Targeting gonadal androgen synthesis (often in conjunction with blockade of androgen receptor) is the cornerstone of treatment of hormone-sensitive metastatic prostate cancer (HSPC). Despite the failure of androgen deprivation therapy, most tumors maintain some dependence on androgen or androgen receptor signaling for proliferation. This article reviews the current standard of care for metastatic HSPC, mechanisms of treatment resistance, novel drugs targeting the androgen signaling pathway, biomarkers predicting response to treatment and survival, future directions, and ongoing clinical trials in HSPC.
Key points
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Targeting gonadal androgen synthesis (often in conjunction with blockade of androgen receptor) is the cornerstone of treatment of hormone-sensitive metastatic prostate cancer.
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Responses are not durable and almost all patients progress, with a median duration of approximately 18 months.
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Over the last decade, it has been recognized that despite the failure of androgen deprivation therapy, most tumors maintain some dependence on androgen or androgen receptor signaling for proliferation.
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Novel agents targeting these pathways continue to be developed.
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An area of active investigation is the identification and validation of biomarkers predicting response to therapy.
Introduction
More than 238,590 men were diagnosed with prostate cancer in 2013, with 29,720 estimated to die of their disease, as a result of progression to metastatic disease. Although most men with metastatic prostate cancer develop metastatic disease after failing definitive therapy for their localized disease, about 5% have metastatic disease at the time of initial diagnosis. In the 1940s, Huggins and Hodges were the first to show that castration induces significant palliation in metastatic prostate cancer. Since then, targeting gonadal androgen synthesis (often in conjunction with blockade of androgen receptor [AR]) has become the cornerstone of treatment of hormone-sensitive metastatic prostate cancer (HSPC). However, responses are not durable, and almost all patients progress, with a median duration of approximately 18 months. Over the last decade, it has been recognized that despite the failure of androgen deprivation therapy (ADT), most tumors maintain some dependence on androgen or AR signaling for proliferation. Many patients with metastatic prostate cancer respond to secondary hormone manipulation, after disease progression on ADT.
Introduction
More than 238,590 men were diagnosed with prostate cancer in 2013, with 29,720 estimated to die of their disease, as a result of progression to metastatic disease. Although most men with metastatic prostate cancer develop metastatic disease after failing definitive therapy for their localized disease, about 5% have metastatic disease at the time of initial diagnosis. In the 1940s, Huggins and Hodges were the first to show that castration induces significant palliation in metastatic prostate cancer. Since then, targeting gonadal androgen synthesis (often in conjunction with blockade of androgen receptor [AR]) has become the cornerstone of treatment of hormone-sensitive metastatic prostate cancer (HSPC). However, responses are not durable, and almost all patients progress, with a median duration of approximately 18 months. Over the last decade, it has been recognized that despite the failure of androgen deprivation therapy (ADT), most tumors maintain some dependence on androgen or AR signaling for proliferation. Many patients with metastatic prostate cancer respond to secondary hormone manipulation, after disease progression on ADT.
Androgen synthesis and AR
The regulation of androgen production by the testicles originates in the hypothalamus, where the pulsatile release of gonadotropin-releasing hormone (GnRH) leads to the release of leutinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary into the blood stream ( Fig. 1 ). Under the effect of LH, androgens are produced in the Leydig cells of the testes (most serum testosterone) and testosterone is converted to dihydrotestosterone (DHT) by 5α–reductase within the prostate. Another source of circulating androgens are the adrenal glands, where androgens, mainly 5-dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione are synthesized in the zona reticularis. The first step in steroid biosynthesis is the formation of cholesterol from acetyl coenzyme A and squalene ( Fig. 2 ). Cholesterol is then converted to pregnenolone and then to progesterone. The pivotal enzymes in androgen synthesis are the CYP17 enzymes (CYP17 hydroxylase, CYP17,20 lyase) located in the Leydig cells of the testes and the zona fasciculata and reticularis of the adrenal glands. CYP17 catalyzes the conversion of pregnenolone and progesterone to the weak androgen steroids, DHEA, and androstenedione, respectively. Both DHEA and androstenedione are converted to testosterone and then to DHT, reactions that are catalyzed by other enzymes.
AR is a steroid hormone receptor located in the cytoplasm that remains bound to heat shock proteins. The functional domains of AR include the C-terminal ligand-binding domain (LBD), a DNA-binding domain, and the N-terminal domain (NTD). When activated, the LBD results in the nuclear translocation of AR. The NTD is essential for the transcriptional activity of the AR in response to a ligand, as well as in the absence of a ligand. When testosterone and DHT bind with LBD, AR dissociates from heat shock protein and undergoes homodimerization and tyrosine kinase phosphorylation, followed by translocation to the nucleus. Within the nucleus, AR binds to androgen response elements in the promoter and enhancer regions of the target gene. This event is followed by the recruitment of several coactivator and corepressor proteins and the formation of an active transcription complex, which induces transcription of several genes involved in cell cycle regulation and proliferation.
Molecular mechanism underlying prostate cancer progression despite ongoing ADT
AR-Dependent Mechanisms
Several mechanisms have been identified to explain the persistent growth and proliferation of prostate cancer despite ongoing ADT. Although ADT reduces the level of serum androgens to very low levels, it does not eliminate them completely. In patients on ADT, the adrenal glands are the major source of androgens. In addition, there is evidence that prostate cancer cells can initiate aberrant androgen signaling, as well as synthesize sufficient amounts of intratumoral androgens to allow continued androgen signaling and tumor growth in a castrate patient. The concentrations of intratumoral testosterone in metastatic prostate tumors in men with castration-resistant prostate cancer (CRPC) are 2 to 3 times higher than in men who have never received ADT, despite the fact that those not receiving ADT have higher serum testosterone levels. After receiving 9 months of neoadjuvant deprivation therapy, men with localized prostate cancer did not have a reduction in the expression of many androgen-responsive genes, including the AR and prostate-specific antigen (PSA), although intratumoral testosterone and DHT levels were reduced by 75%. Many enzymes involved in androgen synthesis are highly upregulated in CRPC compared with those with androgen-sensitive prostate cancer. Castrate-resistant cell lines synthesized a 5-fold higher concentration of testosterone than androgen-dependent cell lines and were capable of directly converting radioactive cholesterol into testosterone in vitro. These data indicate that castration, based on serum testosterone levels, is not synonymous with androgen ablation in the prostate tumor microenvironment. Prostate cancer cells can adapt to castration by intratumoral synthesis or conversion of adrenal androgens to testosterone and DHT and subsequently derive a growth advantage. One known (but rare) mechanism is the mutation of the AR gene, resulting in promiscuous ARs, which are activated by antiandrogens (such as bicalutamide) and other endogenous steroids (such as progesterone or deoxycorticosterone).
Other mechanisms underlying prostate cancer progression, despite ongoing ADT, include increased AR gene expression, either because of AR gene amplification; an increased rate of transcription of AR gene, or from the increased stability of the AR transcript. Somatic AR mutations, developing under the selection pressure of ADT, is another mechanism underlying continued progression of prostate cancer. Antiandrogen therapy–associated AR mutants may provide the basis for the antiandrogen withdrawal syndrome, in which tumors regress and PSA declines on cessation of treatment. This may be a reason why prostate cancer progressing on 1 AR antagonist may show favorable response to another. Sequencing studies have shown prevalence of mutation in both LBD and NTD of the AR coding region. One emerging and recently reported mechanism is AR gene rearrangement, resulting in constitutively active truncated AR splice variants that lack the AR LBD.
These data establish enzymes of the androgen synthesis pathway and AR signaling as valid targets in addition to standard ADT to optimize outcomes in HSPC.
AR-Independent Mechanisms
Although androgen signaling plays an important role, all of the hallmarks of cancer may be invoked to drive the progression of prostate cancer in men being treated with ADT. It is now recognized that stromal-epithelial cross talk in the prostate cancer microenvironment is critical for prostate cancer progression. Hedgehog signaling, Src family kinases, fibroblast growth factors, transforming growth factor β, integrins, vascular endothelial growth factor, insulinlike growth factor, and interleukin 6 are important components and potential targets for drug development. Other important pathways include those that inhibit apoptosis and promote survival, including the mitogen-activated protein kinases and phosphoinositide 3-kinase-Akt pathways. Chromosomal rearrangements or deletions in prostate cancer may result in the overexpression of oncogenes by the androgen or other steroid receptors, providing an opportunity to target gene fusions, such as those involving the members of the ETS and RAF kinase families. Other pathways implicated in the progression of prostate cancer include a dysfunctional epigenetic environment, c-MET-hepatocyte growth factor receptor pathway, cytoprotective chaperone networks, and alternative mitogenic growth factor pathways, such as the epidermal growth factor pathway. These molecular pathways can be singularly differentially upregulated or in combination with other pathways and are responsible for the biological heterogeneity in prostate cancer, as well as the variable response to targeted therapies.
These data establish AR-dependent, as well as AR-independent, molecular pathways as valid targets in prostate cancer in addition to standard ADT to optimize outcomes in HSPC. This review focuses on targeting androgen-dependent pathways in men with HSPC.
Drugs targeting androgen synthesis and AR signaling in metastatic prostate cancer
GnRH agonists and antagonists, which target the hypothalamic-pituitary-gonadal axis, and antiandrogens (AR receptor blockers) are routinely used for the treatment of hormone-sensitive prostate cancer. Several novel agents, which disrupt androgen synthesis, AR signaling, or both, are in development. Many of these agents have recently been shown to be efficacious in the castration refractory setting, and have the potential to improve outcomes in the hormone-sensitive setting when used in combination with standard ADT.
Targeting Hypothalamic-Pituitary-Testicular Axis
GnRH is a peptide hormone that is synthesized in hypothalamic neurons and then intermittently secreted into the hypophysioportal circulation in a pulsatile fashion. GnRH selectively stimulates gonadotroph cells within the anterior pituitary to release gonadotropins (ie, LH and FSH). Secretion of gonadotropins requires intermittent stimulation by GnRH, because continuous stimulation leads to desensitization of gonadotropic cells and inhibition of gonadotropin release.
GnRH analogues or agonists
Unlike natural GnRH peptide, synthetic GnRH analogues or agonists have a higher affinity for gonatroph cells. In addition, they are less susceptible to enzymatic degradation. Binding of synthetic GnRH agonists with gonadotroph cells initially results in the release of LH and FSH. Receptor desensitization results in the inhibition of LH and FSH release. The initial stimulation of LH release results in a transient increase in testosterone from the testis, a phenomenon known as testosterone flare. The GnRH agonists in current use include leuprolide, buserelin, goserelin, histrelin, and triptorelin and are generally used in long-lasting depot forms. GnRH agonists form the backbone of treatment of metastatic prostate cancer by inducing reversible medical castration, as shown in multiple clinical trials (described later).
GnRH antagonist
Degarelix (Firmagon, Ferring Pharmaceuticals, Parsippany, NJ, USA) has been developed as a pure GnRH antagonist, which does not cause an initial stimulation of gonadotroph cells and subsequently, a testosterone flare. In a phase 3 trial, 610 men with prostate cancer were randomized to one of the 3 following regimens: a starting dose of 240 mg of degarelix, given subcutaneously for 1 month, followed by subcutaneous maintenance doses of 80 mg or 160 mg monthly, or intramuscular leuprolide at a dose of 7.5 mg monthly. Therapy was maintained for the 12-month study. Men with prostate cancer of all stages in whom ADT was indicated (except in the neoadjuvant setting) were eligible. Degarelix was not inferior to leuprolide at maintaining low testosterone levels over the treatment period. However, degarelix induced testosterone and PSA suppression significantly faster than leuprolide. The adverse effect profiles were similar for both agents, except for local injection site reactions, which were more frequent with degarelix than with leuprolide (40% vs <1%).
Targeting Androgen Synthesis
Ketoconazole has been historically used as a nonspecific inhibitor of enzymes of the androgen synthesis pathway. Abiraterone, a more specific inhibitor of CYP17 enzymes, has been recently approved for the treatment of CRPC. TAK-700 (orteronel, Millennium Pharmaceuticals, The Takeda Oncology Company, Cambridge, MA, USA), a selective 17,20 hydroxylase inhibitor, and TOK-001 (Galeterone, Tokai Pharmaceuticals, Cambridge, MA, USA), a dual inhibitor of CYP17 and AR are in development.
Ketoconazole
It has a weak and nonspecific inhibitory effect on several enzymes involved in androgen synthesis, including CYP17. However, it had no impact on survival. The advent of effective novel CYP17 inhibitors has made ketoconazole a suboptimal treatment option.
Abiraterone acetate
Abiraterone acetate (Zytiga, Johnson & Johnson, New Brunswick, NJ, USA), a pregnenolone analogue, is an orally administered small molecule that irreversibly inhibits CYP17. In a phase 3 trial, 1195 patients with metastatic CRPC who received previous docetaxel or 2 lines of chemotherapy were randomized in a 2:1 fashion to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). After a median follow-up of 12.8 months, median overall survival (OS), the primary end point, was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs 10.9 months, P <.001), leading to US Food and Drug Administration approval for this indication. Adverse effects were associated with secondary mineralocorticoid excess, including hypertension, hypokalemia, and edema, which were manageable by the addition of a mineralocorticoid antagonist or corticosteroid. Abiraterone acetate has also been evaluated in a separate phase 3 trial of 1088 chemotherapy-naive men with progressive CRPC. In this trial, there was improved radiographic progression-free survival (PFS) with abiraterone over placebo (16.5 months vs 8.3 months, P <.001), leading to the regulatory approval of abiraterone in the prechemotherapy setting as well.
Resistance to abiraterone may be mediated by amplification of CYP17 (suggesting a potential role for dose escalation of abiraterone), as well as AR splice variants.
TAK-700 (orteronel)
TAK-700, a CYP17 inhibitor with a potentially greater 17,20 lyase selectivity (ie, for androgen as opposed to corticosteroid synthesis), is under development. Updated data from the phase 2 portion of a phase 1/2 study of TAK-700 in chemonaive patients with metastatic CRPC were reported. Ninety-seven patients were treated with TAK-700 in 4 different dose cohorts: 300 mg twice daily (n = 23), 400 mg twice daily + prednisone 5 mg twice daily (n = 24), 600 mg twice daily + prednisone (n = 26), or 600 mg 4 times a day (n = 24). The most common adverse effects were fatigue (76%), nausea (47%), and constipation (38%), and the most common adverse effects of grade 3 or higher were fatigue (12%) and hypokalemia (8%). The PSA response rates (≥50%) at 12 weeks were 63%, 50%, 41%, and 60% in the 300 mg twice daily, 400 and 600 mg twice daily + prednisone, and 600 mg 4 times a day groups, respectively. Of 51 RECIST (Response Evaluation Criteria In Solid Tumors)-evaluable patients, 10 had partial responses (of whom 5 were confirmed), 22 had stable disease, and 15 had progressive disease. At 12 weeks, the median serum testosterone levels were decreased from baseline in all groups: (ng/dL, 12 weeks/baseline) 0.98/8.50 (300 mg twice daily), 0.30/9.90 (400 mg twice daily + prednisone), 0.07/7.33 (600 mg twice daily + prednisone), 0.49/6.31 (600 mg 4 times a day). Similarly, at 12 weeks, the median dehydroepiandrosterone sulfate level decreased from baseline in all groups: (μg/dL, 12 weeks/baseline) 8.65/53.0 (300 mg twice daily), 0.10/36.3 (400 mg twice daily + prednisone), 0.10/51.7 (600 mg twice daily + prednisone), 5.30/31.5 (600 mg 4 times a day). Overall, the mean circulating tumor cell (CTC) numbers decreased from 16.6 (per 7.5 mL blood) at baseline to 3.9 at 12 weeks. TAK-700 300 mg or greater twice daily appeared active and well tolerated in patients with metastatic CRPC, with similar efficacy, with and without prednisone.
In a phase 2 study in nonmetastatic CRPC with biochemical recurrence alone, 38 patients were treated with TAK-700 300 mg twice daily without prednisone. Treatment without prednisone was feasible and with manageable toxicities. After 3 months of treatment, 16% achieved a PSA level of 0.2 ng/mL of lower, 76% achieved a PSA decrease of 50% or greater and 32% achieved a PSA reduction of 90% or more. The median time to PSA progression was 14.8 months. TAK-700 without prednisone suppressed adrenal androgens by 85% to 90%. Only 1 patient had laboratory values consistent with a hypoadrenal state, for which he received corticosteroid replacement.
Recently, 2 phase 3 randomized, placebo-controlled trials with TAK-700 have completed accrual in patients with CRPC. Both trials are comparing the efficacy of prednisone 5 mg by mouth twice a day, with or without TAK-700 (400 mg orally twice daily) in predocetaxel and postdocetaxel settings, respectively.
Targeting AR
In addition to enzalutamide (Xtandi, Medivation Inc, San Francisco, CA, USA), a novel AR antagonist with downstream effects on androgen signaling, which was recently approved for CRPC, there are other novel drugs in this class that are in various phases of clinical development, including ARN-509 (Johnson & Johnson, New Brunswick, NJ, USA), TOK-001, and EPI-001.
Antiandrogens
Antiandrogens work by competitively inhibiting the binding of testosterone and DHT with the AR. Only nonsteroidal antiandrogens (eg, bicalutamide, flutamide, and nilutamide) are approved in the United States. In the setting of metastatic prostate cancer, antiandrogens are used as follows: in conjunction with a GnRH agonist initially to prevent testosterone flare, continuously as combined androgen blockade (CAB) therapy (as described later), or after the onset of castration refractory disease, as a part of secondary hormonal manipulation. Monotherapy with antiandrogens (without GnRH agonist) is not recommended because of concerns for inferior survival compared with GnRH agonist therapy alone.
Enzalutamide (MDV3100)
Enzalutamide is a novel AR antagonist that binds to AR with a higher affinity than bicalutamide, blocks nuclear translocation of AR, binding to androgen response elements, recruitment of coactivators by the AR. In addition, enzalutamide does not generally confer agonist activity, or any effects on androgen synthesis. In a phase 1/2 study of 140 patients with progressive, metastatic CRPC, the maximum tolerated dose of enzalutamide for sustained treatment was 240 mg daily. Antitumor effects were seen at all doses, including decreases in serum PSA level of 50% or greater in 56% patients, soft tissue responses in 22% of patients, stabilization of bone disease in 56% of patients, and conversion from unfavorable to favorable CTC counts in 49% of patients. Enzalutamide was generally well tolerated, with fatigue as the most common dose-dependent grade 3 to 4 side effect. These data led to the initiation of placebo-controlled phase 3 trials (without prednisone) in chemonaive and postdocetaxel patients with metastatic CRPC. A 4.8-month advantage in median OS was reported in the postdocetaxel trial (18.4 vs 13.6 months, P <.001), translating into a 37% reduction in the risk of death (hazard ratio [HR] = 0.631). Enzalutamide crosses the blood-brain barrier and leads to sensitization to seizures a few patients. Seizures were reported in 5 of 800 patients (0.6%) receiving enzalutamide and have been hypothesized to be caused by inhibition of the γ-aminobutyric acid–gated chloride channel.
ARN-509
ARN-509 has a mechanism of action similar to enzalutamide. In a phase 1/2 study of 24 men with metastatic CRPC, ARN-509 was well tolerated with promising PSA responses (55% patients had ≥50% PSA declines) and with pharmacodynamic evidence of AR antagonism. Of the 7 dose levels investigated, a dose of 240 mg daily was selected for the phase 2 portion, which planned to enroll patients with nonmetastatic and metastatic CRPC.
TOK-001 (galeterone)
TOK-001 is an oral steroid analogue that inhibits CYP17, blocks AR, and reduces AR levels. In a phase 1 study of chemotherapy-naive men with CRPC, TOK-001 was well tolerated and showed clinical activity. Of 49 patients, 22% showed a decline in PSA level of more than 50%, and an additional 26% had PSA declines of 30% to 50%. Based on these preliminary results, a phase 2 study is planned to begin accruing in 2013.
EPI-001
EPI-001 is a small molecule inhibitor of the NTD of the AR, which confers transcriptional activity. EPI-001 has shown substantial preclinical activity, warranting further clinical development of this class of agents.
Systemic therapy for HSPC
Castration Versus CAB Therapy
Several meta-analyses have shown a modest 2% to 5% improvement in 5-year survival with CAB over castration, although with increased toxicity. One of largest meta-analyses included the individual level data of 8275 patients from 27 trials. Trials that used steroidal as well as nonsteroidal antiandrogens in their CAB regimens were included. Although there was an overall trend toward improved 5-year survival with CAB over castration, this did not reach statistical significance ( P = .11). When trials using steroidal and nonsteroidal antiandrogens were analyzed separately, CAB with nonsteroidal antiandrogens (flutamide and nilutamide) were associated with a statistically significant 8% decrease in the risk of death compared with castration alone (95% confidence interval [CI] 3–13; P = .005, 2-sided), equating to a 2.9% increase in 5-year survival. On the other hand, CAB using steroidal antiandrogens, when compared with castration alone, was associated with a significant 13% increase in the risk of death (95% CI 0–27; P = .04, 2-sided), as well as a 2.8% reduction in 5-year survival rates.
The American Society of Clinical Oncology guidelines state that CAB should be considered as an option and be discussed with patients, with the emphasis that improvement in OS may occur at the cost of higher toxicity. These data provide a compelling rationale for developing more efficacious treatment regimens to improve survival outcome in these patients.
Intermittent ADT Versus Continuous ADT
Preclinical work conducted in the 1980s and early 1990s led to the hypothesis that intermittent ADT may delay the onset of castration resistance by reducing selection pressure on castrate resistance clones. The probability of the onset of androgen-independent prostate cancer in androgen-dependent Shionogi carcinoma mice was greatly increased in an androgen-depleted atmosphere and was perceived to have occurred as a result of diminished androgen-induced differentiation of parent tumor stem cells.
The clinical use of intermittent endocrine therapy in advanced prostate cancer was first reported in 1986, when it was shown that patients with advanced prostate cancer could remain in symptomatic remission for considerable periods, despite interruptions in endocrine therapy with diethylstilbestrol. During the 1990s, intermittent androgen suppression was reported to significantly delay the onset of androgen independence in mouse models, when compared with continuous androgen suppression.
These and other reports provided the rationale for designing an international phase 3 trial (S9346, INT-0162), comparing intermittent ADT with continuous ADT, in newly diagnosed HSPC. Men with HSPC who had a PSA level of 5 ng/mL or greater were treated for 7 months with goserelin, plus bicalutamide. Men who achieved a PSA of 4 ng/mL or less on months 6 and 7 were stratified by previous neoadjuvant ADT/finasteride, performance status, and extent of disease (minimal vs extensive) and then randomized to continuous androgen deprivation (CAD) or intermittent androgen deprivation (IAD) with goserelin plus bicalutamide. The primary objective was to assess whether OS was noninferior with IAD, when compared with CAD. Over a period of 13 years (May, 1995 to September, 2008), 3040 men with HSPC were accrued. After 7 months of CAD, 1535 men achieved a PSA level of 4.0 ng/mL or less, after which they were randomized to CAD (n = 759) or IAD (n = 770). The grade 3 and 4 adverse effects were similar in both groups. After a median follow-up of 9.2 years, the median OS and 10-year OS from study entry were 3.6 years and 17%, respectively. From the time of randomization, the median and 10-year OS in the CAD arm were 5.8 years and 29%, respectively, compared with 5.1 years and 23%, respectively, in the IAD arm (HR [IAD/CAD] = 1.09 [95% CI 0.95, 1.24]). The preliminary report on quality-of-life outcomes showed significantly more impotence, less libido, and diminished emotional function with CAD over IAD. The study conclusion was that survival with IAD was not comparable with CAD, and thus, CAD continues to be the standard of care for men with HSPC. However, patients with HSPC who are interested in IAD should be counseled regarding the outcomes from this trial.
Combining Chemotherapy with Castration in HSPC
In the 1980s, it was hypothesized that if cytotoxic chemotherapy was given early in the course of HSPC, and in combination with castration, androgen-resistant clones in heterogeneous prostate tumors would concomitantly be inhibited, with subsequent improvement in response rates, PFS, and OS. In addition, in metastatic prostate cancer, many chemotherapeutic agents, used either as single agents or in combination with other agents, were reported to have response rates as high as 30% to 40%. In a combined chemohormonal trial, 25 men with new HSPC were treated with bilateral orchiectomy, estrogen, and chemotherapy with 5-fluorouracil and cyclophosphamide. The encouraging response rates provided the rationale for a larger, SWOG (Southwest Oncology Group) 8219 trial. This randomized study of 143 men with new HSPC compared endocrine therapy (diethylstilbestrol or bilateral orchiectomy) alone, followed by cyclophosphamide and doxorubicin chemotherapy at progression, versus initial combined chemoendocrine therapy with all these agents. However, there was no difference in PFS or OS between the 2 groups. Later, in a phase 2 study (SWOG 0032), estramustine, etoposide, and paclitaxel were combined with ADT in 41 men with high-risk HSPC, which was defined as the presence of visceral disease or bone metastases to both the axial and the appendicular skeleton. The median PFS and the OS for the evaluable population were 13 months and 38 months, respectively.
The interest in using combined chemohormonal therapy for the treatment of HSPC was renewed when docetaxel was reported to improve OS in the CRPC setting. These data led to the initiation of an intergroup phase 3 study (ECOG [Eastern Cooperative Oncology Group] 3805/CHAARTED [Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease]) comparing androgen ablation therapy, with or without chemotherapy with docetaxel, with prednisone in men with HSPC. This trial has recently completed accrual, and is expected to define the role of upfront chemotherapy, in combination with ADT in HSPC. The results of another phase 3 trial, evaluating the role of docetaxel, in addition to ADT in HSPC, were recently reported. In this study, 385 men were randomized (1:1) to ADT (surgical or medical castration with or without nonsteroidal antiandrogens) alone or to ADT with docetaxel. OS, the primary end point, was not improved with the addition of docetaxel. STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) is an ongoing multiarm, multistage, adaptively randomized, controlled trial of men with locally advanced or metastatic prostate cancer beginning long-term ADT. Originally, the trial was designed to randomize men to one of the following arms: ADT alone, or ADT plus one of the following: docetaxel, zoledronic acid, celecoxib, zoledronic acid plus docetaxel, or zoledronic acid plus celecoxib. Later, 2 additional treatment arms were added: ADT plus abiraterone, and ADT plus radiation therapy to the prostate. The primary end point is OS. Recently, accrual was discontinued on the 2 arms containing celecoxib, because of lack of benefit.
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