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Keywords:

  • castration-resistant prostate cancer;
  • androgen deprivation;
  • second-line hormonal therapy;
  • adrenal synthesis inhibition;
  • immunotherapy;
  • chemotherapy

Abstract

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

Although the long natural history of prostate cancer presents challenges in the development of novel therapeutics, major contributions have been observed recently. A better understanding of the long-term complications of androgen deprivation has changed the initial approach to most patients with advanced disease. Specifically, recognition of the limitations of prostate-specific antigen has driven the pursuit of new tools capable of becoming true surrogates for disease outcome. Understanding the molecular biology of castration-resistant prostate cancer (CRPC) has led to a dramatic paradigm shift in the treatment of patients with metastatic disease where the androgen receptor becomes a central therapeutic target. Specific adrenal inhibitors and engineered super androgen receptor inhibitors have become the most promising agents in the disease. Novel immune therapies have been shown to improve survival in selected patients with castration-resistant disease despite the inability to impact traditional markers of response. Similarly, agents such as cabazitaxel and abiraterone acetate have demonstrated clinical benefit are now a standard of care in docetaxel-refractory metastatic CRPC patients. All these changes have occurred in a relatively short period and are likely to change the prostate cancer treatment paradigm. This review summarizes the current management of CRPC and discusses potential future directions. Cancer 2011;. © 2011 American Cancer Society.

Although its timing remains controversial, androgen deprivation therapy (ADT) remains the standard initial therapy for advanced prostate cancer. Testosterone suppression can be achieved either through surgical or medical castration. For patients undergoing medical castration, ADT can be prescribed alone or in combination with an androgen receptor (AR) antagonist.1 Although the majority of patients with advanced prostate cancer have an initial response to ADT, nearly all patients will eventually progress to a “castration-resistant” state. The definition for castration-resistant prostate cancer (CRPC) has been standardized and requires castrate levels of testosterone with either rising levels of prostate-specific antigen (PSA), radiographic progression, and/or worsening of symptoms.2, 3 Treatment options for patients with metastatic CRPC have evolved in recent years and include secondary hormonal manipulations, immunotherapy, and chemotherapy.3 In the castrate-resistant state, testosterone does not appear to be the major ligand capable of activating the AR. However, prostate cancer progression continues to be largely dependent on AR and AR-responsive pathways.3, 4 In this review, the current standard of care for CRPC patients, including recent US Food and Drug Administration (FDA)-approved agents, as well as the new generation of compounds undergoing clinical development, are discussed.

Importance of the AR in Castration-Resistant Disease

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

The AR is a member of the nuclear receptor superfamily that acts as a ligand-dependent transcription factor and modulates the growth and development of prostate epithelial cells.5 The role of AR in CRPC has been extensively studied. Despite initial data suggesting the loss of AR activity in this setting, AR overexpression in tissue specimens from castrate-resistant tumors indicates the importance of this gene even in the context of a testosterone-deprived state.6 Although the true biological mechanism responsible for the development of CRPC is not well understood, some of the proposed mechanisms include AR activation in a ligand-independent manner,6, 7 changes in the level of intratumoral ligands, AR gene amplification, changes in AR coregulatory molecules, and activating AR mutations.4, 8-10

Additional Hormonal Manipulations in Castration-Resistant Disease

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

Historically, second-line hormonal manipulations may be broadly grouped into 1 of 4 categories: 1) antiandrogen withdrawal; 2) deferred use of an antiandrogen after castration or use of a second-line antiandrogen; 3) adrenal steroidogenesis inhibition with agents such as ketoconazole or aminogluthimide; or 4) the use of alternative hormones such as estrogens.

Antiandrogen Withdrawal

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

Over the last decade, it has been recognized that biochemical (PSA) responses as well as symptomatic and objective responses can be achieved in CRPC patients upon withdrawal of antiandrogen therapy. This phenomenon was initially described with flutamide,11 as well as 2 other nonsteroidal antiandrogens, bicalutamide12, 13 and nilutamide.14, 15 Responses have also been documented after removal of the steroidal antiandrogen, megestrol acetate,16 and estrogens such as diethylstilbestrol (DES).17 Antiandrogen withdrawal responses occur in 15%-30% of patients. The average response duration is ≈3-6 months, although in a minority of patients, responses can be durable for 2 years or more.11-15 Antiandrogen withdrawal should be the first intervention for patients with progressive CRPC while on combined androgen blockade. This intervention is nontoxic, is required in CRPC clinical trials, and may provide significant benefit to a small subset of patients.

Secondary Hormonal Manipulations

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

Despite exhibiting androgen deprivation, many patients with progressive disease on ADT demonstrate AR promiscuity, whereby AR is activated by nontestosterone ligands—thus the potential clinical use of other hormonal maneuvers in this setting.

Antiandrogens

Second-line antiandrogen therapy is predicated on the possibility that, despite their functional similarities, different antiandrogens have a different mechanism of interaction with the AR.18 For example, ≈20% of patients with progressive disease treated with high-dose bicalutamide (150 mg/d) after initial androgen deprivation will have a >50% decline in PSA, with most responses seen in patients who have received prior flutamide therapy.19 Similar activity has been observed with the antiandrogen nilutamide when administered at 150 mg orally once daily.20, 21 It is unclear as to what is the most appropriate dose of second-line bicalutamide therapy (50 mg vs 150 mg). However, 50 mg orally once daily is perhaps the most common dosage used in the United States.

It is not clear why patients have higher response rates, although it has been hypothesized that a mutant AR induced by prior flutamide therapy may mediate a higher response rate to salvage bicalutamide even when administered in the second or third-line setting.

Adrenal inhibitors

Although 5%-10% of circulating testosterone in humans is synthesized in the adrenal glands, early adrenal androgens such as dehydroepiandrosterone, dehydroepiandrosterone sulfate, and 5-androstenediol can exceed the concentrations of testosterone and dihydrotestosterone and therefore lead to direct activation of wild-type and mutant AR.22, 23 Indirectly, dehydroepiandrosterone and androstenedione can also be metabolized and converted to dihydrotestosterone.24, 25 These facts have led to the testing of agents that inhibit adrenal steroidogenesis as therapy for CRPC (Figure 1).

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Figure 1. Steroid biosynthesis pathway.76

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The clinical efficacy and safety of the antifungal agent ketoconazole has been studied extensively.26-29 Treatment with ketoconazole leads to a PSA decline of >50% in a large number of patients (46%-62%). These responses are irrespective of the antiandrogen withdrawal phenomenon. Ketoconazole inhibits the conversion of cholesterol to pregnenolone and other cytochrome P-450 enzymes such as CYP17 and 11β-hydroxylase, an enzyme responsible for cortisol synthesis. In 2004, the phase 3 study CALGB 9583 investigated the use of antiandrogen withdrawal (AAWD) in patients with CRPC with or without the addition of ketoconazole (400 mg orally three times daily) and hydrocortisone.30 Results of this trial found a PSA response of ≥50% in 27% of patients treated with AAWD and simultaneous ketoconazole compared with 11% of those treated with AAWD alone (P = .002). The corresponding objective response rate was 20% and 2%, respectively (P = .02), and no difference in overall survival (OS) was seen (15.3 months vs 16.7 months, respectively; P = .936).30 In this trial, the use of sequential therapy with ketoconazole also led to PSA and ORR of 32 and 7% respectively. Adrenal insufficiency is one of the major limiting adverse effects of ketoconazole treatment, hence the need for steroid replacement in all patients. In the CALGB 9583 trial, 21% of patients receiving ketoconazole had grade 3 or 4 toxicity, with neurotoxicity and malaise/fatigue being most common.30 Despite this finding, ketoconazole is a good therapeutic option for patients with CRPC with PSA progression-only disease or for patients with no or minimal symptoms and low-volume disease, because it provides selected patients the opportunity to maintain quality of life while still receiving an active treatment for their disease.

Estrogenic therapies

Synthetic estrogens such as DES and synthetic progestins such as megestrol acetate have also been investigated as therapies for CRPC.31, 32 In a phase 2 study, Smith et al33 demonstrated PSA declines of >50% in 43% of patients (n = 21) treated with 1 mg of DES daily. Other studies have shown similar PSA responses (>50%) that have ranged from 29% to 55% using dosages of up to 3 mg daily.34, 35 The use of these agents, and DES in particular, has been limited by the incidence of cardiac toxicity and thromboembolic complications.34, 35

Immunotherapy and Prostate Cancer

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

Although immunotherapy has gained momentum in prostate cancer therapeutics, the vast majority of agents tested in this disease have yielded disappointing results, and in the case of anti-CTLA-4 and GVAX therapy, new concerns of safety have been raised.36-40

Sipuleucel-T is an immunotherapeutic compound designed to stimulate an immune response against CRPC. In a small, randomized, placebo-controlled trial (n = 127), sipuleucel-T was found to confer a significant survival benefit for men with CRPC over placebo (median OS, 25.9 months vs 21.4 months; P = .01).41 It is important to note, however, that OS was not the primary endpoint of this trial, and that the median PFS of sipuleucel-T did not differ from that of the placebo group. An integrated analysis of 2 phase 3 trials also indicated a significant benefit of sipuleucel-T over placebo in median survival (23.2 months vs 18.9 months; P = .011), but not in median time to progression (11.1 months vs 9.7 months; P = .111).42 The results of the IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial—a double-blind, placebo-controlled, multicenter phase 3 trial—were reported in 2010.36 This study enrolled 512 men with asymptomatic or mildly symptomatic metastatic CRPC and randomly assigned them 2:1 to either sipuleucel-T or placebo every 2 weeks for a total of 3 infusions. The median OS was 25.8 months for patients treated with sipuleucel-T compared with 21.7 months for patients receiving placebo (Figure 2), with an adjusted hazard ratio (HR) for death of 0.78 (95% confidence interval (CI), 0.61-0.98), representing a relative reduction in the risk of death of 22% (P = .03). The reduction in the risk of death from prostate cancer in the sipuleucel-T group (HR, 0.77; 95% CI, 0.61-0.98; P = .04) was similar to the reduction in the risk of death from any cause.43 When evaluating the impact of subsequent therapy with outcome, the estimated effect of sipuleucel-T treatment for those patients receiving subsequent docetaxel-based chemotherapy was consistent with the result of the primary efficacy analysis (HR for death, 0.78; 95% CI, 0.62-0.98; P = .03). Additional results from the trial showed no significant difference in median time to objective disease progression (14.6 weeks vs 14.4 weeks; HR = 0.95; 95% CI, 0.77 to 1.17; P = .63), or time to clinical disease progression (HR, 0.92; 95% CI, 0.75-1.12; P = .40). Overall, therapy with sipuleucel-T was well tolerated.43 Almost all patients in the IMPACT trial received all 3 planned infusions, and no patient discontinued the study secondary to toxicity. The most common toxicities were grade 1 and 2 and included chills, fever (pyrexia), headache, influenza-like illness, myalgia, hypertension, hyperhidrosis, and groin pain. Most of these adverse events (AEs) occurred within 1 day after infusion and resolved within 1-2 days. These AEs are consistent with cytokine release as expected from immune therapy.

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Figure 2. Overall survival in the sipuleucel-T trial.43 Reprinted with permission from the New England Journal of Medicine (c) Massachusetts Medical Society. Reproduced from: Kantoff et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1001294.

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Although the immune effects of this product have been characterized in some detail, the appropriate CRPC patient who is likely to obtain the greatest benefit from treatment with sipuleucel-T requires further investigation. Current appropriate candidates for this agent include only those with asymptomatic or mildly symptomatic (non–opioid-requiring cancer pain) disease. Clinically, one difficulty with sipuleucel-T is the lack of effect on PSA, symptoms, or radiographic parameters. That is, benefit to an individual patient is difficult to gauge, and the most beneficial timing of when to initiate sipuleucel-T and any subsequent therapy is still unknown.

Another vaccine approach undergoing further evaluation is PROSTVAC, a construct of fowlpox and vaccinia vectors containing costimulatory molecules (intercellular adhesion molecule 1, B7-1, and leukocyte function–associated antigen 3).44 Initial studies have not only defined the safety profile of this compound, but also have suggested a possible OS improvement in the CRPC setting.45-47 A pivotal phase 3 trial of PROSTVAC-VF is currently planned.

Despite the clinical and logistical challenges involved with these approaches, immunotherapy will likely continue playing a major role in prostate cancer therapeutics especially as newer agents are developed and the appropriate individual who can truly benefit from these interventions is defined.

Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

Mitoxantrone-based chemotherapy

In the early 1990s, 2 studies that demonstrated a benefit in pain control and quality of life led to the FDA approval of mitoxantrone for use in patients with CRPC.48, 49 Both trials randomized patients to either a corticosteroid alone or mitoxantrone plus prednisone (M/P). A PSA decline of >50% was observed in 19% and 33% of CRPC patients who received therapy with mitoxantrone plus a corticosteroid, compared with 14% and 22%, respectively, for patients who received a corticosteroid only.48, 49 The trial by Tannock et al48 also showed that palliation of symptoms was greater in the chemotherapy arm (P = .01) and response duration was also longer with mitoxantrone (43 vs. 18 weeks, P<.0001). Although no survival advantage was observed, these trials provided the proof of principle that clinical benefit can be derived from chemotherapy, and today mitoxantrone remains a viable palliative and well-tolerated intervention, although patient selection for this therapy and timing relative to newer agents is yet to be established.

Docetaxel-based chemotherapy

To date, 2 large, multicenter, randomized, phase 3 trials evaluating chemotherapy with docetaxel-based regimens demonstrated a significant OS improvement in castration-resistant disease.50, 51 In the TAX 327 study, 2 schedules of docetaxel/prednisone (D/P) (75 mg/m2 thrice weekly or 30 mg/m2 once weekly) were compared with the standard M/P regimen (12 mg/m2 every 3 weeks).50 A survival benefit was demonstrated for the combined D/P group and the every 3 weeks D/P group (but not the once weekly D/P group) relative to M/P. The median survival was 18.9 months in the every 3 weeks D/P group; 17.4 months with weekly docetaxel; and 16.5 months with M/P (Figure 3A).50 This OS improvement translated into a 24% relative reduction in the hazard for death (HR, 0.76; 95% CI, 0.62-0.94; P = .009). Measurable tumor response rates were low and comparable in all arms. Significantly more patients in the every 3 weeks D/P arm experienced a reduction in pain compared with M/P (35% vs 22%, respectively; P = .01). Nearly a quarter of patients in each D/P arm (22% with every 3 weeks, 23% with weekly) had a significant improvement in quality of life compared with M/P (13%). The PSA response rate was better in each D/P arm (45% with every 3 weeks administration, 48% with weekly administration versus 32% with M/P). Grade 3/4 neutropenia occurred in 32% of patients treated with every 3 weeks D/P, 22% of patients treated with M/P, and only 2% of patients treated with weekly D/P.

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Figure 3. Overall survival in TAX327 and SWOG 9916.50, 51 3A. Kaplan-Meier overall survival in TAX327.50 Reprinted with permission from the New England Journal of Medicine (c) Massachusetts Medical Society. Reproduced from: Tannock et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. Available at http://www.nejm.org/doi/full/10.1056/NEJMoa040720. 3B. Kaplan-Meier overall survival in SWOG 9916.51 Reprinted with permission from the New England Journal of Medicine (c) Massachusetts Medical Society. Reproduced from: Petrylak et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa041318.

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In the SWOG 9916 phase 3 trial, 770 patients were randomized to docetaxel plus estramustine (EMP) or M/P.51 The median survival was significantly improved (Figure 3B), with the docetaxel/EMP combination (17.5 vs 15.6 months; P = .02), the relative risk of death was reduced by 20%; and the PSA response rate was significantly better (50% vs 27%; P<.001). Greater toxicity was observed in the docetaxel/EMP arm, with grade 3/4 gastrointestinal (20% vs 5%), hematological (neutropenic fever, 5% vs 2%), cardiovascular (15% vs 7%), metabolic disturbance (6% vs 1%), and neurological (7% vs 2%) events more frequent in the docetaxel/EMP arm. Although the magnitude of improvement in survival demonstrated in the TAX327 and SWOG-9916 studies is modest, it represented a significant advance in the management of CRPC and led to docetaxel's approval as the front-line agent of choice in patients with metastatic CRPC. Nonetheless, questions about the appropriate timing for initiation of therapy and optimal number of cycles of therapy remain unanswered. EMP has largely been dropped from this approach given the added toxicity and uncertainty about additional clinical benefit.

Novel docetaxel combinations

Based on initial results observed with docetaxel-based chemotherapy, and along with available preclinical data suggesting the potential synergistic and/or additive activity of other cytotoxic agents, a major focus of prostate cancer research has shifted to the evaluation of novel combinations using docetaxel as the backbone of therapy. The combination of docetaxel with other cytotoxic agents such as gemcitabine have not proven to confer a useful benefit compared with historical experience with docetaxel alone in CRPC.52 Other studies have demonstrated the activity and tolerability of other docetaxel combinations, which remain to be more rigorously evaluated in phase 3 trials;53-56 however, the early phase 1 and 2 studies of novel targeted agents used in combination with docetaxel have generally been disappointing.57-70 For example, although a randomized phase 2 study evaluating DN-101, a high concentration oral formulation of calcitriol71 plus docetaxel against docetaxel plus placebo (ASCENT)72 originally suggested DN-101 treatment was associated with improved survival in men with CRPC; ASCENT 2, a randomized, open-label, phase 3 study of weekly docetaxel plus DN-101 versus standard every 3 weeks docetaxel therapy was halted after an interim analysis demonstrated an increased number of deaths in the DN-101 arm.73 Six months after study termination, the median OS was 16.8 months (95% CI, 15.8-19.3) for patients treated with DN-101 and 19.9 months (95% CI, 18.6-22.7) for controls. In multivariate analyses adjusting for baseline variables, treatment with DN-101 was associated with shorter survival (HR, 1.33; P = .019). Although the OS difference observed in this study could be related to the weekly docetaxel schema used, DN-101 as currently formulated did not augment the clinical activity of docetaxel in CRPC.73

A randomized, double-blind, placebo-controlled phase 3 trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab in men with metastatic CRPC (CALGB 90401) also failed to demonstrate a survival benefit for the addition of bevacizumab to standard docetaxel.74 The median OS for the combination was 22.6 months versus 21.5 months for the placebo arm (P = .18). The progression-free survival (PFS) and response observed in the trial, however, did favor the addition of bevacizumab to docetaxel (median PFS, 9.9 vs 7.5 months, respectively [P<.0001]; overall response rate [ORR], 53% vs 42% [P = .0113]; PSA decline ≥50%, 69.5% vs 57.9% [P = .0002]). The use of bevacizumab or other VEGF-targeting agents in CRPC awaits further investigation.

Second-line chemotherapy

Until recently, the treatment of men with metastatic CRPC progressing after docetaxel-based chemotherapy was a therapeutic challenge, because no treatment had demonstrated survival benefit. Mitoxantrone/prednisone (M/P) had become the de facto second line of choice primarily for its palliative effects and improvement in quality of life, which was initially observed in front-line studies.48, 49, 75 Other cytotoxics explored in the second-line setting have included the epothilones and platinum compounds. Results of a phase 2 study evaluating the combination of M/P plus ixabepilone in docetaxel-refractory patients recently demonstrated a PSA decline ≥50% in 45% of patients.76 Among those with measurable disease, the ORR was 22%. The median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and the median PFS was also 4.4 months (95% CI, 3.0-6.0). The observed median OS was 12.5 months (95% CI, 10.2-15.9). Although this combination led to grade 3 and 4 neutropenia, with 11% of patients developing neutropenic fever, a phase 3 study evaluating this combination is planned.

Satraplatin, a third generation oral platinum has also undergone evaluation in CRPC.77 The SPARC (Satraplatin and Prednisone against Refractory Cancer) trial was a randomized (2:1 satraplatin/placebo), placebo-controlled phase 3 trial designed to investigate the efficacy of satraplatin with prednisone in men (N = 950) with metastatic CRPC who had progressed after at least 1 chemotherapy regimen.78 Although the primary endpoint of the study, PFS, was significantly longer with satraplatin (11.1 vs 9.7 weeks; P<.001), there was no difference in OS (61.3 vs 61.4 weeks; HR, 0.98; 95% CI, 0.84-1.15; P = .80); consequently, satraplatin was not approved by the FDA.

Recently, cabazitaxel became the first FDA-approved agent for the management of patients with metastatic CRPC who have failed docetaxel-based chemotherapy. Cabazitaxel is a semisynthetic, tubulin-binding taxane drug as potent as docetaxel in cell lines with demonstrated antitumor activity in models resistant to paclitaxel and docetaxel.79-81 Phase 1/2 clinical studies have also demonstrated the maximum tolerable dosage and safety of this compound and have shown that neutropenia and diarrhea were the primary dose-limiting toxicities.82, 83 These studies also suggested antitumor activity in solid tumors including docetaxel-refractory metastatic CRPC.

The clinical activity of cabazitaxel in the second-line setting was evaluated in the phase 3 TROPIC trial.84 In this randomized trial, 755 men with metastatic CRPC who had disease progression during or after treatment with docetaxel were randomly assigned to prednisone (10 mg/d) with either cabazitaxel (25 mg/m2) (C/P) or mitoxantrone (12 mg/m2) (M/P), with the primary endpoint of OS. At a median follow up of 12.8 months, the median OS was 15.1 months (95% CI, 14.1-16.3) in the C/P group and 12.7 months (95% CI, 11.6-13.7) in the M/P group (Figure 4). The HR for death of men treated with C/P compared with those taking M/P was 0.70 (95% CI, 0.59-0.83; P<.0001). The median PFS was 2.8 months (95% CI, 2.4-3.0) in the C/P group and 1.4 months (1.4-1.7) in the M/P group (HR, 0.74; 95% CI, 0.64-0.86; P<.0001). The ORR for patients with measurable disease was 14.4% versus 4.4% (P = .0005). Equally, the PSA response rate (PSA decline ≥50%) was 39.2% versus 17.8% (P = .0002). Of concern was the high incidence of grade 3 and 4 neutropenia observed in 82% of patients receiving cabazitaxel. Febrile neutropenia occurred in 8% of these patients, and diarrhea was reported in 6%. Grade 3 peripheral neuropathy was uncommon (1% of patients in each group). Whereas 18 patients in the C/P arm died from treatment-related AEs, including neutropenic fever/sepsis (n = 7), cardiac events (n = 5), dehydration/electrolyte imbalance (n = 1), renal failure (n = 3), cerebral hemorrhage (n = 1), and 1 patient died from unknown causes, only 1 patient in the M/P arm died from febrile neutropenia.

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Figure 4. Overall survival in the TROPIC study. Reprinted from The Lancet, Vol. 363, Kantoff PW et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer, pp 411-422, 2010, with permission from Elsevier.43

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Although cabazitaxel is the first agent capable of demonstrating OS benefit in this setting, the toxicity profile of this agent is noteworthy. Based on the hematological AEs observed in this study, the prophylactic use of growth factors is recommended in patients with high risk of developing neutropenia.85 Currently, a lower dose of cabazitaxel (20 mg/m2) is undergoing testing in a phase 3 post-marketing study (NCT01308580). Similarly, a phase 3 front-line study evaluating C/P against docetaxel plus prednisone has been initiated (NCT01308567).

Novel Oral Agents in CRPC

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

Rationally developed therapeutic strategies in CRPC have gained momentum with the recognition that the AR remains a major player in disease progression. Abiraterone acetate is a novel, selective, irreversible, oral inhibitor of CYP17 (Figure 1) capable of significantly reducing androgenic steroid production downstream from CYP17.86 Initial phase 1/2 studies of abiraterone acetate in chemotherapy-naïve CRPC demonstrated the safety and activity of this agent in castration-resistant disease. No grade 3 or 4 toxicities were reported. All other toxicities were attributable to a syndrome of secondary mineralocorticoid excess and included lower extremity edema, hypokalemia, and hypertension.87 A significant number of patients enrolled in these studies achieved a decline in PSA ≥50% when compared with baseline PSA values. Similarly, the ORR observed in other trials has ranged from 25%-60%.87-89

Recently, the results of COU-AA301, a randomized, double-blind, placebo-controlled phase 3 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-refractory metastatic CRPC were reported.90 Patients (N = 1195) with docetaxel-refractory, metastatic CRPC were randomized in a 2:1 fashion to receive abiraterone acetate 1000 mg/d plus prednisone 5 mg twice a day (n = 797) or placebo/prednisone (n = 398). The median OS for patients treated in the abiraterone/prednisone arm was 14.8 months compared with 10.9 months for the patients in the prednisone/placebo arm (Figure 5; HR, 0.646; P<.0001). The PSA response rate was 38% versus 10% favoring abiraterone acetate (P<.0001). Equally, treatment with abiraterone acetate significantly delayed radiographic PFS (5.6 vs 3.6 months, HR, 0.67; P<.0001). As observed in previous studies, AEs were mainly related to the mineralocorticoid excess syndrome associated with this agent. In this study, 15% of patients in the abiraterone acetate arm developed grade 3 and 4 AEs, including liver dysfunction, hypokalemia, fluid retention, hypertension, and cardiac disorders.

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Figure 5. Overall survival in the COU-AA-301 trial.90

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Recently, abiraterone acetate gained regulatory approval in the United States and is currently considered a standard second-line therapy in men with progressive disease after docetaxel-based chemotherapy. The use of this agent in early settings remains to be defined. COU-AA-302, a study evaluating abiraterone acetate in asymptomatic or mildly symptomatic chemotherapy-naïve metastatic CRPC patients has recently completed accrual, and analysis is underway. Trials evaluating the activity of this adrenal inhibitor in patients without metastatic disease are planned.

Orteronel, also known as TAK-700, is another novel selective inhibitor of 17, 20 lyase that has shown acceptable toxicity and reduced in vivo levels of adrenal androgens with promising clinical activity, as demonstrated in a recently reported phase 1/2 trial in patients with CRPC.91 Similar to other adrenal inhibitors of this type, the most common treatment-related AEs observed included grade 1 fatigue, nausea, constipation, anorexia, and vomiting. Among patients receiving TAK-700 at 300 mg per day for 3 or more consecutive cycles, 80% had a ≥50% decrease in PSA; 27% had a ≥90% decrease. A phase 3 placebo-controlled trial of TAK-700 in combination with prednisone in metastatic docetaxel-refractory CRPC patients is currently underway.

MDV3100 is a small-molecule AR antagonist with a novel mechanism of action that blocks nuclear translocation of AR and DNA binding, and does not have agonist activity when AR is overexpressed. It was identified from a cell-based screen that mimics castration-resistant tumors with overexpressed AR and is active in bicalutamide-resistant prostate cancer models.92 Results of a phase 1/2 trial demonstrated a PSA response of 57% and 45% of chemotherapy-naïve and chemotherapy-refractory metastatic CRPC, respectively. These findings provided a basis for the AFFIRM trial, a randomized, placebo-controlled, phase 3 trial of oral MDV3100 in the docetaxel-refractory CRPC setting. This trial has recently completed accrual, and results are expected shortly. This compound is also undergoing evaluation in the CRPC rising PSA-only disease setting.

Another young yet promising agent is TOK-001. TOK-001 is capable of disrupting several processes responsible for progression in CRPC. It acts as an AR antagonist, a CYP17 lyase inhibitor, and directly leads to decreased AR levels in prostate tumors.93 The ARMOR1 (Androgen Receptor Modulation Optimized for Response) trial is a phase 1/2 study evaluating the safety and MTD of daily treatment with TOK-001 in men with CRPC. The second phase of the trial (ARMOR2) will enroll approximately 40 CRPC patients who will receive 1 of 2 target dosing regimens as identified by the phase 1 results.

Summary and Future Directions

  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES

With antitumor activity demonstrated across a wide mechanistic spectrum including novel hormonal maneuvers (Table 1), immunotherapy, and chemotherapeutics (Table 2), the management of CRPC is currently undergoing significant transformation. Manipulation of the hormonal axis remains the cornerstone of treatment, with novel adrenal androgen inhibitors demonstrating robust antitumor activity. These agents are now being tested in earlier disease stages to hopefully augment existing approaches. Immunotherapy still faces challenges with regard to exact antitumor mechanism, patient selection, and lack of intermediate clinical endpoints to inform clinical decision-making. As a result, a more precise mechanistic understanding of the antitumor effect of immunotherapy is needed to advance this approach. New chemotherapeutic approaches have demonstrated clinical benefit, but with challenges remaining regarding the management of toxicity. As is true across solid tumor oncology, robust predictive biomarkers to select specific patients for specific approaches based on anticipated benefit and/or risk is needed to further build upon the latest wave of therapeutic advances.

Table 1. Novel Hormonal Therapies in Metastatic Castration-Resistant Prostate Cancer Patients With Prior Docetaxel
DrugReferenceStudy Design and Patient GroupKey Efficacy ResultsNotes
  1. CT, chemotherapy; FDA, US Food and Drug Administration; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors.

Abirateronede Bono et al90Phase 3 (COU-AA-301): abiraterone/ prednisone vs placebo/prednisone in CT-resistant mCRPCMedian OS, 14.8 vs 10.9 mo (P<.0001); PSA ≥50%, 38% vs 10% (P<.0001); radiographic PFS, 5.6 vs 3.6 mo (P<.0001)FDA-approved for docetaxel-resistant mCRPC; COU-AA-302 underway, expanded access trial terminated after regulatory approval in the US.
TAK-700Dreicer et al91Phase 1/2: TAK-700 in patients with mCRPCPSA decline ≥50%, 80%; PSA decline ≥90%, 27%Phase 3, placebo-controlled study of TAK-700/prednisone currently underway in docetaxel-refractory mCRPC
MDV3100Scher et al92Phase 1/2: MDV3100 in CT-resistant mCRPCPSA decline ≥50%, 57% in CT-naïve, 45% in CT-refractory; stable disease by RECIST in >80% of patients with measurable disease by 12 wkAccrual completed on placebo-controlled phase 3 trial of oral MDV3100 (AFFIRM) in docetaxel-refractory CRPC
Table 2. Novel Cytotoxics for Metastatic Castration-Resistant Prostate Cancer Patients After Docetaxel
DrugReferenceStudy Design and Patient GroupKey Efficacy ResultsNotes
  1. C/P, cabazitaxel/prednisone; CT, chemotherapy; FDA, US Food and Drug Administration; M/P, mitoxantrone/prednisone; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen.

IxabepiloneHarzstark et al76Phase 2: M/P plus ixabepilone in docetaxel-refractory mCRPC patientsPSA decline ≥50%, 45%; ORR, 22% in patients with measurable disease; median PFS, 4.4 mo; median OS, 12.5 moPhase 3 study evaluating ixabepilone/M/P combination is planned
SatraplatinSternberg et al78Phase 3 (SPARC): satraplatin vs placebo; mCRPC with progression after at least 1 CT regimenPFS, 11.1 vs 9.7 wk (P<.001); OS, 61.3 vs 61.4 wk (P = .80)Not FDA-approved
Cabazitaxelde Bono et al84Phase 3 (TROPIC): C/P vs M/P in docetaxel-refractory mCRPC patientsMedian OS, 15.1 vs 12.7 mo (P<.0001); median PFS, 2.8 vs 1.4 mo (P<.0001); ORR, 14.4% vs 4.4% in patients with measurable disease (P = .0005); PSA decline ≥50%, 39.2% vs 17.8% (P = .0002)Currently FDA-approved for docetaxel-refractory mCRPC

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  1. Top of page
  2. Abstract
  3. Importance of the AR in Castration-Resistant Disease
  4. Additional Hormonal Manipulations in Castration-Resistant Disease
  5. Antiandrogen Withdrawal
  6. Secondary Hormonal Manipulations
  7. Immunotherapy and Prostate Cancer
  8. Chemotherapy for Metastatic CRPC: Historical Development of Front-Line Chemotherapy
  9. Novel Oral Agents in CRPC
  10. Summary and Future Directions
  11. FUNDING SOURCES
  12. REFERENCES
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