Abiraterone and newer antiandrogen compounds for castrate resistant metastatic prostate cancer
INTRODUCTION — Androgen deprivation therapy (ADT) is generally the initial treatment for men with metastatic prostate cancer. Standard approaches include bilateral orchiectomy or medical orchiectomy using a gonadotropin releasing hormone (GnRH) agonist either alone or in combination with an antiandrogen (complete androgen blockade). (See "Initial hormone therapy for metastatic prostate cancer".)
Despite initial response rates of 80 to 90 percent, nearly all men eventually develop progressive disease; this is referred to as castrate-resistant prostate cancer. However, men who progress after initial hormone ablation often have meaningful responses to further hormonal manipulations. The role of various options for secondary hormone therapy after failure of initial ADT is discussed separately. (See "Second-line hormone therapy for metastatic prostate cancer".)
Taxane-based chemotherapy results in an improvement in survival and dramatic reductions in tumor burden in many patients with castrate-resistant prostate cancer. However, taxane-based chemotherapy is not effective in all patients, and patients eventually develop resistant chemotherapy-disease. Furthermore, many men with castrate-resistant prostate cancer are not candidates for cytotoxic chemotherapy due to comorbidity or advanced age, and many patients refuse chemotherapy. (See "Chemotherapy in castrate-resistant prostate cancer".)
An improved understanding of the biology of castrate-resistant prostate cancer is leading to new approaches that are clinically useful both in patients who have progressed while on taxane-based chemotherapy and those who are not candidates for chemotherapy. The biological rationale and clinical results with these approaches are discussed in this topic. An overview of other aspects of the management of advanced prostate cancer is presented separately. (See "Overview of treatment for advanced prostate cancer".)
RATIONALE/MOLECULAR PATHWAYS — Recent advances have demonstrated that androgen-based pathways continue to have a clinically significant role in the progression of castrate-resistant prostate cancer. In addition to androgen production by the adrenal gland and testis, several of the enzymes involved in the synthesis of testosterone and dihydrotestosterone, including cytochrome P450 17 alpha-hydroxysteroid dehydrogenase (CYP17), are highly expressed in tumor tissue [1].
Collectively, these findings change the perspective on prostate cancer from what has long been considered an “endocrine” disease to one that is dependent on “autocrine/paracrine” signaling for tumor progression and survival. This understanding has led to the development of drugs that act by inhibition of the enzymes responsible for androgen production, as well as agents that inhibit the androgen receptor.
Androgen synthesis inhibitors — Abiraterone was developed through screening chemical derivatives of a parent structure of pregnenolone. The structural changes in abiraterone account for potent and irreversible inhibition of CYP17 [2-4]. In preclinical studies, abiraterone was ten times more potent than ketoconazole as an inhibitor of CYP17 [4]. (See 'Abiraterone' below.)
In contrast to abiraterone, ketoconazole is a potent inhibitor of the side chain cleavage enzyme, which plays a critical role in adrenal steroidogenesis. Thus patients treated with these agents are at risk for adrenal insufficiency and require steroid replacement therapy. The use of ketoconazole is further limited by the potential for drug-drug interactions, particularly with statins and anti-depressants. (See "Second-line hormone therapy for metastatic prostate cancer", section on 'Ketoconazole'.)
Androgen receptor antagonists — Some metastatic and primary prostate tumors retain activation of the androgen receptor in processes that are entirely independent of the androgen ligand. Several mechanisms, including up-regulation of androgen receptor expression through amplification of the androgen receptor gene [5-7], increased sensitivity of androgen receptor via overexpression of nuclear coactivators [8], and splice variant mutations of the receptor [9,10], have been proposed and may coexist. Importantly, these data suggest that progression of castrate-resistant prostate cancer in some patients may not be effectively treated by a focus solely on ligand-directed therapy.
Small molecule antagonists of the androgen receptor, such as MDV3100, are being developed and have demonstrated promising clinical activity. (See 'MDV3100: Androgen receptor inhibition' below.)
ABIRATERONE — Abiraterone is an orally administered small molecule that irreversibly inhibits the products of the CYP17 gene (including both 17,20-lyase and 17-alpha-hydroxylase). In doing so, abiraterone blocks the synthesis of androgens in the tumor as well as in the testis and adrenal glands.
Efficacy — The activity of abiraterone was established in a phase III trial, in which 1195 men who had previously been treated with a docetaxel-containing chemotherapy regimen were randomly assigned in a 2:1 ratio to abiraterone (1000 mg/day) plus prednisone (5 mg twice a day) or placebo plus prednisone on the same schedule [11].
Treatment was continued until disease progression (based upon serum PSA, imaging findings, or clinical findings) or death. Disease progression was determined by a composite of worsening pain and decline in performance status, as well as objective progression on scans and by PSA rises. A rise in PSA on therapy (or a lack of decline) was not the sole criterion for discontinuation of therapy.
The trial was terminated based upon an interim analysis when results exceeded prespecified criteria. After a median follow-up of 13 months, treatment with abiraterone significantly increased overall survival, the primary endpoint of the trial, compared to placebo (median 14.8 versus 10.9 months, hazard ratio [HR] 0.65, 95% CI 0.54-0.77). Benefits were similar in all subsets based upon preplanned analyses. Statistically significant improvements were also seen in time to PSA progression, progression-free survival, and PSA response (10.2 versus 6.6 months, 5.6 versus 3.6 months, and 29 versus 6 percent, respectively).
Secondary analyses from the phase III trial focused on the impact of abiraterone on symptoms due to bone metastases. Preliminary results were presented at the 2011 American Society of Clinical Oncology (ASCO) meeting [12]:
- Overall approximately 90 percent of patients had bone metastases, and 44 percent of all patients had clinically significant pain secondary to these metastases.
- There was a statistically significant improvement in palliation of pain due to bone metastases in patients treated with abiraterone plus prednisone compared with placebo plus prednisone. This included clinically meaningful pain palliation for at least two cycles (44 versus 27 percent), median duration of improvement (10.3 versus 5.6 months) and median time to progression in pain intensity (7.4 versus 4.7 months).
- There was a statistically significant increase in the time to first skeletal-related event, defined as pathologic fracture, spinal cord compression, or palliative radiation therapy or surgery (median 301 versus 150 days).
Increased isotope uptake on bone scan suggestive of progressive disease should be interpreted with caution when patients are started on therapy with abiraterone. In a phase II study, follow-up bone scans obtained three months after treatment initiation were interpreted as worsening in 12 of 23 patients (52 percent) with a decrease in serum PSA of 50 percent or more [13]. In 11 of these 12, subsequent bone scans showed improvement or stabilization of bone disease.
Toxicity — The toxicity profile of abiraterone is dependent upon its mechanism of action. CYP17, the target of abiraterone, regulates the conversion of pregnenolone and related steroids into androgens and is relatively specific for androgen production. However, there is a compensatory rise in ACTH, which is mediated by a hypothalamic response to partial adrenal inhibition.
The increased ACTH release can cause increased adrenal mineralocorticoid production, which can lead to hypertension and hypokalemia. When abiraterone is given without concomitant glucocorticoids, patients typically do not experience clinical adrenal insufficiency since cortisol production is preserved. The effects of mineralocorticoid excess can be attenuated by coadministration with prednisone, which reduces ACTH mediated stimulation.
In the phase III trial, the incidence of severe (grade 3 or 4) adverse events leading to discontinuation of treatment was similar in those treated with abiraterone and placebo (10 and 13 percent, respectively) [11]. Side effects that were more common with abiraterone included fluid retention and hypokalemia (31 versus 22 percent and 17 versus 8 percent, respectively). Non-specific cardiac abnormalities and transaminase elevation may also be more common in patients treated with abiraterone, although the extent of this effect is not fully known.
Abiraterone should be administered with 10 mg of prednisone daily, although the safety of lower doses of prednisone during long term therapy is under investigation. Monthly potassium and blood pressure monitoring are essential to the proper management of patients on abiraterone. Because the hypertension is mediated by an excess of mineralocorticoids, specific mineralocorticoid antagonists, such as eplerenone, may be useful; however, standard anti-hypertensive therapies are also of benefit.
Response assessment with CTCs — PSA-producing cells can be detected in the systemic circulation of men with prostate cancer using the reverse transcriptase polymerase chain reaction (RT-PCR) for PSA mRNA [14,15]. The impact of CTCs on prognosis was prospectively assessed in the phase III trial comparing abiraterone plus prednisone with placebo plus prednisone in men with castration-resistant metastatic prostate cancer who had progressed on docetaxel chemotherapy [16]. (See 'Efficacy' above.)
CTCs were measured in 972 of 1195 patients either at baseline or on day 1 of cycle 1 and serially thereafter. Median overall survival was significantly longer in those with CTCs <5 compared with those with CTCs ≥5 (22.1 versus 10.9 months in those assigned to abiraterone and 19.7 versus 8.2 months in those assigned to placebo). Among patients with a CTCs ≥5 at baseline, significantly more patients treated with abiraterone had a decrease in CTC level to <5 compared with placebo (48 versus 17 percent at 12 weeks).
Additional studies are underway to confirm these findings and to combine the CTC level with other parameters in a biomarker panel. These studies do not prove the value of CTCs in an individual patient, the use of this for patient management remains controversial.
The assay system for CellSearch assay CTCs is commercially available for use in patients with castrate-resistant prostate cancer. The significance of circulating prostate cancer cells in men at the time of their initial diagnosis is discussed elsewhere. (See "Early stage prostate cancer: Predicting the pathologic extent of disease and clinical outcome".)
Ongoing clinical trials — The survival benefit in patients who had received prior docetaxel-based chemotherapy was the basis for the regulatory approval of abiraterone [11]. However, abiraterone may also have a role in patients who have not had prior treatment with cytotoxic chemotherapy.
A phase II study in chemotherapy-naïve patients observed that 67 percent of patients experience a ≥50 percent decline in serum PSA [13]. With a median follow-up of 16 months, the median progression-free survival (based upon PSA criteria) was 63 weeks. Similar results were seen in chemotherapy-naïve patients enrolled in phase I studies [17-19]. A phase III trial is being conducted in which men with asymptomatic or minimally symptomatic castration-resistant prostate cancer are randomly assigned to abiraterone or placebo (NCT00887198) [20]. Patients who received prior chemotherapy or ketoconazole are excluded from this trial. This trial has completed enrollment and results are pending. The primary endpoints of this trial are overall and progression-free survival.
Clinical role — Currently, there are multiple approved treatment options for patients with castrate-resistant prostate cancer; these include sipuleucel-T, docetaxel, and cabazitaxel, in addition to abiraterone. (See "Immunotherapy for metastatic prostate cancer", section on 'Sipuleucel-T' and "Chemotherapy in castrate-resistant prostate cancer", section on 'Taxanes'.)
Both cabazitaxel and abiraterone are approved specifically for use in patients who have had prior docetaxel chemotherapy. There are no clinical trials defining the optimal sequencing of these agents. Theoretically, treatment with abiraterone after docetaxel but before cabazitaxel may allow patients to avoid the toxicity associated with continuous exposure to taxane chemotherapy and possibly delay the emergence of taxane-resistant disease. Conversely, using cabazitaxel prior to abiraterone may prolong sensitivity to taxanes. Other patient-specific factors, including age and comorbidities, may also influence the choice of treatment.
EXPERIMENTAL AGENTS
Other androgen synthesis inhibitors — Other agents that inhibit CYP 17 are in clinical trials. The most advanced of these is orteronel (TAK-700), which is currently being compared with placebo in two multicenter, phase III trials. These trials are being conducted in chemotherapy-naïve patients (NCT0193244) and in those who have progressed on docetaxel (NCT01193257) [20].
MDV3100: Androgen receptor inhibition — MDV3100 is being developed as a specific inhibitor of the androgen receptor; the drug has no known effect on androgen production. In preclinical results, MDV3100 exerts anti-proliferative activity on prostate cancer cells that harbor amplification of the androgen receptor. Thus the clinical spectrum of this agent may be independent of that of abiraterone [21-23].
In a phase I/II study, 140 men with progressive castration-resistant prostate cancer were treated with MDV3100 [21]. All had progressed on at least one prior hormonal therapy, and 75 (54 percent) had received prior chemotherapy. Bone disease was present in 78 percent, and 66 percent had soft tissue disease. Only seven patients (5 percent) had a rising PSA only. In chemotherapy-naïve patients, 40 of 65 patients (62 percent) had a ≥50 percent decrease in serum PSA, while 38 of 75 (51 percent) of those previously treated with chemotherapy responded.
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Based upon these results, two phase III trials are comparing MDV 3100 with placebo:
- In the AFFIRM trial, 1199 men with castrate-resistant prostate cancer who had received prior docetaxel-based chemotherapy were randomly assigned to either MDV3100 (160 mg per day) or placebo (NCT00974311) [24]. Results of the trial, based upon a planned interim analysis after 520 deaths, were presented at the 2012 Genitourinary Cancers Symposium. Overall survival, the primary endpoint of the trial, was significantly increased in patients assigned to MDV3100 (median 18.4 versus 13.6 months, hazard ratio 0.63).
- In the PREVAIL trial, asymptomatic or minimally symptomatic men with metastatic prostate cancer who are chemotherapy naive are being randomly assigned to MDV3100 or placebo (NCT01212991).
SUMMARY AND RECOMMENDATIONS
- Androgen deprivation therapy (ADT) is generally the initial treatment for men with metastatic prostate cancer. Standard approaches include bilateral orchiectomy or medical treatment with a gonadotropin releasing hormone (GnRH) agonist. Despite high response rates to ADT, nearly all men eventually develop progressive castrate-resistant disease. In this setting, multiple options are available, including secondary hormonal manipulations, cytotoxic chemotherapy, and immunotherapy, as well as newer therapy directed at the androgen mediated pathway within the tumor. (See "Overview of treatment for advanced prostate cancer".)
- Androgen-based pathways continue to have a clinically significant role in the progression of castrate-resistant prostate cancer. In addition to androgen production by the adrenal gland, several of the enzymes responsible for the subsequent conversion of these hormones to testosterone and dihydrotestosterone, including cytochrome P450 17 alpha-hydroxysteroid dehydrogenase (CYP17), are highly expressed in tumor tissue. Abiraterone irreversibly inhibits the products of the Cyp17 gene. (See 'Rationale/molecular pathways' above.)
- Abiraterone plus prednisone significantly improved overall survival compared with placebo plus prednisone in the randomized phase III trial. Treatment with abiraterone significantly improved symptoms due to bone metastases, which were present in approximately 90 percent of the study population. Cabazitaxel plus prednisone also significantly improved overall survival, but there are no randomized clinical trials comparing these two agents. (See 'Efficacy' above and "Chemotherapy in castrate-resistant prostate cancer", section on 'Cabazitaxel'.)
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