Antiandrogens
Abiraterone acetate
This compound, first described in 1995, is an orally-available, highly selective, irreversible inhibitor of the CYP17A enzyme, which is responsible for 17α-hydroxylase and c17,20-lyase activity in steroidogenesis (Figure 1). The inhibition of the CYP17A enzyme results in the suppression of serum androgens derived from adrenal and testicular sources.[16,17] Castration through androgen deprivation therapy (ADT)—namely treatment with leutenizing-hormone releasing hormone (LHRH) agonists and newer antagonists—primarily affects the gonadal, but not the extra-gonadal production of androgens from the adrenal glands and from intratumoral sources. The antifungal ketoconazole(Drug information on ketoconazole) acts through a mechanism similar to abiraterone acetate, however its activity is non-specific and associated with a number of adverse effects, which limits its durability and efficacy.[18-20] Ketoconazole’s antitumor activity in patients with CRPC, however, supports the rationale for pursuing a more targeted, specific agent against the extra-gonadal production of testosterone.
FIGURE 1 Overview of Steroidogenesis in the Adrenal Gland |
The initial phase I trial of abiraterone acetate examined its safety and tolerability in 21 patients. Eligibility criteria included good performance status (Eastern Cooperative Oncology Group performance status 0-1); progressive disease (radiographic enlargement or increasing serum PSA); no prior chemotherapy or radionuclide treatment; and castrate levels of testosterone (< 50 ng/dL). For patients with PSA progression during the study period, investigators allowed for the addition of dexamethasone(Drug information on dexamethasone) as salvage therapy to modulate adrenocorticotropic hormone (ACTH) production. ACTH is up-regulated in response to low levels of cortisol induced by abiraterone acetate.[17] The primary toxicities reported were related to secondary mineralocorticoid excess, presenting as hypertension, hypokalemia and peripheral edema. These were treated with a potassium-sparing aldosterone receptor antagonist or escalation to dexamethasone if needed (occurred in two patients). With a plateau effect noted at doses above 750 mg daily, the recommended phase II dosing was designated as 1000 mg daily. Patients with progression (indicated by rising PSA) were noted to have no increase in androgenic compounds downstream of CYP17, indicating that resistance most likely occurs through some other mechanism.
An early, 54-person phase II study of abiraterone acetate was designed to examine its effect in chemotherapy-naïve CRPC patients.[21] This study’s primary end point was a ≥ 50% reduction in PSA any time after 12 weeks of entering the trial, confirmed four weeks later by a follow-up PSA test. Other secondary end points were also defined, including radiological assessment of soft tissue tumors using Response Evaluation Criteria in Solid Tumors (RECIST) criteria [22] and circulating tumor cell (CTC) counts. Circulating tumor cell counts have previously been shown to correlate to survival.[23,24] Specifically, CRPC patients with an unfavorable CTC level (≥ 5 per 7.5 mL blood) have exhibited decreased overall survival (11.5 versus 21.7 months) compared to those with favorable levels (<5 per 7.5 mL of blood). Furthermore, if a patient transitions from an unfavorable to favorable CTC level with treatment, they assume the good prognosis observed in the favorable CTC group. Given the difficulty of using PSA as a survival surrogate, some researchers have advocated use of CTC counts as a clinical marker instead.
The results of this trial of 54 chemotherapy-naïve CRPC patients treated with abiraterone acetate showed that 28 of 42 of patients (67%) had PSA declines of ≥ 50%.[21] Additionally, nine of 24 patients (38%) with soft tissue masses were found to have partial responses by RECIST criteria, and 10 of 17 patients (59%) went from an unfavorable CTC level at baseline to a favorable CTC level with treatment. Secondary mineralocorticoid excess (presenting as hypokalemia [88%], hypertension [40%], and peripheral edema [31%]) was the primary side effect noted. Three patients required dexamethasone for symptomatic fluid overload. The median time to PSA progression was 229 days.
Interestingly, 39 of these 54 patients eventually received dexamethasone in response to PSA progression (after initial treatment with single-agent abiraterone acetate), and 33% of this group of patients experienced a secondary PSA decline of ≥ 50%. The authors hypothesize that this may be related to upstream steroidal precursors activating androgen receptor (AR), and that the addition of dexamethasone suppresses central ACTH that would otherwise enhance the synthesis of upstream steroidal compounds.
Phase II results from testing abiraterone acetate (1,000 mg daily) with and without prednisone(Drug information on prednisone) (5 mg twice daily) in patients who failed cytotoxic therapy were reported at the beginning of 2010.[25,26] The first study of abiraterone acetate plus prednisone revealed PSA declines of ≥ 50% from baseline in 22 of 58 patients (36%); soft tissue tumor partial responses in 4 of 22 patients (18%) and CTC conversions from unfavorable to favorable counts in 10 of 29 patients (34%). Notably, 47% of patients in this study had received prior ketoconazole therapy, which may confer some resistance and account for the decreased effect reported in this population. The overall median time to PSA progression was 169 days, but when accounting for prior ketoconazole exposure, naïve versus ketoconazole-treated patients had a median time to progression of 198 versus 99 days, although this difference was not significant. Profiles from earlier studies showed similar side effects, and no grade 4 adverse events were seen. The incidences of symptoms from secondary mineralocorticoid excess were reduced with the concomitant use of low-dose prednisone—only 5%, < 5% and < 10% were reported to have hypokalemia, hypertension or edema during the study period, respectively.
The primary and secondary outcomes of the phase II study without prednisone in docetaxel(Drug information on docetaxel)-treated patients (n = 47) were nearly identical, but with 55%, 17% and 15% experiencing hypokalemia, hypertension or edema, suggesting that low-dose corticosteroid should be used in this population to mitigate these side effects.[26] Some debate exists, however, over the use of prednisone in chemotherapy-naïve patients who are otherwise asymptomatic and could potentially be treated with an aldosterone receptor antagonist. Attard et al have suggested that a randomized trial in asymptomatic, pre-docetaxel patients be conducted to compare concomitant use of low-dose corticosteroids with abiraterone acetate to abiraterone acetate alone, with addition of low-dose corticosteroids only when disease progression is identified.[27]
A randomized, multicenter phase III trial of abiraterone acetate plus prednisone against placebo plus prednisone in CRPC patients who failed docetaxel therapy is now completely accrued, though the final results are not yet available.[28] A second phase III trial of abiraterone acetate in metastatic, chemotherapy-naïve, CRPC was also recently fully accrued.[29] Given the suggestion that prior ketoconazole exposure may reduce the efficacy of abiraterone acetate, a dedicated study of this phenomenon was performed and reported in 2010. Results showed that 47% of those with prior ketoconazole treatment versus 64% without prior exposure experienced a PSA decline of ≥ 50%.[30] Further study of the presumed resistance conferred by ketoconazole in patients treated with abiraterone acetate is planned. For now, prior treatment with ketoconazole constitutes one of the exclusion criterion in ongoing phase III studies.
MDV3100
This experimental compound, a non-steroidal, second-generation antiandrogen, has been shown to be a highly potent antagonist of AR, with an affinity for AR that is five times greater than the affinity of bicalutamide(Drug information on bicalutamide) for AR.[31] While other drugs in this class have some measurable agonist activity, MDV3100 is unique in that it exhibits no such activity, reduces nuclear translocation of AR, and blocks binding of the receptor to DNA androgen response elements.[32] Initial characterization of MDV3100 showed a five-fold reduction of nuclear versus cytoplasmic AR concentrations when compared to bicalutamide. Given that the development of CRPC involves cellular changes that include up-regulation of ARs in the setting of LHRH agonist or antagonist therapy, MDV3100 could potentially be used in combination with ADT, taking advantage of their different mechanisms of action in targeting AR. Several studies have demonstrated persistent intratumoral androgen synthesis despite central suppression of the hypothalamus-pituitary-adrenal axis, and the effect of this local production may be effectively blocked by MDV3100.[33,34]
In a phase I-II study of MDV3100 involving 140 men with CRPC (of whom 75 failed taxane-based therapy), a 50% reduction in PSA was noted in 62% of chemotherapy-naïve patients and 51% of post-chemotherapy patients.[35] The median time to PSA progression was 41 weeks for chemotherapy-naïve patients and 21 weeks for patients with prior cytotoxic therapy. Additionally, 22% of patients with measurable disease (13 of 59 patients) responded by RECIST criteria and 56% of bone lesions were stabilized. The most commonly observed adverse event was fatigue (in 12 patients), and seizures were observed in two patients who were at doses of 360 and 600 mg daily. Subsequent doses were reduced to 240 mg daily, and most patients were found to tolerate this regimen.
The effect of MDV3100 on CTCs has also been examined. Of patients in the phase I/II trial with an unfavorable baseline CTC count, 49% converted to favorable counts, including 75% of chemo-naïve and 37% of the post-chemo patients. Additionally, 76% of those with a favorable CTC conversion had a PSA decrease of 50% or more.
MDV3100 is currently being evaluated in a multicenter phase III randomized trial (AFFIRM trial) which is evaluating MDV3100 versus placebo in men with CRPC who failed prior docetaxel therapy with a primary endpoint of overall survival.[36]
Cytotoxics
Cabazitaxel
The development and use of cytotoxic chemotherapy for the treatment of prostate cancer has lagged behind the use of this type of therapy in other common epithelial cancers. In the 1990s, mitoxantrone(Drug information on mitoxantrone) in combination with prednisone was approved for the treatment of advanced prostate cancer, based on improvement in palliative and quality of life measures.[37] In 2004, docetaxel was reported to yield an improvement in survival when compared to mitoxantrone, in men with advanced CRPC.[38] Tannock et al compared docetaxel and prednisone, given every one or every three weeks, to mitoxantrone and prednisone administered every three weeks.[39] This study showed a statistically significant improvement in survival (of approximately three months) with mature follow-up data comparing mitoxantrone to docetaxel given every three weeks.[40] On this basis, docetaxel chemotherapy has become the standard first-line chemotherapy treatment for advanced CRPC.
Since the approval of docetaxel, there has been no clear standard of care in the second-line chemotherapy setting. Mitoxantrone has been used, but its activity after docetaxel progression is modest.[41] Cabazitaxel (Jevtana), a microtubule inhibitor with a mechanism of action that is similar to docetaxel, was approved by the FDA in June of 2010 for the treatment of metastatic CRPC after the use of docetaxel chemotherapy.[42] In a recently reported, randomized, phase III trial, cabazitaxel given every three weeks with prednisone improved the median overall survival by 2.4 months (15.1 versus 12.7 months), when compared to mitoxantrone and prednisone.[43] Overall, this therapy was well tolerated, with a median of six cycles of cabazitaxel versus four cycles of mitoxantrone administered to study participants, respectively. Notably, bone marrow suppression was observed in those treated with cabazitaxel, with a 7.5% incidence of febrile neutropenia versus 1.3% in the mitoxantrone arm. Based on its mechanism of action on the microtubules, special attention was paid to cumulative neurotoxicity, but this was not commonly observed as a severe (grade 3-4) adverse event, despite previous docetaxel treatment in all of these patients. In summary, cabazitaxel is now established as a standard of care treatment for prostate cancer patients fit for second-line treatment after docetaxel chemotherapy. The main serious toxicity is bone marrow suppression, which may be minimized by granulocyte-colony stimulating factor (G-CSF) support.
Future Directions
We have presented five newly
Conclusion
For many years, the only treatment that showed a true survival advantage for CRPC was docetaxel chemotherapy. However, as we have described here, sipuleucel-T and cabazitaxel have been approved by the FDA and offer an improvement in overall survival when used in this setting. Several other agents, including abiraterone acetate, MDV3100, and denosumab are in the late stages of clinical development for men with CRPC, and these new treatments represent a dramatic period of therapeutic advancement in the field of urologic oncology, and promise a much-improved therapeutic armamentarium for the treatment of CRPC.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
