo (median 18.4 versus 13.6 months, HR 0.63, 95% CI 0.53-0.75). The survival benefit was consistent across all subgroups.
●Enzalutamide was significantly better than placebo in all secondary efficacy endpoints, including prostate-specific antigen (PSA) response (>50 percent decrease, 54 versus 2 percent of patients, and >90 percent decrease, 25 versus 1 percent), soft tissue response (29 versus 4 percent), quality of life response (43 versus 18 percent), time to PSA progression (8.3 versus 3.0 months), radiographic PFS (8.3 versus 2.9 months), and time to first skeletal-related event (16.7 versus 13.3 months).
●Treatment was well tolerated. For patients treated with enzalutamide, there was a higher incidence of fatigue (34 versus 29 percent), diarrhea (21 versus 18 percent), hot flashes (20 versus 10 percent), musculoskeletal pain (14 versus 10 percent), and headache (12 versus 6 percent). The one toxicity of potential concern was the development of seizures, which occurred in seven patients (0.9 percent) treated with enzalutamide and no patients assigned to placebo [49]. There was no statistically significant difference in the rate of treatment discontinuation due to adverse events (8 versus 10 percent with placebo).
Several secondary analyses of the AFFIRM trial were undertaken:
●Health-related quality of life was significantly improved across all domains with enzalutamide compared with placebo, based upon the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores [48].
●In addition, the benefits in overall survival and delayed disease progression associated with enzalutamide were similar in older adult males (≥75 years) compared with those seen in younger males [50].
●Although benefits were independent of glucocorticoid use, the benefits of enzalutamide were less in patients receiving concomitant glucocorticoids [51]. Further study is needed to determine clinical settings in which the short-term benefits of glucocorticoid use outweigh the potential for adverse effects and inferior oncologic outcomes.
Chemotherapy-naïve — The primary data supporting the role of enzalutamide in chemotherapy-naïve patients come from the large randomized PREVAIL trial in males with known metastatic disease. Data in males without detectable metastatic disease are described in detail below. (See 'Enzalutamide' below.)
In the PREVAIL trial, 1717 males with metastatic disease who had not received prior docetaxel chemotherapy were randomly assigned to enzalutamide or placebo [52-55]. The coprimary endpoints of the trial were overall survival and radiographic PFS. The trial was stopped after a planned interim analysis, based upon a survival benefit for patients treated with enzalutamide.
●At the planned interim analysis, with a median duration of follow-up of 22 months, overall survival was significantly increased with enzalutamide compared with placebo (median 32.4 versus 30.2 months, HR 0.71, 95% CI 0.60-0.84). An extended analysis at 31 months' follow-up included five months in an open-label extension, during which patients could cross over from placebo to enzalutamide [55]. Median overall survival was significantly increased (35.3 versus 31.3 months, HR 0.77, 95% CI 0.67-0.88).
●At a median follow-up of 22 months for enzalutamide and 11 months for placebo, there was a significant decrease in the risk of radiographic progression with enzalutamide (median 20 versus 5.4 months, HR 0.32, 95% CI 0.28-0.36). Time to first skeletal-related event was significantly longer in those treated with enzalutamide (median 31 months for both groups, HR 0.72, 95% CI 0.61-0.84).
●Based upon patient responses to the FACT-P questionnaire, quality of life was significantly better with enzalutamide, with median time to clinically significant deterioration longer in those assigned to enzalutamide compared with placebo (median 11.3 versus 5.6 months, HR 0.62, 95% CI 0.54-0.72).
●In the latest analysis with greater than five-year follow-up, the median overall survival benefit of enzalutamide persisted (median 36 versus 31 months), but there was also a higher rate of fatal treatment-emergent side effects with enzalutamide (6.9 versus 3.8 percent), including fatal cardiovascular events (1.6 versus 0.4 percent) [56].
Additional support for the role of enzalutamide in males with chemotherapy-naïve metastatic CRPC comes from two randomized trials comparing enzalutamide with bicalutamide:
●In the TERRAIN trial, 375 asymptomatic or minimally symptomatic patients with metastatic disease were randomly assigned to either enzalutamide (160 mg/day) or bicalutamide (50 mg/day) [57]. PFS, the primary endpoint of the trial, was significantly longer with enzalutamide compared with bicalutamide (15.7 versus 5.8 months, HR 0.44, 95% CI 0.34-0.57).
●In the STRIVE trial, 396 males with either metastatic or nonmetastatic disease were randomly assigned to enzalutamide or bicalutamide [58]. PFS, the primary endpoint of the trial, was significantly longer with enzalutamide compared with bicalutamide (19.4 versus 5.7 months, HR 0.24, 95% CI 0.18-0.32). The data from both of these trials are limited to patients with CRPC, and bicalutamide may continue to have a role in other clinical settings. (See "Alternative endocrine therapies for castration-resistant prostate cancer", section on 'Older antiandrogens'.)
Toxicity — Fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache are the most common reported adverse effects of enzalutamide. Seizures are infrequent, occurring in less than 1 percent of treated patients. In addition, all treatments directed at the androgen receptor have adverse effects on other critical physiologic functions, including the cardiovascular system [28,29,59,60]. The decision to use abiraterone in males with preexisting cardiovascular disease, optimizing cardiovascular risk, and monitoring for potential cardiovascular side effects should include input from cardiologists. (See "Side effects of androgen deprivation therapy", section on 'Potential cardiovascular harm'.)
Prior abiraterone therapy — Enzalutamide appears to retain some activity in patients who have been previously treated with abiraterone, although the clinical benefit is less than in patients who have not received prior abiraterone [39,42-44]:
●The most extensive data come from a multicenter, single-arm phase IV study in which 214 patients were treated with enzalutamide, including 145 who were chemotherapy naïve [44]. All patients had been treated with abiraterone for a minimum of 24 weeks, and all had metastatic disease. The median duration of radiographic PFS, the primary endpoint of the study, was 8.1 months and was similar in those who had received prior chemotherapy and those who were chemotherapy naïve. The overall rate of PSA decline ≥50 percent was 27 percent, and the median time to PSA progression was 5.7 months.
●Data are also available from the CARD trial in which 255 patients with metastatic CRPC who had progressed on docetaxel and either abiraterone or enzalutamide were randomly assigned to cabazitaxel or the other antiandrogen previously received, outcomes were significantly better with cabazitaxel [27]. In the group receiving the androgen receptor inhibitor, the median PFS was only 2.7 months, a PSA response occurred in only 14 percent, and 12 percent had an objective tumor response.
Treatment at progression — As noted above, although the practice of switching between abiraterone and enzalutamide after progression with the other is common, particularly to delay initiation of chemotherapy, few data are available to support meaningful benefit from use of abiraterone after failure of enzalutamide. We do not routinely use this approach. (See 'Prior abiraterone therapy' above.)
Other therapies (taxane-based chemotherapy using either docetaxel [if not previously received] or cabazitaxel, alternative endocrine therapies, immunotherapy) may be more appropriate, particularly for males with more extensive disease progression. (See "Chemotherapy in advanced castration-resistant prostate cancer" and "Immunotherapy for castration-resistant prostate cancer".)
For patients not previously treated with docetaxel, limited data from the phase III PRESIDE trial suggest there might be benefit for continued enzalutamide in conjunction with docetaxel [61]. In this trial, 687 patients with chemotherapy-naïve metastatic CRPC and disease progression on androgen deprivation therapy (ADT) alone all received open-label enzalutamide plus continued ADT; those with a PSA response ≥50 percent at week 13 and later progression (n = 273) received docetaxel plus prednisolone and were randomized to continue enzalutamide or switch to placebo. In a preliminary report presented at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, continuation of enzalutamide in conjunction with docetaxel was associated with modestly but significantly better PFS (defined by radiographic or clinical progression or death, median 9.53 versus 8.28, HR 0.72, 95% CI 0.53-0.96). Combined therapy also improved median time to PSA progression (8.44 versus 6.24 months); overall survival endpoints were not reported. These benefits came at the cost of more treatment related toxicity; treatment-emergent adverse effects were reported in more patients receiving combined therapy (49 versus 39 percent), and there were more deaths in this group as well (13 versus 7, 9.6 versus 5.2 percent). We await more mature data from this trial in order to define which populations of patients stand to benefit the most.
Abiraterone versus enzalutamide — There are limited data comparing abiraterone with enzalutamide in the initial management of patients with CRPC, and the choice of one agent over another should be based on toxicity profiles and patient-specific factors, including reimbursement from third-party payers. Many insurers are requiring abiraterone first because it is available as a generic drug and is somewhat less expensive.
Results are available from a randomized phase II trial in which 202 treatment-naïve males with metastatic CRPC were assigned to abiraterone plus prednisone followed by crossover to enzalutamide at the time of progression, or the opposite sequence [62]. Although there was a higher prostate-specific antigen (PSA) response rate with first-line enzalutamide (82 versus 68 percent), the time to PSA progression was not significantly different (10.2 versus 11.2 months). Furthermore, there was a significant benefit to initial treatment with abiraterone in terms of time to PSA progression after crossover (median 3.5 versus 1.7 months) and PSA response to second-line therapy (36 versus 4 percent). The most common grade 3 or 4 adverse events for first-line therapy were hypertension (23 versus 13 percent for initial abiraterone versus enzalutamide), fatigue (6 versus 2 percent), and increased alanine aminotransferase (6 versus 1 percent). The most common grade 3 or 4 adverse events with second-line therapy were hypertension (18 versus 13 percent for second-line enzalutamide versus abiraterone), fatigue (5 versus 3 percent), back pain (3 versus 4 percent), and extremity pain (4 versus 1 percent). In our view, these are very minor differences.
Combining abiraterone and an AR antagonist — Until further information becomes available, we suggest not pursuing combined therapy with abiraterone plus either enzalutamide or apalutamide in males with CRPC.
Androgen synthesis inhibitors (such as abiraterone) and androgen receptor antagonists (such as enzalutamide and apalutamide) target androgen-based pathways by different mechanisms, and mechanisms of resistance also differ. Several retrospective studies indicate that either using abiraterone after enzalutamide or using enzalutamide after abiraterone in CRPC has limited activity [40-42]. There are no data on sequential use of abiraterone and apalutamide. (See 'Prior abiraterone therapy' above and 'Prior enzalutamide therapy' above.)
The hypothesis that coadministration might forestall disease resistance or prolong survival has been addressed in the following studies:
●The phase III ALLIANCE A031201 trial, which compared enzalutamide 160 mg daily plus abiraterone (1000 mg daily) and prednisone 5 mg twice daily versus enzalutamide alone in 1311 males with progressive metastatic CRPC [63]. In a preliminary report presented at the 2019 annual ASCO meeting, combined therapy did not improve overall survival (32.7 versus 33.6 months) or the 50 percent prostate-specific antigen (PSA) decline rate (77 versus 80 percent), and it increased rates of grade 3 or 4 hypertension, fatigue, transaminitis, and hypokalemia.
Whether this approach has clinical utility is the subject of a second ongoing randomized trial comparing combined therapy versus abiraterone alone.
●On the other hand, modest benefit for combined therapy with abiraterone plus apalutamide was suggested in the phase III ACIS trial, in which 982 males with progressive metastatic chemotherapy-naïve metastatic CRPC receiving ongoing ADT alone were randomly assigned to apalutamide plus abiraterone and prednisone or placebo plus abiraterone plus prednisone [64]. At a median follow-up of 55 months, the median radiographic PFS (the primary endpoint) was prolonged by six months by the addition of apalutamide (24 versus 16.6 months, HR 0.70 [95% CI 0.60-0.83]), and there was a modest but significantly higher rate of PSA response as well (decline of at least 50 percent, 79 versus 73 percent); the difference in median overall survival was not significant (median 36.2 versus 33.7 months, HR 0.95 [95% CI 0.81-1.11]). Combined therapy was associated with more frequent grade 3 or 4 treatment-related adverse effects, although there were fewer grade 5 (fatal) toxicities in the combined therapy group (17 versus 37 events, 3 versus 8 percent).
Combining enzalutamide with a PARP inhibitor — Use of the poly(ADP-ribose) polymerase (PARP) inhibitor talazoparib concurrently with enzalutamide has shown PFS benefit relative to enzalutamide alone, but further study and/or regulatory approval are needed prior to routine clinical use of this strategy.
In the TALAPRO-2 trial, 805 patients with asymptomatic or mildly symptomatic metastatic castrate-resistant prostate cancer receiving ongoing ADT were randomly assigned to enzalutamide and talazoparib or enzalutamide and placebo [65]. Approximately 80 percent were taxane chemotherapy-naïve. At a median follow-up of 24.6 months, PFS was not reached in the talazoparib group and was 21.9 months in the placebo group (HR 0.63, 95% CI 0.51-0.78). Benefits were observed both among those with homologous recombination repair deficient tumors (HR 0.46) and among those non-deficient or unknown status (0.70). Overall survival results are immature. In the talazoparib group, 59 percent had grade ≥3 treatment-related adverse events, versus 18 percent in the placebo group.
While these results are promising, longer term data are needed.
PATIENTS WITH NONMETASTATIC CRPC — For males with nonmetastatic CRPC, phase III trials with enzalutamide, apalutamide, and darolutamide have shown that all three drugs significantly prolong metastasis-free survival and delay the use of other antitumor therapy. In this setting, the efficacy of these three agents has not been compared directly, but it appears to be similar. Differences in the safety and side effect profile may drive treatment decisions [66]. Notably, darolutamide has not been reported to induce fewer central nervous system side effects compared with enzalutamide and, to a lesser extent, apalutamide. All three agents carry a risk of drug-drug interactions, which should be examined closely prior to choosing one agent over another.
Enzalutamide — Data on the efficacy of enzalutamide in males with CRPC without detectable distant metastases come from the PROSPER trial, in which 1401 males with high-risk CRPC, a PSA doubling time ≤10 months, and a serum PSA ≥2 ng/mL, but without metastatic disease (M0) were randomly assigned to enzalutamide or placebo, while continuing on ADT [67]. The following were noted:
●The primary endpoint of the trial was metastasis-free survival, which was prolonged with enzalutamide compared with placebo (36.6 versus 14.7 months, HR 0.29, 95% CI 0.24-0.35).
●Time to first use of a new antineoplastic agent, a secondary endpoint, was prolonged (39.6 versus 17.7 months, HR 0.21, 95% CI 0.17-0.26), and time to PSA progression was significantly prolonged (37.2 versus 3.9 months, HR 0.07, 95% CI 0.05-0.08).
●A later analysis also demonstrated improved overall survival of enzalutamide plus ADT over ADT alone (median 67 versus 56 months, HR 0.73, 95% CI 0.61-0.89) [68].
Largely based on the results of the PROSPER trial, enzalutamide was approved by the US Food and Drug Administration (FDA) for treatment of all males with nonmetastatic CRPC.
Apalutamide — Apalutamide binds to the androgen binding site in the androgen receptor and has shown considerable activity against CRPC in both the metastatic [69] and nonmetastatic setting [70,71]. Its mechanism of action and efficacy profile are very similar to enzalutamide; however, it has fewer central nervous system toxicities.
The bulk of the data are in males with nonmetastatic CRPC. In the phase III SPARTAN trial, 1207 males with nonmetastatic CRPC were randomly assigned to apalutamide or placebo in a 2:1 ratio while continuing ADT [70]. Patient eligibility requirements included the absence of metastases and a PSA doubling time of ≤10 months. At a median follow-up of 20 months, key results included the following:
●Metastasis-free survival, the primary endpoint of the trial, was increased compared with placebo (median 40.5 versus 16.2 months, HR 0.28, 95% CI 0.23-0.35). Secondary endpoints, including time to metastasis, progression-free survival, and time to PSA progression, were also significantly better with apalutamide. In a later analysis, overall survival was also better with apalutamide (median 73.9 versus 59.9, HR for death 0.78, 95% CI 0.64-0.96) [72].
●Treatment was generally well tolerated. The most common grade 3 to 4 side effects associated with apalutamide were hypertension and rash (14.3 and 5.2 percent, respectively). Other noteworthy side effects attributed to the study drug included fatigue, falls, fractures, hypothyroidism, and mental impairment (overall incidence 30, 16, 12, 8, and 5 percent, respectively). Cerebrovascular events occurred in 4.7 percent of patients treated with apalutamide, compared with 0.8 percent of those receiving placebo [73]. Seizures occurred in only 0.2 percent of patients treated with apalutamide.
Largely based on these data, apalutamide was approved by the FDA for treatment of nonmetastatic CRPC.
Darolutamide — Darolutamide (ODM-221) is an androgen receptor antagonist with a distinct structure that offers the potential for fewer and less severe toxic effects than either enzalutamide or apalutamide because of its low penetration of the blood-brain barrier and low binding affinity for gamma-aminobutyric acid type A (GABAA) receptors (which are thought responsible for the tendency of other androgen receptor antagonists to induce seizures) [74,75]. In addition, darolutamide also blocks the activity of mutant androgen receptors that arise in response to antiandrogen therapies, which confer resistance to other androgen receptor antagonists.
Efficacy in metastatic CRPC was initially suggested in a combined phase I/II trial [76]. Efficacy in nonmetastatic CRPC was later shown in a double-blind phase III trial (ARAMIS) in which 1509 males with nonmetastatic CRPC and a PSA doubling time of <10 months were randomly assigned to darolutamide (600 mg orally twice daily) or placebo; both groups continued primary ADT [77]. Median metastasis-free survival (the primary endpoint) was significantly longer with darolutamide (40.4 versus 18.4 months, HR 0.41, 95% CI 0.31-0.50), and there were significant benefits with regard to all secondary endpoints, including overall survival (HR 0.69, 95% CI 0.53-0.88) [78], time to pain progression, time to need for cytotoxic chemotherapy, and time to a symptomatic skeletal event. Treatment was well tolerated overall, and darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension.
Largely based on these data, darolutamide was approved by the FDA for treatment of nonmetastatic CRPC [79]. A reduced initial dose is recommended for individuals with severe renal impairment (estimated glomerular filtration rate [eGFR] <29 mL/min/1.73 m2) or moderate hepatic impairment (Child-Pugh class B cirrhosis (table 5)).
Is any one drug superior to the others in nonmetastatic CRPC? — For males with nonmetastatic CRPC, phase III trials with enzalutamide, apalutamide, and darolutamide have shown that all three drugs significantly prolong metastasis-free survival and overall survival, and delay the use of other antitumor therapy. In this setting, the efficacy of these three agents has not been compared directly, but it appears to be similar. Differences in the safety and side effect profile may drive treatment decisions [66].
Darolutamide has been reported to induce fewer side effects compared with enzalutamide and apalutamide, although the data are less than definitive. A systematic review and meta-analysis of all three studies concluded that there was no difference in prostate cancer outcomes among any of the three drugs, and no statistically significant differences in the adverse event profiles [80]. An indirect analysis of individual patient data from the three trials also came to this conclusion [81]. However, a separate analysis of the published data from all three trials emphasized the remarkable differences in adverse event reporting in the trials, as well as differences in the absolute adverse event risks in all three placebo arms, concluding that the available data are insufficient to differentiate adverse event profiles of these agents in nonmetastatic CRPC [82].
All three agents carry a risk of drug-drug interactions, which should be examined closely prior to choosing one agent over another.
ASSESSMENT DURING TREATMENT — For males with CRPC 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 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 [83]. 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".)
SUMMARY AND RECOMMENDATIONS
●Rationale for continued targeting of androgen receptor pathways
•Despite high response rates to androgen deprivation therapy (ADT) in males with advanced prostate cancer, nearly all eventually develop progressive castration-resistant prostate cancer (CRPC). Despite castration "resistance," androgen-based pathways can continue to stimulate disease progression in males with CRPC. This understanding has led to the development of alternative treatments that target the androgen pathway by inhibiting the enzymes responsible for androgen production, as well as agents that inhibit the androgen receptor. (See 'Rationale' above.)
•The clinical role of treatments for CRPC that target the androgen pathway is evolving. Contemporary research in males with CRPC has led to the development of multiple agents that have significantly improved overall survival in phase III trials conducted in individuals with metastatic and nonmetastatic CRPC (table 2 and table 1). These agents have not been compared with each other, and the appropriate sequencing of them in males with advanced disease is not established. The factors affecting the choice and sequence of therapies in the setting of CRPC are discussed separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
●Patients with metastatic CRPC
•The efficacy of both abiraterone and enzalutamide in conjunction with continued ADT have been established in placebo-controlled trials for males with metastatic CRPC, both in the docetaxel-naïve and chemotherapy refractory settings. (See 'Abiraterone' above and 'Enzalutamide' above.)
•All males receiving abiraterone should also receive prednisone to mitigate mineralocorticoid excess. The standard dose is 5 mg twice daily, and we do not use either lower prednisone doses or substitute dexamethasone for prednisone. (See 'Concurrent glucocorticoid therapy' above.)
There are only limited data comparing abiraterone with enzalutamide in the initial management of patients with metastatic CRPC, and the choice of one agent over another should be individualized and based on toxicity profiles and patient-specific factors, including reimbursement from third-party payers. Many insurers are requiring abiraterone first because it is available as a generic drug and is somewhat less expensive. (See 'Abiraterone versus enzalutamide' above.)
•Until further information becomes available, we suggest not pursuing combined therapy with abiraterone plus either enzalutamide or apalutamide in males with CRPC (Grade 2C). (See 'Combining abiraterone and an AR antagonist' above.)
•Although the practice of switching between abiraterone and enzalutamide after progression with the other is common, particularly to delay initiation of chemotherapy, few data are available to support meaningful benefit from use of abiraterone after failure of enzalutamide and vice versa, and we do not routinely use this approach. (See 'Prior enzalutamide therapy' above and 'Prior abiraterone therapy' above.)
●Patients with nonmetastatic CRPC
•For patients with nonmetastatic CRPC, phase III trials with enzalutamide, apalutamide, and darolutamide have shown that all three drugs significantly prolong metastasis-free survival and overall survival, and delay the use of other antitumor therapy. In this setting, the efficacy of these three agents has not been compared directly, but it appears to be similar (table 2). (See 'Patients with nonmetastatic CRPC' above.)
Differences in the safety profile may drive treatment decisions. Darolutamide has not been reported to induce fewer central nervous system side effects compared with enzalutamide and, to a lesser extent, apalutamide. All three agents carry a risk of drug-drug interactions, which should be examined closely prior to choosing one agent over another. (See 'Is any one drug superior to the others in nonmetastatic CRPC?' above.)
ACKNOWLEDGMENTS
The UpToDate editorial staff acknowledges Charles J Ryan, MD, who contributed to earlier versions of this topic review.
We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.
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