Prostate Cancer

Advanced Systemic Disease

Defining advanced disease

Metastatic prostate cancer. This is a heterogeneous group of patients that ranges from those with pathologically detected locoregional nodal metastases at the time of radical prostatectomy to those with widespread systemic disease. The most common sites of metastatic disease are the bone and pelvis and abdominal lymph nodes. Other less common sites include the liver and lungs. Complications of metastatic prostate cancer include pain, fatigue, skeletal fractures, spinal cord compression, urinary outlet obstruction, and failure to thrive. First-line hormonal therapy for men with metastatic prostate cancer delays these complications.

Rising PSA level. A large series of more than 2,000 patients treated with radical prostatectomy at Johns Hopkins University demonstrated that approximately 17% of cases recurred, with only 5.8% being local disease. In the remaining patients, disease recurred initially with either a rise in PSA levels alone (9.7%) or evidence of clinical metastases (1.7%).

Outcomes for men with only a rising PSA level can vary greatly. Time to PSA recurrence (< 2 vs > 2 years), PSA doubling time (< 9 vs > 9 months), and Gleason score (8–10 vs 5–7) are among the important factors for predicting the development of metastatic disease and survival. There is a wide variation in the PSA value seen at the onset of bone metastases; one study documented an average PSA of 33 at this onset; however, about 25% of men will develop skeletal metastases with a PSA of less than 10, and another 25% will not develop metastases even with a PSA of 50 to 90. Thus, PSA alone does not necessarily predict the onset of metastatic diseases, and other factors such as PSA doubling time, life expectancy, comorbidities, and patient concern often dictate when hormonal therapy is initiated.

The major developments for hormonal therapy in advanced prostate cancer were achieved prior to routine PSA testing and were often complicated by problematic study design. There are no prospective data that confirm a benefit to early hormonal therapy for men with a rising PSA alone. However, for patients with a rising PSA level who are at high risk for the development of metastases, some physicians agree that early hormonal therapy is likely to benefit this group of patients as well as those with radiologic evidence of metastatic disease. Ongoing randomized phase III studies are also testing the role of docetaxel (Taxotere) with androgen deprivation therapy in this setting, but the role of chemotherapy in the nonmetastatic setting remains experimental.

First-line therapies for advanced disease

The standard first-line treatment of advanced prostate cancer, regardless of whether local treatment has been applied, is to ablate the action of androgens by medical or surgical means. For the majority of patients, androgen ablation can result in a decline in PSA level, palliation of disease-related symptoms, and regression of metastatic disease on imaging.

Bilateral orchiectomy. The advantages of orchiectomy over other means of castration include an immediate decline in testosterone levels and ease of compliance for patients. Given these advantages, however, many men still opt for medical castration, with the potential advantage of intermittent hormonal therapy. In addition, the psychological impact of orchiectomy can be significant. Nonetheless, bilateral orchiectomy may be appropriate and cost-effective for a select group of patients.

TABLE 5Hormonal approaches to the treatment of advanced prostate cancer

LHRH analogs. LHRH agonists, such as leuprolide and goserelin(Drug information on goserelin), interfere with the normal pulsatile secretion of luteinizing hormone from the pituitary gland, resulting in an eventual decline in serum testosterone levels. The effect is reversible with cessation of therapy. Because luteinizing hormone is initially increased with LHRH agonists, testosterone levels increase initially as well. This finding can result in a transient rise in PSA levels and potential growth of metastatic sites. Because of this initial "flare response" with LHRH agonists, consideration should be given to the administration of an antiandrogen prior to the LHRH, especially in patients who are at risk for complications from the disease (such as spinal cord compression, worsening pain, or urinary outlet obstruction; Table 5). Side effects of androgen deprivation therapy include hot flashes, metabolic-type syndrome and weight gain, loss of libido, loss of peripheral hair growth, gynecomastia, an elevated risk of diabetes, loss of bone mineral density and an increased risk of fracture, and finally an increased risk of cardiovascular complications (including myocardial infarction, stroke, sudden cardiac death, deep venous thrombosis, and angina). The overall risk/benefit profile of androgen deprivation therapy thus depends on an individual man's preexisting cardiovascular risk and comorbidities, and it should be individually tailored based on this risk assessment.

The flare phenomenon can also be avoided through the use of gonadotropin-releasing hormone (GnRH) antagonists. This class of drugs leads to immediate suppression of androgen production without the initial testosterone surge that results with GnRH agonist therapy. Abarelix (Plenaxis) is a GnRH antagonist that was approved in 2003. However, the manufacturer halted US sales to new patients in 2005. A second agent, degarelix for injection (Firmagon), was approved by the FDA in December 2008. It is currently available in a monthly formulation and is not associated with anaphylaxis. As a receptor antagonist, degarelix reversibly binds to the GnRH receptors in the pituitary gland, immediately suppressing the secretion of the LH, follicle-stimulating hormone (FSH), and, subsequently, testosterone levels.

Antiandrogens. Antiandrogens function to block the binding of dihydrotestosterone (DHT) to the androgen receptor, blocking the translocation of the DHT-androgen receptor complex into the nuclei of cells. There are two general classes: steroidal and nonsteroidal. Steroidal antiandrogens include cyproterone and megestrol. The most commonly used antiandrogens include the nonsteroidal agents flutamide(Drug information on flutamide), bicalutamide, and nilutamide. These agents differ slightly in their affinity for the androgen receptor and their side-effect profiles. For example, nilutamide has been associated with interstitial lung disease and visual adaptation (light-dark) disturbances, whereas flutamide is associated with diarrhea. Antiandrogens as a category have not been as highly associated with cardiovascular risk outcomes, but this may be due to the low numbers of patients treated with antiandrogen monotherapy. Consideration of prophylactic breast radiation prior to the use of prolonged antiandrogen monotherapy should be considered, given the high risk (> 50%) of developing gynecomastia. Tamoxifen has also been shown to prevent gynecomastia in these men but is associated with other adverse events such as deep venous thrombosis/pulmonary embolism.

Typically, antiandrogens are used in combination with surgical or medical castration. Some trials comparing antiandrogens alone with LHRH analogs have shown similar efficacy, but more recent trials in metastatic disease suggest that monotherapy with antiandrogens may be inferior in terms of time to disease progression and possibly survival. For example, a randomized trial of monotherapy with high-dose bicalutamide (150 mg daily) compared with flutamide plus goserelin demonstrated that patients treated with bicalutamide monotherapy had fewer side effects, such as loss of libido or erectile dysfunction, and trended toward improved quality of life. However, in patients with radiographic evidence of metastases, bicalutamide monotherapy was associated with a small 6-week decrease in survival (HR = 1.3). Despite this finding, for men who are intolerant to the side effects of LHRH analogs, monotherapy with antiandrogens can be considered after careful discussion with patients.

Antiandrogen monotherapy with flutamide or bicalutamide is also sometimes used to treat PSA recurrence. Used alone or in combination with a 5-alpha reductase inhibitor (finasteride or dutasteride(Drug information on dutasteride)), this approach is associated with fewer side effects than traditional AST, but the approach is not considered standard and its efficacy relative to primary gonadal suppression is not established. A significant downside is nipple tenderness or gynecomastia, but this "peripheral blockade" approach may preserve potency and libido. Prophylactic breast irradiation may prevent this complication.

CAB. Complete androgen blockade (CAB) refers to the elimination of testicular androgens in combination with blockade of adrenal androgens, generally with an LHRH analog and an antiandrogen agent. The use of CAB is somewhat controversial. Several randomized trials comparing LHRH agonists alone vs CAB have demonstrated a survival benefit with CAB. However, in one of the largest trials conducted by the United States Intergroup, more than 1,300 men were randomized to undergo orchiectomy vs orchiectomy plus flutamide. There was no significant advantage to CAB in terms of time to disease progression or overall survival. Some investigators believe that bicalutamide, a more potent agent, may be associated with greater survival when used as part of CAB. Recent meta-analyses suggest a small but incremental benefit of noncyproterone antiandrogens in combination with GnRH agonists in terms of overall survival (15% to 20% relative risk reduction). This finding led American Society of Clinical Oncology (ASCO) to advise an informed discussion of the risks and benefits of CAB.

Several phase III trials evaluating the role of intermittent androgen deprivation are ongoing. A phase III European trial investigating the use of intermittent hormone therapy in patients with locally advanced or metastatic prostate cancer was reported by Calais da Silva et al in 2009. In this trial, 766 patients were registered, and 626 patients whose PSA level decreased to < 4 ng/mL or to 80% below the initial value after 3 months of induction treatment were randomized to receive continuous vs intermittent hormone therapy. The primary outcome of disease progression was not statistically different between groups. There was also no significant difference in overall survival. Among the 314 patients on intermittent therapy, 50% were off therapy for at least 52 weeks following initial LHRH induction. Patients whose PSA level dropped below 2 ng/mL spent a median of 82% of their time receiving no therapy.

Many investigators believe that the advantages observed in trials that include an LHRH antagonist exist because of the "flare phenomenon," which occurs with LHRH agonists alone and may be lost with a short period of treatment with antiandrogens during the expected flare period. ASCO has published guidelines for the initial management of androgen-sensitive (recurrent, metastatic) prostate cancer. Based on the literature, immediate androgen deprivation was associated with a moderate decrease in prostate cancer mortality and a moderate increase in other causes of mortality. Currently, there is no definitive evidence favoring the early initiation of androgen deprivation in this population.

Diethylstilbestrol (DES). Estrogen administration, in the form of DES, also produces chemical castration. DES inhibits prostate growth, primarily through the inhibition of the hypothalamic-pituitary-gonadal axis, which blocks testicular synthesis of testosterone and thus lowers plasma testosterone levels. Since doses higher than 3 mg/day cause significant cardiovascular mortality, DES has fallen out of favor as a first-line therapy to induce castration.

Ketoconazole. Ketoconazole is an antifungal agent that can inhibit adrenal and testicular steroid synthesis at higher doses, leading to a decline in adrenal and testicular androgens. It has the benefit of a rapid decline in testosterone, which can be useful for patients who present emergently with a complication of newly diagnosed advanced disease. Ketoconazole is started at a dose of 200 mg three times daily and is increased to a total dose of 400 mg three times daily. Ketoconazole is associated with significant side effects (such as fatigue, nausea, and vomiting) and drug interactions, however, and must be given with supplemental hydrocortisone to avoid symptoms of adrenal insufficiency. Because of the side effects, its use is more common in the second-line setting, where responses can be expected in 20% to 40% of patients following disease progression with complete androgen blockade.

Abiraterone acetate (Zytiga). Recent evidence suggests that androgen production is not limited to the testicles and adrenal glands, but that prostate cancer and the surrounding microenvironment can contribute to androgen synthesis in an autocrine/paracrine manner. This is mediated by overexpression of key androgen synthetic enzymes such as cytochrome P450 17-hydroxylase/lyase (CYP17) and other enzymes, overexpression of androgen transport molecules that allow cancer cells to import circulating androgen precursors, and reductions in androgen-metabolizing enzymes that degrade androgens. Given these findings, combined with additional findings of androgen receptor (AR) mutations, amplifications, and splice variants that can lead to constitutive or overactive AR signaling, there have been significant recent efforts to inhibit AR signaling in tumors that were previously deemed hormone-refractory but are now classified as castration-resistant, a more biologically correct term. One such CYP17 inhibitor is abiraterone acetate, an oral agent with potent CYP17 inhibitory activity that leads to a dramatic reduction in systemic androgen levels. Feedback upregulation of ACTH can be seen with this agent alone; thus low-dose prednisone is combined with abiraterone to prevent adrenal insufficiency as well as to reduce the mineralocorticoid excess (hypertension, fluid retention, hypokalemia) seen with abiraterone. The use of prednisone also improves upon the overall efficacy of this agent. Additional CYP17 inhibitory agents are in development, such as TAK-700 (orteronel). Currently, abiraterone acetate is only FDA-approved for use in the post-docetaxel setting for men with metastatic castration-resistant prostate cancer. However, emerging evidence suggests its effectiveness and safety in delaying progression, inducing responses, and possibly improving overall survival in men with metastatic CRPC who have not yet received docetaxel (see below).

Enzalutamide (Xtandi). This novel androgen-signaling inhibitor (formerly known as MDV3100) has the ability to bind the amplified androgen receptor (AR), prevent nuclear translocation, and result in cytocidal effects in preclinical models of CRPC, even in cellular models that are bicalutamide-resistant. Phase I/II studies have demonstrated efficacy and safety in the pre-docetaxel and post-docetaxel CRPC setting, and results from AFFIRM, a large phase III trial, demonstrated a nearly 5-month improvement in overall survival compared with placebo in the post-docetaxel metastatic CRPC setting. After priority review, the FDA approved enzalutamide in August 2012 for patients with metastatic CRPC previously treated with docetaxel. The side effect profile includes fatigue, fall risk, a low incidence of seizures (< 1%), and hot flushing. PSA responses occurred in 50% of men, and pain palliation, soft tissue responses, delays in progression-free survival (8 months), and delays in skeletal-related events have been notable. Its position with cabazitaxel and abiraterone remains to be determined and comparative effectiveness studies and combination studies are needed. Currently, this agent is in phase III trials in the pre-docetaxel setting and in phase II trials as combined androgen blockade.

TABLE 6The incidence of complications from advanced prostate cancer with immediate vs deferred androgen deprivation

Early vs late treatment. Whether to treat patients early with hormonal therapy or wait until patients become symptomatic has been tested in a large European trial conducted by the Medical Research Council (MRC). Men were randomized to receive immediate hormonal therapy (orchiectomy or an LHRH analog) vs delayed therapy, which was initiated with symptomatic disease progression. Men who were treated with early therapy were less likely to experience urinary obstructive symptoms requiring intervention, pathologic fractures, and spinal cord compression than those treated in the delayed arm (Table 6). The survival benefit was less clear, however, because many of the men in the delayed arm died before they received any hormonal therapy. This study was also complicated by the initiation of PSA monitoring during the study period. Many patients and physicians currently are not comfortable delaying therapy until the onset of symptoms while the PSA level is rising; this fact limits the applicability of its findings in the modern era.

Other smaller trials have examined this issue as well. A Cochrane Database review was conducted in 2002; it demonstrated an increase in progression-free survival and a small but significant improvement in survival with early hormonal therapy. A randomized EORTC study (30891) of early vs deferred androgen deprivation therapy for men with localized prostate cancer not amenable to local treatment did not show a prostate cancer-specific survival advantage to the immediate use of androgen deprivation therapy in these men. Balancing comorbidity and the risk of cardiovascular complications is an important consideration in the timing of androgen deprivation therapy in this population, given the competing causes of mortality.

One setting in which early adjuvant hormonal therapy has been associated with a survival benefit is in the postprostatectomy setting in men found to have pathologic lymph node-positive disease. Messing et al published an adjuvant study that evaluated immediate hormonal therapy vs delayed treatment upon detection of distant metastases or symptomatic recurrence in men who had undergone radical prostatectomy and lymph node dissection and were found to have nodal metastases. At a median follow-up of 11.9 years (range, 9.7–14.5 for surviving patients), men assigned immediate androgen deprivation therapy had a significant improvement in overall survival, prostate cancer-specific survival, and progression-free survival.

Immunotherapy. In 2010, sipuleucel-T (Provenge) became the first autologous cellular therapy approved for use in patients with solid tumors. The phase III IMPACT trial demonstrated a 4.1-month survival advantage over sham vaccination. Thus, autologous dendritic cell therapy vaccination (three infused doses over 4 weeks following initial leukapheresis), utilizing a prostatic acid phosphatase–granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion protein to stimulate immune cells, has become a standard of care prior to docetaxel in men with metastatic asymptomatic to minimally symptomatic CRPC. Men with pain requiring narcotics, with visceral metastases, and with a life expectancy < 6 months are not eligible for this therapy. Of note, vaccination did not lead to PSA declines, tumor responses, improved palliation, or delayed tumor progression by our current measures, and thus this therapy should be regarded as adjunctive to other current therapies that are more cytoreductive and palliative.

Sipuleucel-T therapy involves an initial leukapheresis whereby a small fraction of leukocytes are removed by a pheresis procedure, typically through the American Red Cross, and sent to the manufacturer, Dendreon, for modulation. During a proprietary next step, the white blood cells are then pulsed with an antigen cassette composed of prostatic acid phosphatase (PAP) fused to GM-CSF, an immune adjuvant. After 3 days, these newly primed CD54 positive cells, which have been stimulated and expanded ex vivo, are shipped back to the patient and infused in a local treatment facility. This process is then repeated two more times during a 1-month procedure. Side effects have included infusional reactions (fever, headache, perioral numbness, chills, muscle aches, and back pain) that are typically mild and transient (1–3 days) and can be treated with acetaminophen or NSAIDs. Other side effects may include the need for a central line for leukapheresis in about 25% of men, which may require heparin and may increase the risk of infection. In a double-blind, placebo-controlled, multicenter phase III trial, 512 patients were randomly assigned in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients). The median survival was 4.1 months longer in the sipuleucel-T group than in the placebo group (25.8 months vs 21.7 months). The estimated probability of survival 36 months after randomization was 31.7% in the sipuleucel-T group and 23% in the placebo group.

Intermittent androgen deprivation. Androgen deprivation is associated with several short-term and long-term adverse effects. These side effects make treatment breaks provided by intermittent androgen deprivation an attractive option. Additionally, results from preclinical studies suggest that hormonal resistance may be delayed with intermittent androgen deprivation. These potential advantages have led to significant interest among patients and caregivers in intermittent androgen deprivation.

Over the past decade, several phase II-III studies of intermittent androgen deprivation have demonstrated feasibility and safety with suggestion of improved quality of life without negative effects on time to disease progression or survival. More recently, the phase III SWOG/NCIC/UK cooperative group trial of continuous vs intermittent androgen-deprivation therapy in men with M0 PSA recurrent prostate cancer was reported. In this trial, 690 patients randomized to the intermittent therapy arm were found to have improved quality of life with less sexual dysfunction, hot flashes, and improved physical function and fatigue with no significant difference in time to disease progression or overall survival. The final results of several ongoing phase III trials in metastatic disease and PSA-only relapse will better define the role of intermittent androgen deprivation; however, most trials suggest that IADT is non-inferior to continuous ADT in M0 disease and may result in improved quality of life and reduced cost. With the currently available information, intermittent androgen deprivation may be considered in most patient settings as a standard of care for nonmetastatic disease. However, for M1 disease, the results of the recently presented SWOG 9346 trial have challenged this dogma and suggest that intermittent therapy in the face of metastatic disease may result in a higher risk of death from prostate cancer. In this trial of more than 3,000 men with M1 disease starting ADT, 1,749 men were randomized to intermittent ADT vs continuous ADT, with resumption of ADT being performed if the PSA rose to the baseline value or a PSA of 20. In this study, while there were some improvements in fatigue, libido, emotional function, and erectile function in the IADT arm, IADT was found not to be noninferior according to the study design, with a HR of 1.09 (95% CI, 0.95–1.24). This translated into a 0.7-year improvement in survival with continuous therapy. However, therapeutic equivalence could not be excluded in this trial. Unplanned subgroups unexpectedly showed worse outcomes with IADT in patients with nodal and axial metastatic bone disease, suggesting that IADT should only be considered in men with M1 prostate cancer who experience severe side effects from ADT and under informed consent about the overall risks/benefits of this approach.

Treatment recommendations. Just as for localized disease, initial treatment for advanced prostate cancer must be individualized. A patient who presents with a rising PSA level only after local treatment and a slow PSA doubling time, a prolonged time to PSA recurrence, and a low initial Gleason score may not require immediate therapy, especially if there are other more likely significant comorbidities. However, a patient with multiple metastatic sites will need immediate treatment, generally with orchiectomy, LHRH agonists or antagonists, or CAB initially followed by monotherapy with an LHRH analog, to prevent the sequelae of metastatic disease, such as fracture, spinal cord compression, and ureteral obstruction. Degarelix or ketoconazole may be considered as initial systemic therapies for patients presenting with spinal cord compression as the first sign of prostate cancer, as well as combined androgen blockage. Palliative radiation in this setting should also be considered. Given the overall limitations of hormone therapy, all appropriate patients should be offered access to clinical trials. Intermittent ADT should be considered in men with M0 disease and in some men with low-volume M1 disease who have ADT-related toxicity.

For patients with a rising PSA level who are at high risk for the development of metastases, a discussion regarding the potential advantages to early treatment and an explanation of the lack of randomized prospective data are warranted. Some investigators favor early treatment for these patients based on the data from the MRC trial and the Cochrane Database review, understanding that this information is extrapolated from data obtained prior to PSA testing and from patients with clinical and radiographic metastases.

Second-line hormonal therapies

It is important to realize that there has been a shift in terminology from "androgen-independent" or "hormone-refractory" prostate cancer to a newer term: castration-resistant prostate cancer. This change reflects an understanding that prostate cancer often remains dependent on androgenic signaling, even in the presence of castrate levels of testosterone. Tumors may produce their own androgens through autocrine signaling, amplify low levels of testosterone ligand signaling through androgen receptor mutations or duplications, and may have activation of the AR through other ligands. Thus, progression of disease despite castration does not necessarily imply resistance to all hormonal strategies, as exemplified by the response to antiandrogens, ketoconazole, and newer second-generation agents such as enzalutamide or abiraterone acetate. Thus, true hormone-refractory disease may refer to disease that has progressed despite therapies employing all known hormonal strategies.

Outcomes with initial androgen ablation can vary from responses that last from months to years; they also vary as a function of the Gleason grade, pretreatment PSA velocity, and extent of disease at the time of initiating treatment. Once PSA levels begin to rise with androgen ablation, the disease is often referred to as "hormone-refractory." This term is actually a misnomer, because preclinical data suggest that tumors may become hypersensitive to androgens, resulting in worsened disease if androgen ablation is removed entirely. Moreover, many patients have disease that remains sensitive to further hormonal manipulations, such as second-line antiandrogens, steroids, or ketoconazole.

An example of this sensitivity to hormonal manipulation is exemplified in the antiandrogen withdrawal response. Up to one-third of patients with a rising PSA level while receiving treatment with an antiandrogen will have a decline in PSA level and or clinical regression with antiandrogen withdrawal. The mechanism of this response has not been fully elucidated but supports the hypothesis that the androgen receptor remains important in progressive disease.

TABLE 7Phase III trials in the postdocetaxel castration-resistant prostate cancer setting

Although second-line hormonal therapy has demonstrated benefit in terms of PSA levels and response, there are no data to demonstrate a survival advantage with second-line hormonal therapy. Its role has further come into question with data that support the use of docetaxel chemotherapy for men with metastatic androgen-independent prostate cancer to improve survival. The survival advantage of docetaxel is not limited by the number of prior hormonal therapies. However, as exemplified by recent novel antiandrogens (enzalutamide [MDV3100]) and adrenal/autocrine synthesis-inhibiting agents (abiraterone acetate), men with castration-resistant disease remain sensitive to agents targeting the androgen receptor, and this remains a rich area of clinical investigation. In phase I/II trials, the novel oral antiandrogen enzalutamide demonstrated striking PSA declines (50% to 70% achieved a > 30% decline) and partial tumor responses both in the pre-docetaxel and post-docetaxel settings (see below), with responses that were durable in many men over 6 months. The drug can prevent androgen-induced nuclear translocation and has shown tumoricidal activity even in bicalutamide-resistant model systems. Abiraterone acetate with prednisone has demonstrated similar outcomes in these settings as well, showing that hormonal sensitivity may remain even among docetaxel-resistant men. Phase III trials of these agents are completed or ongoing (Table 9).

For patients with a rising PSA level only, timing of chemotherapy is even less clear. The ECOG attempted a trial comparing ketoconazole/hydrocortisone with docetaxel in patients with a rising PSA level but no evidence of metastatic disease after hormonal therapy, but the trial was closed early due to lack of accrual. Ongoing randomized studies of androgen deprivation therapy with and without chemotherapy should address this question within the coming few years. Until prospective data are available, physicians will need to counsel patients carefully on the different options and timing of those options available at the time of disease progression, including second-line hormonal manipulation, chemotherapy, and especially clinical trials.

Chemotherapy for castration-resistant disease

Docetaxel. The role of chemotherapy changed significantly in 2004 with the results of two large randomized trials demonstrating a survival benefit for men with castration-resistant metastatic prostate cancer treated with docetaxel-based chemotherapy (Table 8). Investigators from the SWOG 9916 trial randomized patients to receive mitoxantrone plus prednisone vs docetaxel (60 mg/m²) plus estramustine (Emcyt) and dexamethasone every 3 weeks. Patients in the docetaxel arm had a significant improvement in survival by 2 to 3 months. Currently, estramustine is no longer used in combination with docetaxel in the front-line setting given the lack of additional efficacy and the certain added toxicity.

TABLE 8Standard chemotherapy regimens for prostate cancer

A second international randomized phase III trial (TAX327) by Tannock et al showed a similar survival benefit of 3 months with docetaxel (at 75 mg/m²) plus prednisone given every 3 weeks compared with mitoxantrone and prednisone. These trials were the first to demonstrate a survival benefit with chemotherapy in advanced prostate cancer and have sparked numerous studies involving docetaxel in combination with newer agents. Toxicities of docetaxel include myelosuppression and peripheral neuropathy, both of which can be dose-limiting. Additional toxicities include constipation, tearing due to docetaxel deposition in tear ducts, onycholysis, and fluid retention (peripheral or pulmonary edema, pleural effusion). Weekly docetaxel with prednisone (30 mg/m²) for 5 of 6 weeks provided an intermediate level of control and survival that was not statistically different from that with mitoxantrone (Novantrone) and prednisone, despite favorable PSA declines and tumor and pain responses. Weekly docetaxel is less well tolerated, and early treatment discontinuation likely limits this schedule's utility. The activity of docetaxel following abiraterone acetate is unknown.

A 5-year update of this study has confirmed a 3-month survival advantage to every-3-week docetaxel in the overall study population. Additional benefits of docetaxel over mitoxantrone included superior PSA responses, pain and quality-of-life responses, greater durability of response, and improved radiographic responses. In addition, nearly 18% of men experienced normalized PSA levels with every-3-week docetaxel, as opposed to 8% of men treated with mitoxantrone. Men with normalized PSA levels lived on average 33 months, compared with 16 months for men without normalized PSA levels—nearly a twofold difference. Current studies indicate that a 30% or greater decline in the serum PSA level within 3 months of treatment initiation may be the best predictor of overall survival of all current surrogate markers in this disease and may be used to assist in prognostication after treatment initiation. Although not a credentialed surrogate for FDA approval, this level of PSA decline was shown in both pivotal studies to be highly associated with survival as compared to other outcomes and PSA metrics, including the traditional confirmed > 50% decline in PSA level and pain responses. The timing of docetaxel initiation is controversial, given its known toxicities and the many active hormonal and now immunologic therapies that can be administered prior to docetaxel. However, it has been demonstrated that the absolute survival advantage of docetaxel is greatest (3 to 4 months) in men with minimal symptoms, whereas men who have impaired performance status or pain due to cancer are not able to tolerate 10 full cycles well and often have a reduction in the overall survival benefit (1 to 2 month advantage). Thus, the early timely use of docetaxel in men with clear prostate cancer progression based on PSA or radiographic disease is warranted for palliation and prevention of pain onset as well as improved survival.

Several nomograms currently exist for men with metastatic castration-resistant prostate cancer that can predict overall survival (Halabi; Memorial Sloan-Kettering Cancer Center; Armstrong, TAX327). These studies indicate that the presence of visceral metastatic disease, anemia, performance status, PSA level, PSA doubling time, elevated alkaline phosphatase, low albumin, Gleason score, the presence of significant pain, the type of progression, and lactate dehydrogenase level are highly predictive of survival and can be used to predict prognosis. In addition, circulatory tumor cells are FDA-approved as prognostic markers of survival in men receiving docetaxel. These cells can be enumerated in 7.5 mL of whole blood either prior to systemic chemotherapy or while the patient is receiving chemotherapy, and the number of circulating tumor cells (CTCs) in whole blood correlates strongly with overall survival. Although CTCs are not credentialed at this time as surrogates and thus have not been used or studied to guide therapeutic choices in men with CRPC, the ability to detect and characterize these cells holds promise as a predictive and intermediate biomarker to aid in personalized medicine approaches. These cells can be further characterized in research settings for molecular profiling, indicating their potential to help guide systemic therapy in the future.

Mitoxantrone plus prednisone. Mitoxantrone (12 mg/m²) plus prednisone has been approved for use in advanced prostate cancer based on improvement in palliation of pain and quality of life over prednisone alone despite no improvement in overall survival. Toxicities of mitoxantrone include a cumulative cardiotoxicity, typically after 10 to 12 cycles of therapy. Thus pretreatment ejection fraction assessment is recommended in all men as well as serial ejection fraction assessments every 4 to 5 cycles or based on new onset of cardiac symptoms. Given the recent approval of cabazitaxel (Jevtana; see discussion later in this chapter), use of mitoxantrone has generally been limited to third-line therapy, or for palliative therapy in men who are not candidates for microtubule-targeting therapies because of neuropathy, for example.

Bisphosphonates. Bone metastases from prostate cancer are associated with increased bone formation around tumor deposits, resulting in characteristic osteoblastic metastases. However, concomitant with the osteoblastic activity is a marked increase in bone resorption and osteolysis, which can be inhibited by bisphosphonates.

Studies of bisphosphonates in prostate cancer have demonstrated mixed results. A combined analysis of two multicentered randomized controlled trials comparing pamidronate with placebo in men with androgen-independent progressive prostate cancer demonstrated no benefit in terms of skeleton-related events or palliation of symptoms. A phase III trial with an oral bisphosphonate, clodronate (Bonefos), demonstrated no difference in either symptomatic bone metastases or prostate cancer–related deaths when compared with placebo.

A phase III trial demonstrated a reduction in skeleton-related events for men with castration-resistant metastatic prostate cancer with a more potent bisphosphonate, zoledronic acid (Zometa). However, it is important to note that this trial did not show an improvement in quality of life with zoledronic acid, nor did it demonstrate a reduction in the development of new metastases. Zoledronic acid did demonstrate a delay in the need for radiation to bone, pathologic fracture onset, and bone pain, providing some evidence of clinical benefit over time. At this time, the recommendation for zoledronic acid in prostate cancer is limited to men with castration-resistant metastatic prostate cancer, pending ongoing randomized studies in the hormone-sensitive population. It is important to recognize the limitations of this therapy and to understand that there is no defined role for its use in men with androgen-dependent prostate cancer. Although these men are at higher risk for osteoporosis, use of less-potent oral bisphosphonates may be a more reasonable approach, given the long-term side effects associated with zoledronic acid (renal insufficiency and osteonecrosis of the mandible).

Denosumab (Xgeva). A novel approach to the prevention of bone loss and skeletal events in recurrent prostate cancer involves the use of an inhibitor antibody to block RANKL (receptor activator of nuclear factor-κB ligand), a molecule involved in osteoclast-mediated bone resorption and remodeling. This antibody, termed denosumab, has demonstrated an ability to improve bone mineral density in men undergoing androgen deprivation theapy, as well as an improved capability in preventing pathologic fractures, the need for radiation or surgery to bone, or spinal cord compression (so-called skeletal-related events) and restoring bone density as compared with zoledronic acid in head-to-head studies. While osteonecrosis is also a side effect with this compound (1% to 4% risk over time), its subcutaneous administration and lack of kidney toxicity have led to an approved and now standard role for this agent for the prevention of skeletal events in men with castration-resistant prostate cancer.

Further studies of the role of denosumab in the prevention of metastasis and hormone therapy–induced clinical fractures will help to guide the rational use of this agent, which is given by subcutaneous injection. Side effects of denosumab include hypocalcemia and hypophosphatemia and osteonecrosis of the jaw, with risks similar to or slightly greater than those of zoledronic acid.

Second-line therapy after docetaxel

Cabazitaxel (Jevtana) with prednisone. In 2010, it was demonstrated that a novel synthetic taxane, cabazitaxel, demonstrated improved overall survival compared with mitoxantrone in men with metastatic CRPC whose disease had progressed on docetaxel chemotherapy. As reported by de Bono et al in a randomized, open-label, phase III study of 755 patients (377 in the mitoxantrone group, 378 in the cabazitaxel group), the overall survival benefit was 2 months (from 12.7 to 15.1 months; HR = 0.70; 95% CI, 0.59–0.83; P < .0001), and improvements in PSA response, tumor response, and progression-free survival were notable. Each regimen was similarly palliative, but the duration of response favored cabazitaxel. Cabazitaxel is given intravenously at 25 mg/m² every 3 weeks with prednisone dosed at 5 mg orally twice daily. The risk of neutropenia and sepsis due to myelosuppression in this heavily pretreated group of men is high (7% to 8%) and prophylactic GM-CSF should strongly be considered. Other toxicities include neuropathy, fatigue, diarrhea, nausea, and vomiting. Continuation of testosterone suppression was required. Cabazitaxel has demonstrated activity in docetaxel-resistant cell lines and was approved by the FDA in 2010 for second-line treatment of men with chemorefractory CRPC.

Abiraterone acetate with prednisone. In April 2011, the FDA approved the androgen synthesis inhibitor abiraterone acetate in combination with low-dose prednisone for the treatment of men with metastatic CRPC who have received prior chemotherapy containing docetaxel. Autocrine and/or paracrine androgen synthesis is known to be enhanced in the tumor microenvironment during castration-resistant progression in many men, and abiraterone acetate inhibits a key step in testosterone/dihydrotestosterone precursor synthesis, notably the cytochrome P450 c17 (lyase, hydroxylase) enzyme. Blockade of this enzyme is known to reduce testosterone production from the adrenal gland and is thought to reduce intratumoral synthesis as well, mediated by a reduction in androgen receptor activity, as described by Attard et al.

The FDA approval is based on the results of a randomized, placebo-controlled, multicenter trial reported by de Bono in 2011, in 1,195 patients with metastatic CRPC previously treated with docetaxel-containing regimens. Patients were randomly allocated (2:1) to receive either abiraterone acetate orally at a dose of 1,000 mg once daily (n = 797) or placebo once daily (n = 398). Patients in both arms (abiraterone acetate and placebo) received prednisone 5 mg orally twice daily because of the ability of prednisone to improve both the safety and efficacy profile of abiraterone acetate as well as to serve as an efficacy control group, given the modest but known efficacy of prednisone alone in this population. Treatment continued until disease progression (defined as a 25% increase in PSA level over the patient's baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), unacceptable toxicity, initiation of new treatment, or withdrawal. Patients with prior ketoconazole treatment for prostate cancer were excluded, although as Ryan et al discuss, abiraterone acetate is known to have some benefit in these patients, albeit probably to a lower degree.

A prespecified interim overall survival analysis was performed when 552 events had occurred. This analysis demonstrated a statistically significant improvement in overall survival in patients receiving abiraterone acetate compared with those on the placebo-containing arm (HR = 0.646; 95% CI, 0.543–0.768; P < .0001). Median overall survival was 14.8 vs 10.9 months in the abiraterone and placebo arm, respectively. Abiraterone acetate was also shown to result in improved pain palliation and had a significant delay in the time to pain progression compared with prednisone alone. Improvements in progression-free survival (5.6 months vs 3.6 months) and PSA responses (29% vs 6%) were also noted. All subgroups based on baseline characteristics (age, performance status, PSA, pain intensity, visceral metastases) demonstrated improvements in outcomes over prednisone alone.

The most common adverse reactions seen with abiraterone/prednisone (> 5%) were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. The most common adverse drug reactions resulting in drug discontinuation were increased aspartate aminotransferase and/or alanine aminotransferase levels, urosepsis, and cardiac failure (each in < 1% of patients taking abiraterone). The most common electrolyte imbalances in patients receiving abiraterone were hypokalemia (28%) and hypophosphatemia (24%). Following interruption of daily corticosteroids and/or with concurrent infection or stress, adrenocortical insufficiency (< 1%) has been reported in clinical trials in patients receiving abiraterone acetate at the recommended dose in combination with prednisone. It is recommended that close monitoring of serum electrolytes and liver enzymes be conducted during therapy with abiraterone. Abiraterone should be taken in a fasting state due to the higher levels of drug exposure when taken with food. Interestingly, bone scan healing flares are commonly seen early on with abiraterone (and cabazitaxel), despite pain and PSA reductions, indicating the need to obtain confirmatory bone scans that show additional new lesions before stopping therapy in the absence of other evidence of clinical progression.

Thus, following docetaxel chemotherapy for metastatic CRPC, the hormonally active androgen synthesis inhibitor abiraterone acetate has demonstrated clinical benefit and therefore represents a new standard of care in this setting. The NCCN Prostate Cancer Guidelines also acknowledge that some men with metastatic CRPC are not candidates for chemotherapy (docetaxel or mitoxantrone) because of comorbidities, peripheral neuropathy, or concerns over tolerability and risk/benefit. In these men, abiraterone acetate with prednisone may be an appropriate therapy, given its survival and palliative benefits and reasonable toxicity profile. However, its routine use in the pre-docetaxel setting should be discouraged until level 1 evidence from an ongoing randomized study of abiraterone acetate and prednisone vs prednisone alone in this setting has been reported. This trial has completed accrual, and initial results are expected soon.

Abiraterone pre-docetaxel. In 2012, data were presented from the phase III Cougar 302 trial of abiraterone/prednisone vs prednisone alone, which was a randomized international study of men with metastatic CRPC in the pre-docetaxel clinical state. These men had minimally symptomatic disease (ie, little pain from their prostate cancer) and no visceral metastatic disease. Results were presented by Ryan et al at the 2012 meeting of ASCO and published in early 2013. In this trial, 1,088 men were randomized 1:1 to abiraterone/prednisone vs prednisone with a co-primary endpoint of overall survival and progression-free survival. This study was placebo-controlled and blinded, and it was stratified based on performance status. The progression-free survival definition was a composite radiographic definition that accounted for the known bone scan flares that occur with this agent in the short term, and did not include PSA criteria. Dosing is 1,000 mg daily without food, with prednisone given at 5-mg twice daily. With 311 mortality events, the survival data were immature; however, the study was stopped and unblinded early by the data and safety monitoring board due to the positive results for both progression-free survival and all secondary outcomes, combined with a strong trend to improved survival. Specifically, progression-free survival was improved (HR = 0.43; 95% CI, 0.35–0.52; P < .0001) with a likely 7 to 10 month improvement in progression-free survival observed. OS was improved (HR = 0.75; 95% CI, 0.61–0.93; P = .0097) but this did not meet prespecified criteria (alpha of 0.0008) at the time of the ASCO presentation. PSA responses (50% or greater decline) were observed in 62% vs 24% of patients, respectively, while radiographic RECIST responses were observed in 36% vs 16% of patients (P < .0001 for each endpoint). Improvements in time to performance status deterioration, time to chemotherapy administration, and time to pain onset were all improved, reflecting a clear clinical benefit. Notably, this trial was not compared with docetaxel and had limited eligibility for a head-to-head comparison with chemotherapy. Nevertheless, given the established palliative role and improved survival with abiraterone even in the post-docetaxel space, many patient and providers will prefer a trial of abiraterone prior to docetaxel unless there is evidence for rapid visceral or pain progression requiring immediate chemotherapy. No biomarkers have yet been identified that can select a man with CRPC for abiraterone or chemotherapy, and these studies are now warranted. Toxicities of this agent in the pre-docetaxel space were as expected, with evidence of mineralocortocoid excess (hypertension, edema, hypokalemia) occurring in 2% to 3% of men, grade 3/4 elevated liver enzymes in 3% to 6% of men, and cardiac disorders (atrial fibrillation, CHF) in 19% of men (6% grade 3/4). In addition to the efficacy of abiraterone observed in this trial, the 8-month progression-free survival observed with prednisone alone testifies to the efficacy of corticosteroids in the management of these men. Currently, abiraterone remains approved only in the post-docetaxel CRPC space and for men who are not candidates for docetaxel; however, these data are compelling and will likely alter treatment guidelines in 2012–2013.

Newer therapies

Several newer therapies for men with prostate cancer (some available as single agents and some to be given with chemotherapy) are under investigation. Since docetaxel is the only approved chemotherapy in the front-line setting to date associated with a survival advantage in patients with metastatic CRPC, it has become the "backbone" upon which novel therapies and response modifiers are added in an attempt to improve patient outcomes. For example, neither the addition of bevacizumab (Avastin) or aflibercept (VEGF trap) nor any of the endothelin antagonists to docetaxel improved overall survival in men with metastatic CRPC. Thus, docetaxel-prednisone remains the front-line treatment of choice for men with metastatic CRPC who have failed to respond to prior hormonal therapy.

TABLE 9Phase III docetaxel combination trials in castration-resistant metastatic prostate cancer

Based on promising results in phase II testing, several phase III trials building upon docetaxel were opened (Table 9). Whether building upon docetaxel with targeted therapy will be of benefit is still unknown pending the results of the remaining phase III trials. Phase III trials of other therapies both before or after docetaxel, including novel agents targeting the androgen receptor (MDV3100, TAK-700 for example), immune therapies (lenalidomide [Revlimid], tasquinimod, Prostvac), and bone microenvironment agents (dasatinib [Sprycel], zibotentan [ZD4054]) are awaited. Tasquinimod is one novel agent worthy of mention. This is an oral anti-angiogenic and immunomodulatory small molecule inhibitor of the myeloid suppressor cell, with a target likely being S100A9 and potentially thrombomodulin. Its clinical safety and efficacy have been demonstrated in a phase II randomized placebo-controlled international trial reported by Pili et al, in which tasquinimod was shown to delay radiographic progression by 5 to 7 months and have an acceptable safety profile. However, agents such as these will need to show an improvement in both progression-free and overall survival to be incorporated into the standard of care in this disease, given the clear disconnect between progression-free survival and overall survival seen with immune therapies and anti-angiogenic drugs (see biomarker review in Armstrong et al, Eur Urol 2012). Finally, many of these agents are being tested in men with asymptomatic CRPC or minimally symptomatic men with metastatic CRPC (ie, the window prior to docetaxel use), with the aim of delaying chemotherapy use/need.

As noted previously, sipuleucel-T vaccine was approved for advanced prostate cancer in April 2010. In addition, current trials are investigating the use of systemic agents, including docetaxel, in locally advanced or PSA-recurrent disease, either prior to treatment or as adjuvant therapy following surgery or radiation therapy. Accrual to these trials has been a priority (in RTOG 0521 [now completed], VA 553, and CALGB 90203), as they are investigating the role of systemic therapy to prevent disease recurrence, similar to the widely accepted use of systemic therapy for other tumor types such as breast and colorectal cancers. RTOG is exploring the role of docetaxel in addition to long-term androgen-deprivation therapy for men with locally advanced high-risk prostate cancer who have completed IMRT of the prostate. CALGB 90203 randomized high-risk men (Gleason score > 8 or nomogram-defined high risk) to immediate radical prostatectomy vs docetaxel for 6 cycles with androgen deprivation therapy followed by radical prostatectomy. The use of neoadjuvant or adjuvant docetaxel for high-risk men will be guided by evidence from these trials.

Recent guidelines by the Prostate Cancer Working Group (PCWG)2 have updated methods for categorizing disease states in men with CRPC (node only, PSA only, locally advanced, bone metastatic visceral disease). In addition, the requirements for confirmation bone scans and changes in the reporting and assessment of disease progression have been updated to be more consistent with our understanding of prostate cancer biology, including the lesion flare response on bone scan with effective therapy, and to prevent the unnecessary early abandonment of potentially active agents based on PSA changes alone. For example, healing of bone lesions may cause an apparent "worsening" of disease on bone scan despite declines in PSA levels and improvement in pain, likely due to osteoblastic activity in regressing tumors. Physicians are encouraged to evaluate these potential flare cases with a confirmatory bone scan 6 or more weeks later; if the patient develops no additional new lesions or disease progression, he should be maintained on therapy. Many older therapies may have been unnecessarily stopped prematurely due to this misclassification of bone scan progression using older criteria.

Radiation therapy for palliating bone metastasis

Radiotherapy is effective in controlling local pain associated with skeletal prostate metastasis. In general, a treatment regimen of 30 Gy over 10 treatments results in rapid and durable local symptom control and a reduced dependence on analgesics. Single-dose palliative radiation therapy may provide equal palliation as well.

For patients with more extensive bone involvement causing pain that may be difficult to address with localized EBRT, alternatives include wide-field irradiation (ie, hemibody irradiation) or systemic administration of radioactive bone-seeking isotopes that can deliver therapeutic doses to skeletal metastatic disease. Radioactive isotopes used in this fashion include strontium-89 chloride (Metastron) and samarium SM 153 lexidronam (Quadramet).

Alpharadin (Radium-223). In 2011–2012, the results of the phase III ALSYMPCA trial (Alpharadin in Symptomatic Prostate Cancer) were presented and are expected to lead to the regulatory approval of the novel alpha particle emitter radium-223 in men with bone-metastatic symptomatic prostate cancer. Alpharadin is a calcium-mimetic radiopharmaceutical that is incorporated into bone and produces alpha particles capable of tumor killing with a 2–10 cell diameter penetration, and has demonstrated palliative benefits and acceptable safety with minimal myelosuppression in phase I-II trials to date. The ALSYMPCA trial, reported by Parker et al, was a phase III 2:1 randomized trial of radium-223 (50 kBq/kg × 6 every 4 weeks) or placebo in men with bone-metastatic symptomatic CRPC who had failed to respond to docetaxel or who were considered unfit for docetaxel by their treating physicians. Men could also receive concurrent hormonal therapies or radiation or glucocorticoids during this trial. In this trial, 921 men were randomized, 57% of whom had received prior docetaxel. More than 60% of men were able to complete the planned 6-month course of therapy. Overall survival improved from 11.3 months to 14.9 months (HR = 0.695; 95% CI, 0.581–0.832; P = .00007). Improvements were seen in men with prior docetaxel or among those considered not to be docetaxel candidates; benefits seemed particularly robust among men with elevated alkaline phosphatase levels (> 220 U/L), with a survival improving from 8.1 to 11.4 months, while those with normal bone markers had a less substantial and non-significant benefit. Delays in skeletal events were noted and data on pain palliation are not yet available. Toxicities were mild and did include vomiting, diarrhea (25%), and thrombocytopenia (12%). Rates of severe anemia and neutropenia were similar. Thus, this radiopharmaceutical represents a potential new treatment option for symptomatic men, pending regulatory approval.