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Update on Castration-resistant Prostate Cancer: A Review of Systemic Innovations

TOP - May 2010 Vol 3, No 3 published on June 9, 2010

Approximately 192,000 men developed prostate cancer in 2009 and 27,000 died from the disease.1 Prostate cancer is the most frequently diagnosed cancer in North America and the second most common cause of cancer death in men. Although the number of new cases of prostate cancer has increased in the past decade, the absolute number of deaths has slowly declined.1 As the incidence of prostate cancer increases, controversies continue about the best possible methods for screening, detection, and treatment.

The optimal management of prostate cancer is dependent on patient age, overall health, and tumor risk assessment. Just as the history of prostate cancer ranges from an incidental finding to widespread metastatic disease, management varies widely. Localized prostate cancer is treated with radical prostatectomy, external-beam radiation therapy, brachytherapy, or observation alone. Treatment of locally advanced disease involves a multimodality approach, including radiation, androgen ablation, and possible androgen-deprivation therapy.2

Unfortunately, even after initial successful treatment of localized prostate cancer, recurrence is common, with approximately 10% to 50% of men progressing to advanced or metastatic disease.3 Prostate cancer is an androgendependent malignant disease, and androgen-deprivation therapy is commonly used following local therapy (Figure). One method to suppress androgen levels is to reduce circulating androgens by surgical or chemical castration with the use of luteinizing hormonereleasing hormone agonists. Unfortunately, although castration removes the gonadal testosterone source, androgens from other sources many continue to act as ligands and result in androgenreceptor signaling. Androgen-mediated effects on prostate cancer cells may also be blocked with androgen-receptor antagonists or a combination of therapies. An increasing prostate-specific antigen (PSA) level after definitive local therapy is termed recurrence. Most patients will experience progression within a median of 12 to 20 months4 and will eventually develop androgenindependent prostate cancer.

Androgen-independent prostate cancer is also known as hormone-resistant prostate cancer, hormone-refractory prostate cancer, and more recently referred to as castration-resistant prostate cancer (CRPC). Therapies for patients who develop CRPC include withdrawal of the androgen-receptor antagonist, secondary hormonal therapy, and chemotherapy. Hormone-refractory prostate cancer arises when disease progression continues despite antiandrogen withdrawal. CRPC represents a spectrum of disease ranging from asymptomatic patients to those with metastasis or debilitating cancer symptoms.

Current therapies for CRPC

Mitoxantrone, an anthracenedione, has been studied in patients with metastatic CRPC. Three randomized controlled trials compared mito xantrone and low-dose corticosteroids with the same corticosteroid alone.5-7 All three randomized controlled trials have reported overall survival (OS) results but none detected an improvement due to mitoxantrone. In addition to examining survival, the two trials by Tannock and associates assessed pain and quality of life through self-reported questionnaires.7,8 In these early trials, objective response rates were low, and median survival did not exceed 12 months. Mitoxantrone was approved in 1996 by the US Food and Drug Administration (FDA) based on the finding of symptomatic improvement in a large randomized, phase 3 trial.8 It was almost a decade later when newer regimens, particularly those including taxanes, were shown to improve objective tumor response and increase survival.

Docetaxel was approved by the FDA in 2004 for advanced prostate cancer following the results of the TAX 327 trial.7 In this trial, 1006 men were randomized to docetaxel plus prednisone or mitoxantrone plus prednisone. Median survival of all patients treated with docetaxel was 18.2 months compared with 16.5 months for those treated with mitoxantrone. Following this trial, Southwest Oncology Group (SWOG) 9916 compared docetaxel and estramustine with mitoxantrone and prednisone. The docetaxel arm was favored, with a median OS of 17.5 months compared with 15.6 months for mitoxantrone.5

Hormone manipulations, systemic chemotherapy, palliation of bone pain with bisphosphonates, and externalbeam irradiation are included in the treatment of CRPC. In addition to the chemotherapeutic agents discussed, vinblastine, vinorelbine, paclitaxel, cyclophosphamide, 5-fluorouracil, carboplatin, and prednisone have been studied extensively. Unfortunately, the results of many of the trials with conventional cytotoxic agents were disappointing, leaving an apparent need to identify novel agents and drug targets that not only improve quality of life, but also prolong survival. This review will focus on newly approved and investigational agents in CRPC.

New therapy

Sipuleucel-T (Provenge). Sipuleucel- T, a novel cellular immunotherapy, was FDA-approved for the treatment of metastatic CRPC on April 29, 2010. Given the possibility that there are many active targets in prostate cancer (including PSA and prostatic acid phosphatase [PAP]), biologic targeted therapies make sense in this disease state.9 Sipuleucel-T is derived from autologous peripheral blood cells that are collected during leukapheresis.10 After removing erythrocytes, granulocytes, platelets, and lymphocytes, the remaining product consists of dendrites, T-cells, monocytes, and natural killer cells. The cellular product con-sisting of a patient’s antigen-presenting cells is processed and cultured ex vivo with a recombinant fusion protein containing PAP. A phase 3 randomized, placebo-controlled trial evaluated the safety and efficacy of sipuleucel-T for metastatic, asymptomatic CRPC (D9901).11 One hundred twenty-seven men with a progressive PSA level and an Eastern Cooperative Oncology Group performance score of zero or one were enrolled. Patients were randomized to receive a single sipuleucel-T infusion on weeks 1, 2, and 4 or placebo infusions given on the same schedule. Patients in the placebo group were allowed to receive salvage treatment with sipuleucel-T if disease progression occurred after week 8 of therapy. The primary outcome was time to progression (TTP). A difference for median TTP was not detected when comparing the treatment arm with placebo; however, patients in the treatment arm had improved OS of approximately 4.5 months compared with the placebo (P = .01). At a 36- month follow-up, 34% of patients receiving sipuleucel-T were alive compared with 11% of patients re ceiving placebo (P = .0046). Sipuleucel-T was well tolerated, the most common adverse events reported being fever and chills lasting for 1 to 2 days. This trial had several limitations, including the small number of patients and the use of TTP as a primary outcome.

A second phase 3 trial (D9902)10 was terminated early when the results from D9901 were published demonstrating a lack of improvement with sipuleucel-T. Following termination, 98 men en - rolled in D9902 and were followed for further safety and efficacy data. The investigators revised secondary end points for D9902 to include OS and renamed the trial D9902A. Again, no difference was detected in TTP or OS in the 98 subjects.10

Approval was based on a third trial of more than 500 patients, Identification of Men with a Genetic Predisposition to Prost Ate Cancer: Targeted Screening in BRCA1 and BRCA2 Mutation Carriers and Controls (IMPACT), or D9902B.12 In this multicenter, randomized, doubleblind, placebo-controlled study, sipuleucel- T extended median survival by 4.1 months and improved 3-year survival by 38%. As reported at the 2009 American Urological Association annual meeting, sipuleucel-T successfully met the prespecified statistical significance defined by the protocol and reduced the overall risk of death by 22.5% compared with placebo (P = .032).12 Overall, sipuleucel-T appears to be well tolerated, with most adverse events of grade 1 or 2 severity resolving within 48 hours10-12 (Table 1). No difference in significant serious adverse events has been reported for patients treated with sipuleucel-T compared with placebo. Various administration frequencies were examined throughout the phase 1, 2, and 3 trials. Most recently, a biweekly dosing interval has been used to avert delays in therapies at weeks 0, 2, and 4 following standard leukapheresis. Although the primary end point of TTP has not been met in the studies discussed, final results are pending from the ongoing phase 2 Treatment of Prostate Cancer with Active Cellular Immun otherapy (ProACT) trial.10

Investigational systemic therapies

Atrasentan (ABT-627 or Xinlay). Endothelins have been implicated in numerous physiologic and pathologicconditions, including cancer.13 Evidence suggests that endothelin-1, a small vasoconstrictor peptide, is produced by several tumor cell lines. Endothelin-1 levels are increased in prostate cancer and modulate mitogenesis and apoptosis on binding to the endothelin-A (ETA) receptor. Multiple in vivo models have examined the role of endothelin antagonism in tumorigenesis. Atrasentan, an orally bioavailable investigational agent, is a selective ETA receptor antagonist that exhibits low-level inhibition of the endothelin-B (ETB) receptor in addition to inhibition of the ETA receptor.14 Xenograft studies conducted with atras - entan in combination with paclitaxel demonstrated a significant reduction in tumor growth compared with monotherapy alone.15 Following additional phase 1 and 2 trials, multiple phase 3 trials have focused on the efficacy of atrasentan in CRPC (Table 2).

Beginning in June 2001, a multinational, phase 3, randomized, controlled, double-blind study was conducted in patients with metastatic CRPC.16 Eighthundred nine patients were randomized to receive atrasentan 10 mg by mouth daily (n = 408) or placebo (n = 401). The primary end point was time to disease progression, defined by the first occurrence to a radiographic or clinical event, including bone lesion and metastatic pain. Atrasentan did not reduce the risk of disease progression (P = .136) compared with placebo; however, increases from baseline in bone alkaline phosphatase and PSA were significantly lower with atrasentan treatment.16 Given the relative success in patients with metastatic cancer, a follow-up phase 3, randomized controlled trial was conducted in patients with nonmetastatic CRPC. Patients who had adequate androgen suppression and no radiographic evidence of metastases were randomized to receive atrasentan 10 mg daily or placebo. Secondary end points included time to PSA progression and OS. A 3-month delay in the median TTP was demonstrated with atrasentan compared with placebo (P = .288). Although there was no difference in the median OS, atrasentan lengthened the PSA doubling time and slowed the increase in bone alkaline phosphatase (P <.01).16-18

Phase 1 and 2 trials with atrasentan have demonstrated safety and tolerability with mild side effects, including edema, rhinitis, and headache17,18 (Table 1). To date, phase 3 trials of atrasentan as monotherapy have not established significant changes in disease progression but have demonstrated changes in objective markers including PSA. The phase 3 SWOG S0421 trial continues toinvestigate docetaxel plus atrasentan compared with docetaxel alone.19

Zibotentan (ZD4054). Zibotentan, another endothelin receptor antagonist, is being investigated in CRPC.20 Zibotentan is an orally bioavailable inhibitor of the ETA receptor. Pre - clinical mouse models demonstrated high affinity for the ETA receptor without measurable activity on the ETB receptor. A multicenter, open-label, phase 1 study begun in June 2003 was conducted to determine the safety and tolerability of zibotentan in patients with metastatic CRPC.20 Sixteen patients were enrolled and treated with escalating doses of oral zibotentan starting at 10 mg once daily. The primary outcome, maximum tolerated dose, was determined to be 15 mg, and secondary end points, including disease assessment, revealed stable disease in nine of the 16 patients. Following the completion of the phase 1 trial, a phase 2 randomized, double-blind, placebo-controlled trial was conducted in patients with CRPC and bone metastasis.21 A total of 312 patients were randomized ina 1:1:1 design to receive zibotentan 10 mg, zibotentan 15 mg, or placebo. The primary end point was progression-free survival (PFS) with secondary end points including OS, time to PSA progression, and safety. Preliminary analyses did not reveal a difference in PFS between the control and placebo arms; however, a median OS of 24.5 months was found in the 10-mg zibotentan arm and 23.5 months in the 15-mg zibotentan arm, compared with 17.3 months in the placebo arm (P = .008). The early results of the phase 2 trials suggest that zibotentan may provide clinical efficacy in prostate cancer. Phase 3 trials are currently being performed to further investigate the efficacy of zibotentan in CRPC. The Endothelin A Antagonist in Hormone Resistant Prostate Cancer with Bone Metastases (ENTHUSE M1) trial is randomizing chemotherapy-naïve CRPC patients to receive zibotentan 10 mg daily or placebo with best supportive care.22 The primary end point in this study is OS with an estimated accrual of 1000 patients. Other phase 3 trials are addressing combination therapies with docetaxel to determine potential additive or synergistic effects of zibotentan and chemotherapy (Table 2).

Abiraterone acetate (CB7630). Abira - terone acetate is an orally available, selective and irreversible inhibitor of cytochrome P17, a key enzyme in the generation of androgens and estrogens by the adrenal gland and tumor tissue.23 In 2004, the first human studies reported successful suppression of testosterone levels in noncastrated patients given a 12- day regimen of daily abiraterone acetate. Suppression of testosterone was not sustained, however, because of effects of luteinizing hormone.24 Therefore, further investigations with this agent required concomitant castration.

Attard and colleagues25 reported a phase 1 trial with abiraterone acetate in chemotherapy-naïve men with CRPC. This dose-escalating trial investigated doses ranging from 250 mg to 2000 mg daily. Although no dose-limiting toxicity was found, a plateau effect was identified for the endocrine effects of abiraterone acetate in doses exceeding 750 mg. In addition to endocrine levels, a decline in PSA 50% occurred after 1 month of continuous therapy and was maintained for 3 months in 57% of patients. A target dose of 1000 mg daily was identified for abiraterone acetate and was further investigated in a phase 2 trial.

During the phase 2 clinical trial, the chemotherapy-naïve CRPC patients were given abiraterone acetate 1000 mg daily to evaluate the possibility of a durable response to treatment in a larger cohort of patients.26 Forty-two patients were included in the efficacy analysis. Of these 42 patients, 67% met the primary end point of a decline in PSA 50% after 12 weeks of abiraterone acetate treatment confirmed by an additional PSA test 4 weeks later. PSA declines of 90% were observed in 19% of patients. Median time to PSA progression on abiraterone acetate alone for all phase 2 patients was 225 days (95% confidence interval, 162-287 days). Thirty-seven percent of patients with measurable disease attained a partial response by independent radiologic evaluation. For patients who had disease progression, an a priori addition of daily dexamethasone of 0.5 mg was allowed. Tumor response was 33% in patients who received dexamethasone in addition to abiraterone acetate at disease progression.26

These early clinical trials demonstrated good tolerability in addition to tumor response. There were no treatment- related grade 3 or 4 toxicities during the phase 1 trial and limited toxicities in the phase 2 trial. However, abiraterone acetate treatment causes impairment of androgen biosynthesis and increased production of deoxycorticosterone and corticosterone, resulting in secondary mineralocorticoid syndrome (Table 1). In the phase 1 trial by Attard and colleagues, the incidence of hypertension appeared to be similar across all doses with a rate of 33%; this estimate may not be accurate, however, given the limited number of patients in the phase 1 trial.

According to phase 1 and 2 clinical trial data, abiraterone acetate has been shown to be safe and moderately effective in CRPC. Several phase 3 studies are currently under way and will provide further information concerning this agent’s potential future role in prostate cancer care. MDV3100. Drug resistance in CRPC is thought to be due to increased androgen receptors. Current antiandrogens have agonistlike properties when an - dro gen receptors are overexpressed.

MDV3100 is a second-generation anti - androgen that attempts to overcome this resistance (Figure).27 Built on the structure backbone of a nonsteroidal thiohydantoin agonist, MDV3100 was selected from a panel of about 200 derivatives for its high affinity and selectivity for androgen receptors.28

In preclinical studies, MDV3100 demonstrated a five-time to eight-time greater affinity for androgen receptors, and was only two to three times less selective than native dihydrotestosterone. It showed androgen-receptor antagonism in cells engineered to express in creased numbers of androgen receptors and increased activity in mouse models of CRPC when compared with bicalutamide. The in vitro and in vivo activity, combined with optimal pharmacokinetic and structure activity relationship properties, resulted in MDV3100 moving from preclinical testing into human trials.28

At the 2009 annual meeting of the American Society of Clinical On cology, data from phase 1 and 2 trials of MDV3100 were presented. After a safe dose was determined in the phase 1 portion with 114 patients, the phase 2 portion enrolled patients into one of two groups: one consisting of chemo therapynaïve patients (n = 65), the other consisting of postchemotherapy patients (n = 49). The investigators followed PSA, circulating tumor cells (CTCs), tumor response time, and time on treatment in a total of 140 patients. At the 600-mg daily dose, two of three patients experienced dose-limiting toxicities of rash and seizure (Table 1). At the next two lower doses (480 mg/day and 360 mg/day), fatigue was a problem, and thus the dose was reduced to 240 mg daily, which was determined to be the optimal dose. A dose-responsive decline in PSA was noted, with 58% of patients responding at the 240-mg and 360-mg doses compared with only 32% of patient at the 60- mg and 150-mg doses. At 12 weeks, a PSA decline of greater than 50% was noted in 57% of the chemotherapynaïve patients and 45% of the postchemotherapy patients. No progression was seen on radiograph in 74% of patients with mea surable disease in the soft tissue or in 62% of patients with bone lesions. Ninety-two percent of patients with CTC in the favorable range (defined as less than five cells) maintained the response over time. The authors concluded that MDV3100 was a promising compound and that the 240- mg/day dose should be developed further.29 A phase 3 trial evaluating MDV3100 versus placebo in docetaxelresistant metastatic prostate cancer is under way.30

In a phase 3 study presented at the 2010 Genitourinary Cancers Symposium, the second-generation taxane cabazitaxel combined with prednisone significantly improved OS by 30% in men with metastatic CRPC who progressed after treatment with a docetaxel-containing regimen.31 Median OS was 15.1 months in men who received cabazitaxel plus prednisone compared with 12.7 months in those who received mitoxantrone with predisone. PFS was also significantly greater in the cabazitaxel group (2.8 vs 1.4 months).

Discussion

Long-term survival after the diagnosis of prostate cancer is dependent on age at diagnosis, comorbid illnesses, stage, and grade of disease. With an increase in awareness and screenings, more men are being diagnosed at earlier stages; however, given the slow progression of the disease most patients present with advanced or metastatic disease. In patients with localized or locally ad vanced disease, adjuvant hormonal therapy is used to decrease androgens and eradicate residual disease. Initially, prostate cancer patients have effective responses with surgical or medical castration; however, up to half of these men will relapse, and nearly all relapsed patients will progress to CRPC.

Systemic therapy has become an important component for the treatment of CRPC, but even chemotherapy agents have little success in extending survival. Important innovations including therapies targeting both signal transduction and hormonal manipulation have been studied. Sipuleucel- T, a novel immunotherapy made by combining autologous dendritic cells with a recombinant fusion protein, has demonstrated survival advantage in the pivotal phase 3 IMPACT trial. In addition, atrasentan and zibotentan are two investigational agents that target endothelin receptors. Atrasentan has been extensively studied, and recently two randomized, placebo-controlled, phase 3 trials have been reported in the CRPC setting. Atra sentan did not affect time to disease progression compared with placebo, despite evidence of biologic effects on PSA and bone alkaline phosphatase. In contrast, zibotentan, which potentially is more selective, was shown in a double-blind, phase 2 trial, to produce a significant improvement in OS compared with placebo. Finally, the more recent agents, abiraterone and MDV3100, have been described as “super androgen in hibitors” by reducing androgen production in the testis, adrenals, and prostate. Abiraterone acetate, an enzyme in hibitor, has shown early successin phase 1 and 2 trials in reducing PSA levels and decreasing tumor size. MDV3100, an oral antiandrogen, has demonstrated androgen suppression in preclinical studies as well as the ability to induce cell death in bicalutamideresistant tumors. Phase 1 and 2 trials have found that MDV3100 can reduce PSA levels and decrease CTC.

Conclusion

Sipuleucel-T offers a new treatment option for men with metastatic CRPC. In addition, a number of different agents are currently being investigated in this disease. Therapies that work through enzyme inhibition, receptor blockade, and even immunogenetic stimulation can manipulate the growth and progression of prostate tumors. Research efforts are ongoing, and it is hoped that publication of results of current trials will provide additional data to support the use of these agents in improving outcomes and survival for patients with CRPC. !

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Last modified: July 22, 2021