Urologic Oncology: Seminars and Original Investigations 33 (2015) 289–294
Seminar article
The development of abiraterone acetate for castration-resistant prostate cancer Emily Grist, M.B.B.S., M.R.C.P.a,b, Gerhardt Attard, M.D., Ph.D., M.R.C.P.a,b,* a
b
The Institute of Cancer Research, London, UK Royal Marsden NHS Foundation Trust, London, UK
Received 15 December 2014; received in revised form 27 March 2015; accepted 29 March 2015
Abstract Abiraterone acetate is a novel CYP17A1 inhibitor demonstrated to prolong survival in castration-resistant prostate cancer (CRPC). This review explores key stages in the almost 20-year history of abiraterone acetate's development, starting with a program aiming to develop inhibitors of androgen synthesis at the Institute of Cancer Research, London. Clinical development was initially slow owing to insufficient data supporting targeting of androgen synthesis as a therapeutic approach in CRPC and safety concerns of adrenocortical insufficiency from suppression of cortisol. Regulatory authorities approved abiraterone acetate in 2011 after a survival benefit was demonstrated when given in combination with prednisone as compared with prednisone alone in docetaxel-treated men. Licensing approval extended to include chemotherapy-naive patients with CRPC in 2012 following a significant increase in radiographic progression-free survival. Ongoing research focuses on identifying predictive biomarkers and understanding mechanisms of resistance to improve its administration. r 2015 Elsevier Inc. All rights reserved.
Introduction
CYP17A1 and its role in androgenic steroid production
Treatment of castration-resistant prostate cancer (CRPC), the second commonest cause of cancer-related mortality in men, has improved significantly in recent years [1]. Abiraterone acetate is 1 of 5 survival-prolonging treatments approved since 2009 for CRPC. Enzalutamide, a small molecule inhibitor of the androgen receptor (AR) and discussed elsewhere in this series, also demonstrated a survival benefit and was approved in 2012 for use in patients with CRPC who have previously received docetaxel treatment [2]. The efficacy of both novel treatments targeting the AR confirmed CRPCs' ongoing dependency on the androgen axis. An additional 3 novel therapies now approved for use in CRPC include radium-223 for patients with symptomatic bone-only metastases [3], the vaccine sipuleucel-T [4], and the second-generation taxane chemotherapy cabazitaxel [5]. Nonetheless, drug resistance invariably develops, and CRPC remains an invariably lethal condition.
CYP17A1 is responsible for catalyzing 2 enzymatic reactions. The first is the 17α-hydroxylation of pregnenolone to the precursor of cortisol, 17α-hydroxy-pregnenolone. This is then converted to the 19-carbon sex steroids dehydroepiandrostenedione (DHEA), DHEA-sulfate, and androstenedione by CYP17A1 C17,20 lyase. DHEA or androstenedione are mostly converted peripherally to testosterone by 17βhydroxysteroid dehydrogenase and to dihydrotestosterone by 5α-reductase.
*
Corresponding author. E-mail address: [email protected] (G. Attard).
http://dx.doi.org/10.1016/j.urolonc.2015.03.021 1078-1439/r 2015 Elsevier Inc. All rights reserved.
Rational approach to the development of a specific and potent CYP17A1 inhibitor Abiraterone is a pregnenolone analogue and a highly specific and irreversible CYP17A1 inhibitor [6,7]. Abiraterone acetate is a 3β-acetoxy prodrug of abiraterone with improved bioavailability compared with abiraterone [8]. After absorption, the 3β-acetoxy prodrug is rapidly hepatically deacetylated to abiraterone. Before the approval of abiraterone, ketoconazole, a nonspecific CYP17 inhibitor, was sometimes used to treat CRPC. Responses were
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reported in 40% to 60% of patients and associated with reduced levels of testosterone, androstenedione, and DHEA at doses of 400 mg 3 times daily. However, as ketoconazole has low specificity for CYP1A1, the dose required for inhibition of CYP17A1 could be associated with significant toxicity. Moreover, loss of CYP17 inhibition with an increase in circulating adrenal androgens often occurred at progression [9]. Abiraterone inhibited both 17α-hydroxylase and C17,20 lyase activities significantly more potently than ketoconazole. Abiraterone acetate preclinically reduced circulating testosterone levels in male rat and mouse and reduced the weights of androgen-dependent organs [8,10]. Important features of abiraterone include the pyridyl ring at C17 (the 2-pyridyl and 4-pyridal analogues are less potent) and the C16, 17 double bond [11]. The ideal agent would inhibit specifically CYP17A1 lyase activity, and not affect cortisol. This to date has been a significant challenge with a number of more specific C17,20 lyase inhibitors currently undergoing evaluation in early clinical trials. The x-ray crystal structures of CYP17A1 bound to abiraterone was also recently reported and confirmed abiraterone binding to cytochrome p450 haem iron [12]. Abiraterone also binds AR weakly and is a weak AR antagonist [13]. The clinical relevance of the latter is uncertain given the clinical activity of abiraterone in patients could be entirely explained by suppression of androgen levels.
Clinical evaluation of abiraterone acetate Phase I/II development Abiraterone acetate was assessed in a series of 3 small phase I trials in the late 1990s. The first in-human trial demonstrated that abiraterone was safe when administered for 12 consecutive days to a small number of patients with prostate cancer who were not considered to require treatment [14]. Although testosterone levels were initially suppressed in noncastrated men, a compensatory surge in luteinizing hormone overcame this testosterone suppression after 2 days; therefore, subsequent trials mandated the recruitment of castrated patients. Attard et al. [15] conducted the first phase I/II clinical study assessing drug safety, pharmacokinetics, and activity in chemotherapy-naive patients with CRPC. Escalating doses of abiraterone acetate from 250 to 2,000 mg in a 3 þ 3 design were tested. Plasma pharmokinetic analysis demonstrated that the terminal half-life was a mean of 10.3 hours; however, when administered with a high-fat content diet, drug exposure was increased 4.4-fold as compared with fasting administration. The previous evaluation of abiraterone continuously for 12 days had shown a reduced cortisol reserve with an incomplete increase in cortisol after adrenocorticotropic hormone (ACTH) stimulation following 12 days of abiraterone. However, it was hypothesized that
increases in weak glucocorticoids upstream of CYP17A1 would ameliorate the effects seen from cortisol deficiency as reported in families with a congenital deficiency of CYP17A1 [16]. Abiraterone's inhibition of CYP17A1 led to a compensatory increase in ACTH. This resulted in an increase in upstream steroid precursors including progesterone, 11-deoxycorticosterone, 18-hydroxycorticosterone, and corticosterone. As predicted, hypoadrenalism was not observed because corticosterone is a glucocorticoid, albeit many fold weaker than cortisol. The new steady state achieved to maintain sufficiently high levels of corticosterone therefore also required high levels of mineralocorticoids upstream of corticosterone. Consequently, the main adverse events reported in more than two-thirds of patients with single-agent abiraterone acetate were a result of secondary mineralocorticoid excess. This clinically manifested in patients as hypertension, hyperkalemia, and fluid retention. These adverse events were managed with eplerenone, a mineralocorticoid antagonist, and can be prevented when abiraterone acetate is administered with prednisone, which prevents an increase in ACTH. A decrease in prostate-specific antigen (PSA) level of greater than or equal to 50% was observed in 28 (67%) of 42 patients, and 8 patients had a decrease in PSA greater than 90%. In 24 patients with measurable disease, 38% had a partial response by the “Response Evaluation Criteria in Solid Tumors” (RECIST). The median time to PSA progression was 225 days (95% CI: 162–287 d). The addition of dexamethasone at progression extended time on treatment and improved drug tolerability. No increase in testosterone or DHEA was observed at PSA or radiographic progression. As there were no dose-limiting toxicities and significant activity at all doses, the best dose to proceed with was not obvious. It was decided that owing to a plateau in the increase of upstream steroids more than 750 mg, 1,000 mg dosing was to be taken forward into the phase II expansion. A parallel phase I dose-escalation trial by Ryan et al. [17] assessed abiraterone acetate 250 to 1,000 mg daily in 33 chemotherapy-naive patients with CRPC. Again, no dose-limiting adverse events were observed, and a highfat meal increased drug exposure. Greater than or equal to 50% decreases in PSA level at week 12 were seen in 18 (55%) of 33 patients. The median time to PSA progression for all patients was 234 days (95% CI: 174–341 d). Moreover, 2 phase II trials proceeded to assess the activity of abiraterone acetate in patients with CRPC who had received prior docetaxel chemotherapy [18,19]. Reid et al. [19] recruited 47 patients and observed greater than or equal to 50% decrease in PSA level in 24 (51%) patients. A greater than or equal to 90% decrease in PSA level was reported in 7 (15%) of 47 patients. RECIST partial responses were reported in 8 (25%) of 30 patients with measureable disease, and median time to PSA progression was 169 days (95% CI: 113–281 d). Danila et al. [18] recruited 58 patients pretreated with docetaxel chemotherapy. Abiraterone acetate was administered with 5-mg
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twice-a-day prednisone. A greater than or equal to 50% decrease in PSA level was seen in 22 (36%) of 58 patients. A greater than or equal to 90% decrease in PSA level was reported in 16% of patients. Of 22 patients with RECISTevaluable target lesions, partial responses were seen in 4 patients. Median time to PSA progression was again 169 days (95% CI: 82–200 d). Significant activity was also observed in both chemotherapy-naive and chemotherapytreated patients who had previously received ketoconazole. Phase III development The first phase III double-blind, placebo-controlled, multicentered trial (COU-AA-301) recruited 1195 docetaxel-treated patients with CRPC [20]. Patients were randomized 2:1 to either abiraterone acetate 1,000 mg and prednisone (5 mg twice a day) or the same dose prednisone and placebo. Patients were recruited with a performance status of 2 or less and disease progression. Patients were excluded if they had previously been treated with ketoconazole, had uncontrolled hypertension, or had a history of adrenal or pituitary dysfunction or clinically significant heart disease. Patients required adequate organ function and were excluded if they had an aspartate aminotransferase or alanine aminotransferase that was Z2.5 times the upper level of the normal range (however, patients with known liver metastasis who had levels of aspartate aminotransferase or alanine aminotransferase that were r5 times the upper level of the normal range were eligible to participate). The study was designed to incorporate 1 interim analysis after 534 deaths. After a median follow-up of 12.8 months, the median overall survival was 14.8 months in the abiraterone acetate and prednisone group and 10.9 months in the placebo and prednisone group (hazard ratio [HR] ¼ 0.65; 95% CI: 0.54–0.77; P o 0.001). Time to PSA progression was 10.2 months in the abiraterone acetate and prednisone group vs. 6.6 months in the placebo and prednisone group. After 775 of the prespecified 799 death events and a median 20.2 months of follow-up, final median overall survival was 15.8 months in the abiraterone acetate and prednisone group vs. 11.2 months in the placebo and prednisone group (HR ¼ 0.74; 95% CI: 0.64–0.86; P o 0 0001) [21]. Median time to PSA progression was 8.5 months in the abiraterone acetate and prednisone treated group vs 6.6 months in the placebo and prednisone group. In subgroup analysis, abiraterone acetate with prednisone was also seen to improve overall survival in patients with visceral disease (HR ¼ 0.70; 95% CI: 0.52–0.94). Abiraterone acetate also significantly reduced intensity of fatigue [22], demonstrated rapid pain reduction [23], and prolonged the median time to first skeletal-related event. The COU-AA-302 phase III trial was designed to assess the efficacy of abiraterone acetate and prednisone in chemotherapy-naive CRPC [24]. In total, 1,088 patients were randomly assigned 1:1 to either abiraterone acetate
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and prednisone 5 mg twice a day or prednisone at the same dose with placebo. Important differences in eligibility criteria as compared with the COU-AA-301 trial include that a performance status of 1 or less and no symptoms or mild symptoms as defined by the Brief Pain Inventory-Short Form were necessary. Patients with visceral metastases were excluded. The COU-AA-302 had both overall survival and radiographic progression-free survival as co–primary end points. A total of 3 interim analyses were planned for overall survival, with the first analysis after the observation of approximately 116 of the required 773 events (15%), the second analysis planned after 311 events (40%), and the third analysis planned after 425 events (55%); a final analysis was planned after 773 events had occurred. At the second interim analysis, after a median follow-up of 22.2 months, overall survival was improved with abiraterone acetate and prednisone (median not reached vs. 27.2 mo for prednisone and placebo; HR ¼ 0.75; 95% CI: 0.61–0.93; P ¼ 0.01) but did not cross the prespecified O'Brien-Fleming efficacy boundary [24]. Radiographic progression-free survival was a median of 16.5 months in the abiraterone acetate and prednisone group compared with 8.2 months with prednisone and placebo (HR ¼ 0.53; 95% CI: 0.45–0.62; P o 0.001). The final median overall survival was significantly longer in the abiraterone acetate and prednisone group than in the placebo and prednisone group (34 7 vs. 30 3 mo, HR ¼ 0 81; 95% CI: 0 70– 0 93; P ¼ 0 0033) [25]. This improved overall survival was observed despite 238 patients initially assigned to placebo subsequently receiving abiraterone acetate and prednisone (93 patients crossed over as per protocol). Combination treatment with abiraterone acetate and prednisone was also superior to placebo and prednisone with respect to time to initiation of cytotoxic chemotherapy, performance status decline, opiate use for cancer-related pain, and PSA progression. Overall, abiraterone acetate was well tolerated. In both COU-AA-301 and COU-AA-302 phase III trials, adverse events secondary to mineralocorticoid excess were more common in patients receiving abiraterone acetate and prednisone rather than placebo and prednisone. Grades 3 and 4 hypertension, hypokalemia, and fluid retention were between 2% and 4% in both trials. Abiraterone acetate and prednisone also led to a higher rate of grades 3 and 4 hepatotoxicities with an elevation in liver transaminases (4% in the AA-COU-301 and 8% in the COU-AA-302 trial), which when observed in clinical practice can in a minority of cases require a dose reduction or treatment discontinuation. Resistance mechanisms With the concurrent approval of both enzalutamide and abiraterone and the exclusion of patients treated with either drug in the regulatory studies, the activity of one agent
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when used after the other is uncertain. Enzalutamide appears to be less active when sequenced after abiraterone acetate [26,27], and abiraterone acetate treatment is less active when sequenced after enzalutamide [28,29]. Retrospective studies have also suggested a lower activity with docetaxel following abiraterone acetate [30]. In vitro studies suggest that the activity of docetaxel may in part be because of disruption of AR nuclear trafficking, and it could explain this observed cross-resistance [31]. In contrast, cabazitaxel has been reported to retain activity after abiraterone and enzalutamide [32]. AR mutations and amplifications are reported following castration resistance but are rarely reported before endocrine treatment [33,34]. This suggests that treatment resistance occurs secondary to genomic adaptions maintaining AR signaling [35,36]. Genomic aberrations of the AR have been associated with AR promiscuity and activation by cortisol [37]. We have recently identified AR mutations in circulating tumor DNA collected from sequential samples in a small number of patients with CRPC. This demonstrated a temporal association between clinical progression and emergence of AR mutations activated by glucocorticoids in approximately 20% of patients progressing on abiraterone acetate and prednisone (L702H) [38]. It is possible concomitant glucocorticoid treatment with abiraterone acetate may drive the emergence of resistant mutant AR clones. In addition, increased glucocorticoid receptor expression and activation has been suggested as a mechanism for bypassing AR blockage in preclinical studies with enzalutamide, although this has not been shown with abiraterone treatment to date [39]. Although wild-type AR is only weakly stimulated by progesterone, T878A AR mutants can be strongly activated. It is hypothesized that abiraterone acetate treatment selects for and increases T878A mutated AR clones because of increased upstream progesterone because of CYP17A1 inhibition. Combination treatment with dutasteride and abiraterone acetate or with a progesterone-suppressing agent has been suggested to inhibit selection of these mutants and delay emerging resistance [40]. AR splice variants encode a truncated AR that lacks the ligand-binding domain and is constitutively active. Recently published data suggest that the presence of ARV7 splice variants detected in circulating tumor cells may associate with resistance to abiraterone [41]. AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P ¼ 0.004) and shorter PSA progression-free survival (median ¼ 1.3 mo vs. not reached; P o 0.001). Moreover, the detection of AR-V7 using this test increased from 10% of patients before abiraterone to more than 50% after treatment. CYP17A1 upregulation or amplification resulting in de novo intratumoral androgen production, independent of circulating androgens, has been suggested as a mechanism of resistance to abiraterone. It has been demonstrated in CRPC xenograft models that enzymes required for de novo
androgen production were present [42]. CYP17A1 upregulation was associated with relapse during abiraterone acetate treatment in VCAP xenograft models, potentially because of increased tumor de novo steroidogenesis, and CYP17A1 expression was increased in tumor biopsies from patients with CRPC who were pretreated with a CYP17A1 inhibitor [43].
Future directions Given the efficacy and tolerability of abiraterone in CRPC, trials have been designed to assess abiraterone in earlier stages of prostate cancer disease. Abiraterone acetate is being assessed in castrate men in both the neoadjuvant setting before radical radiotherapy (NCT02160353) and after biochemical relapse following radical surgery, in combination with salvage radiotherapy (NCT01780220). A number of trials have been designed to assess the tolerability and efficacy of combination treatment strategies of abiraterone acetate and prednisone with enzalutamide. A phase I trial from MD Anderson suggests combination treatment strategies will be well tolerated [44]. PLATO is a multicenter trial evaluating the efficacy of adding abiraterone acetate and prednisone vs. placebo and prednisone to enzalutamide at the point of progression (clinicaltrials.gov NCT01995513) to further suppress AR activation, which may be re-emerging on resistance to enzalutamide. Furthermore, given the tolerability of single-agent abiraterone acetate in phase I trials, its administration without concomitant glucocorticoids is being re-evaluated (NCT02025010). Additionally, abiraterone is undergoing evaluation in combination with other approved (e.g., radium-223, NCT02034552) and multiple experimental agents.
Conclusion The development of abiraterone acetate for treatment of patients with CRPC highlights how better understanding of the biology of a disease can drive drug development. Abiraterone acetate treatment not only prolongs survival but is well tolerated and maintains quality of life. Efforts are being directed toward identifying predictive biomarkers for both primary and acquired abiraterone resistance and optimizing its efficacy through exploring combination treatment strategies to overcome resistance mechanisms.
Conflict of interest The ICR developed abiraterone and therefore has a commercial interest in this agent. G.A. is on the ICR list of rewards to inventors for abiraterone. G.A. has received honoraria, consulting fees or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen,
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Takeda, and Sanofi-Aventis and grant support from Janssen, Arno and AstraZeneca. [18]
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Seminar article
The development of abiraterone acetate for castration-resistant prostate cancer Emily Grist, M.B.B.S., M.R.C.P.a,b, Gerhardt Attard, M.D., Ph.D., M.R.C.P.a,b,* a
b
The Institute of Cancer Research, London, UK Royal Marsden NHS Foundation Trust, London, UK
Received 15 December 2014; received in revised form 27 March 2015; accepted 29 March 2015
Abstract Abiraterone acetate is a novel CYP17A1 inhibitor demonstrated to prolong survival in castration-resistant prostate cancer (CRPC). This review explores key stages in the almost 20-year history of abiraterone acetate's development, starting with a program aiming to develop inhibitors of androgen synthesis at the Institute of Cancer Research, London. Clinical development was initially slow owing to insufficient data supporting targeting of androgen synthesis as a therapeutic approach in CRPC and safety concerns of adrenocortical insufficiency from suppression of cortisol. Regulatory authorities approved abiraterone acetate in 2011 after a survival benefit was demonstrated when given in combination with prednisone as compared with prednisone alone in docetaxel-treated men. Licensing approval extended to include chemotherapy-naive patients with CRPC in 2012 following a significant increase in radiographic progression-free survival. Ongoing research focuses on identifying predictive biomarkers and understanding mechanisms of resistance to improve its administration. r 2015 Elsevier Inc. All rights reserved.
Introduction
CYP17A1 and its role in androgenic steroid production
Treatment of castration-resistant prostate cancer (CRPC), the second commonest cause of cancer-related mortality in men, has improved significantly in recent years [1]. Abiraterone acetate is 1 of 5 survival-prolonging treatments approved since 2009 for CRPC. Enzalutamide, a small molecule inhibitor of the androgen receptor (AR) and discussed elsewhere in this series, also demonstrated a survival benefit and was approved in 2012 for use in patients with CRPC who have previously received docetaxel treatment [2]. The efficacy of both novel treatments targeting the AR confirmed CRPCs' ongoing dependency on the androgen axis. An additional 3 novel therapies now approved for use in CRPC include radium-223 for patients with symptomatic bone-only metastases [3], the vaccine sipuleucel-T [4], and the second-generation taxane chemotherapy cabazitaxel [5]. Nonetheless, drug resistance invariably develops, and CRPC remains an invariably lethal condition.
CYP17A1 is responsible for catalyzing 2 enzymatic reactions. The first is the 17α-hydroxylation of pregnenolone to the precursor of cortisol, 17α-hydroxy-pregnenolone. This is then converted to the 19-carbon sex steroids dehydroepiandrostenedione (DHEA), DHEA-sulfate, and androstenedione by CYP17A1 C17,20 lyase. DHEA or androstenedione are mostly converted peripherally to testosterone by 17βhydroxysteroid dehydrogenase and to dihydrotestosterone by 5α-reductase.
*
Corresponding author. E-mail address: [email protected] (G. Attard).
http://dx.doi.org/10.1016/j.urolonc.2015.03.021 1078-1439/r 2015 Elsevier Inc. All rights reserved.
Rational approach to the development of a specific and potent CYP17A1 inhibitor Abiraterone is a pregnenolone analogue and a highly specific and irreversible CYP17A1 inhibitor [6,7]. Abiraterone acetate is a 3β-acetoxy prodrug of abiraterone with improved bioavailability compared with abiraterone [8]. After absorption, the 3β-acetoxy prodrug is rapidly hepatically deacetylated to abiraterone. Before the approval of abiraterone, ketoconazole, a nonspecific CYP17 inhibitor, was sometimes used to treat CRPC. Responses were
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reported in 40% to 60% of patients and associated with reduced levels of testosterone, androstenedione, and DHEA at doses of 400 mg 3 times daily. However, as ketoconazole has low specificity for CYP1A1, the dose required for inhibition of CYP17A1 could be associated with significant toxicity. Moreover, loss of CYP17 inhibition with an increase in circulating adrenal androgens often occurred at progression [9]. Abiraterone inhibited both 17α-hydroxylase and C17,20 lyase activities significantly more potently than ketoconazole. Abiraterone acetate preclinically reduced circulating testosterone levels in male rat and mouse and reduced the weights of androgen-dependent organs [8,10]. Important features of abiraterone include the pyridyl ring at C17 (the 2-pyridyl and 4-pyridal analogues are less potent) and the C16, 17 double bond [11]. The ideal agent would inhibit specifically CYP17A1 lyase activity, and not affect cortisol. This to date has been a significant challenge with a number of more specific C17,20 lyase inhibitors currently undergoing evaluation in early clinical trials. The x-ray crystal structures of CYP17A1 bound to abiraterone was also recently reported and confirmed abiraterone binding to cytochrome p450 haem iron [12]. Abiraterone also binds AR weakly and is a weak AR antagonist [13]. The clinical relevance of the latter is uncertain given the clinical activity of abiraterone in patients could be entirely explained by suppression of androgen levels.
Clinical evaluation of abiraterone acetate Phase I/II development Abiraterone acetate was assessed in a series of 3 small phase I trials in the late 1990s. The first in-human trial demonstrated that abiraterone was safe when administered for 12 consecutive days to a small number of patients with prostate cancer who were not considered to require treatment [14]. Although testosterone levels were initially suppressed in noncastrated men, a compensatory surge in luteinizing hormone overcame this testosterone suppression after 2 days; therefore, subsequent trials mandated the recruitment of castrated patients. Attard et al. [15] conducted the first phase I/II clinical study assessing drug safety, pharmacokinetics, and activity in chemotherapy-naive patients with CRPC. Escalating doses of abiraterone acetate from 250 to 2,000 mg in a 3 þ 3 design were tested. Plasma pharmokinetic analysis demonstrated that the terminal half-life was a mean of 10.3 hours; however, when administered with a high-fat content diet, drug exposure was increased 4.4-fold as compared with fasting administration. The previous evaluation of abiraterone continuously for 12 days had shown a reduced cortisol reserve with an incomplete increase in cortisol after adrenocorticotropic hormone (ACTH) stimulation following 12 days of abiraterone. However, it was hypothesized that
increases in weak glucocorticoids upstream of CYP17A1 would ameliorate the effects seen from cortisol deficiency as reported in families with a congenital deficiency of CYP17A1 [16]. Abiraterone's inhibition of CYP17A1 led to a compensatory increase in ACTH. This resulted in an increase in upstream steroid precursors including progesterone, 11-deoxycorticosterone, 18-hydroxycorticosterone, and corticosterone. As predicted, hypoadrenalism was not observed because corticosterone is a glucocorticoid, albeit many fold weaker than cortisol. The new steady state achieved to maintain sufficiently high levels of corticosterone therefore also required high levels of mineralocorticoids upstream of corticosterone. Consequently, the main adverse events reported in more than two-thirds of patients with single-agent abiraterone acetate were a result of secondary mineralocorticoid excess. This clinically manifested in patients as hypertension, hyperkalemia, and fluid retention. These adverse events were managed with eplerenone, a mineralocorticoid antagonist, and can be prevented when abiraterone acetate is administered with prednisone, which prevents an increase in ACTH. A decrease in prostate-specific antigen (PSA) level of greater than or equal to 50% was observed in 28 (67%) of 42 patients, and 8 patients had a decrease in PSA greater than 90%. In 24 patients with measurable disease, 38% had a partial response by the “Response Evaluation Criteria in Solid Tumors” (RECIST). The median time to PSA progression was 225 days (95% CI: 162–287 d). The addition of dexamethasone at progression extended time on treatment and improved drug tolerability. No increase in testosterone or DHEA was observed at PSA or radiographic progression. As there were no dose-limiting toxicities and significant activity at all doses, the best dose to proceed with was not obvious. It was decided that owing to a plateau in the increase of upstream steroids more than 750 mg, 1,000 mg dosing was to be taken forward into the phase II expansion. A parallel phase I dose-escalation trial by Ryan et al. [17] assessed abiraterone acetate 250 to 1,000 mg daily in 33 chemotherapy-naive patients with CRPC. Again, no dose-limiting adverse events were observed, and a highfat meal increased drug exposure. Greater than or equal to 50% decreases in PSA level at week 12 were seen in 18 (55%) of 33 patients. The median time to PSA progression for all patients was 234 days (95% CI: 174–341 d). Moreover, 2 phase II trials proceeded to assess the activity of abiraterone acetate in patients with CRPC who had received prior docetaxel chemotherapy [18,19]. Reid et al. [19] recruited 47 patients and observed greater than or equal to 50% decrease in PSA level in 24 (51%) patients. A greater than or equal to 90% decrease in PSA level was reported in 7 (15%) of 47 patients. RECIST partial responses were reported in 8 (25%) of 30 patients with measureable disease, and median time to PSA progression was 169 days (95% CI: 113–281 d). Danila et al. [18] recruited 58 patients pretreated with docetaxel chemotherapy. Abiraterone acetate was administered with 5-mg
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twice-a-day prednisone. A greater than or equal to 50% decrease in PSA level was seen in 22 (36%) of 58 patients. A greater than or equal to 90% decrease in PSA level was reported in 16% of patients. Of 22 patients with RECISTevaluable target lesions, partial responses were seen in 4 patients. Median time to PSA progression was again 169 days (95% CI: 82–200 d). Significant activity was also observed in both chemotherapy-naive and chemotherapytreated patients who had previously received ketoconazole. Phase III development The first phase III double-blind, placebo-controlled, multicentered trial (COU-AA-301) recruited 1195 docetaxel-treated patients with CRPC [20]. Patients were randomized 2:1 to either abiraterone acetate 1,000 mg and prednisone (5 mg twice a day) or the same dose prednisone and placebo. Patients were recruited with a performance status of 2 or less and disease progression. Patients were excluded if they had previously been treated with ketoconazole, had uncontrolled hypertension, or had a history of adrenal or pituitary dysfunction or clinically significant heart disease. Patients required adequate organ function and were excluded if they had an aspartate aminotransferase or alanine aminotransferase that was Z2.5 times the upper level of the normal range (however, patients with known liver metastasis who had levels of aspartate aminotransferase or alanine aminotransferase that were r5 times the upper level of the normal range were eligible to participate). The study was designed to incorporate 1 interim analysis after 534 deaths. After a median follow-up of 12.8 months, the median overall survival was 14.8 months in the abiraterone acetate and prednisone group and 10.9 months in the placebo and prednisone group (hazard ratio [HR] ¼ 0.65; 95% CI: 0.54–0.77; P o 0.001). Time to PSA progression was 10.2 months in the abiraterone acetate and prednisone group vs. 6.6 months in the placebo and prednisone group. After 775 of the prespecified 799 death events and a median 20.2 months of follow-up, final median overall survival was 15.8 months in the abiraterone acetate and prednisone group vs. 11.2 months in the placebo and prednisone group (HR ¼ 0.74; 95% CI: 0.64–0.86; P o 0 0001) [21]. Median time to PSA progression was 8.5 months in the abiraterone acetate and prednisone treated group vs 6.6 months in the placebo and prednisone group. In subgroup analysis, abiraterone acetate with prednisone was also seen to improve overall survival in patients with visceral disease (HR ¼ 0.70; 95% CI: 0.52–0.94). Abiraterone acetate also significantly reduced intensity of fatigue [22], demonstrated rapid pain reduction [23], and prolonged the median time to first skeletal-related event. The COU-AA-302 phase III trial was designed to assess the efficacy of abiraterone acetate and prednisone in chemotherapy-naive CRPC [24]. In total, 1,088 patients were randomly assigned 1:1 to either abiraterone acetate
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and prednisone 5 mg twice a day or prednisone at the same dose with placebo. Important differences in eligibility criteria as compared with the COU-AA-301 trial include that a performance status of 1 or less and no symptoms or mild symptoms as defined by the Brief Pain Inventory-Short Form were necessary. Patients with visceral metastases were excluded. The COU-AA-302 had both overall survival and radiographic progression-free survival as co–primary end points. A total of 3 interim analyses were planned for overall survival, with the first analysis after the observation of approximately 116 of the required 773 events (15%), the second analysis planned after 311 events (40%), and the third analysis planned after 425 events (55%); a final analysis was planned after 773 events had occurred. At the second interim analysis, after a median follow-up of 22.2 months, overall survival was improved with abiraterone acetate and prednisone (median not reached vs. 27.2 mo for prednisone and placebo; HR ¼ 0.75; 95% CI: 0.61–0.93; P ¼ 0.01) but did not cross the prespecified O'Brien-Fleming efficacy boundary [24]. Radiographic progression-free survival was a median of 16.5 months in the abiraterone acetate and prednisone group compared with 8.2 months with prednisone and placebo (HR ¼ 0.53; 95% CI: 0.45–0.62; P o 0.001). The final median overall survival was significantly longer in the abiraterone acetate and prednisone group than in the placebo and prednisone group (34 7 vs. 30 3 mo, HR ¼ 0 81; 95% CI: 0 70– 0 93; P ¼ 0 0033) [25]. This improved overall survival was observed despite 238 patients initially assigned to placebo subsequently receiving abiraterone acetate and prednisone (93 patients crossed over as per protocol). Combination treatment with abiraterone acetate and prednisone was also superior to placebo and prednisone with respect to time to initiation of cytotoxic chemotherapy, performance status decline, opiate use for cancer-related pain, and PSA progression. Overall, abiraterone acetate was well tolerated. In both COU-AA-301 and COU-AA-302 phase III trials, adverse events secondary to mineralocorticoid excess were more common in patients receiving abiraterone acetate and prednisone rather than placebo and prednisone. Grades 3 and 4 hypertension, hypokalemia, and fluid retention were between 2% and 4% in both trials. Abiraterone acetate and prednisone also led to a higher rate of grades 3 and 4 hepatotoxicities with an elevation in liver transaminases (4% in the AA-COU-301 and 8% in the COU-AA-302 trial), which when observed in clinical practice can in a minority of cases require a dose reduction or treatment discontinuation. Resistance mechanisms With the concurrent approval of both enzalutamide and abiraterone and the exclusion of patients treated with either drug in the regulatory studies, the activity of one agent
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when used after the other is uncertain. Enzalutamide appears to be less active when sequenced after abiraterone acetate [26,27], and abiraterone acetate treatment is less active when sequenced after enzalutamide [28,29]. Retrospective studies have also suggested a lower activity with docetaxel following abiraterone acetate [30]. In vitro studies suggest that the activity of docetaxel may in part be because of disruption of AR nuclear trafficking, and it could explain this observed cross-resistance [31]. In contrast, cabazitaxel has been reported to retain activity after abiraterone and enzalutamide [32]. AR mutations and amplifications are reported following castration resistance but are rarely reported before endocrine treatment [33,34]. This suggests that treatment resistance occurs secondary to genomic adaptions maintaining AR signaling [35,36]. Genomic aberrations of the AR have been associated with AR promiscuity and activation by cortisol [37]. We have recently identified AR mutations in circulating tumor DNA collected from sequential samples in a small number of patients with CRPC. This demonstrated a temporal association between clinical progression and emergence of AR mutations activated by glucocorticoids in approximately 20% of patients progressing on abiraterone acetate and prednisone (L702H) [38]. It is possible concomitant glucocorticoid treatment with abiraterone acetate may drive the emergence of resistant mutant AR clones. In addition, increased glucocorticoid receptor expression and activation has been suggested as a mechanism for bypassing AR blockage in preclinical studies with enzalutamide, although this has not been shown with abiraterone treatment to date [39]. Although wild-type AR is only weakly stimulated by progesterone, T878A AR mutants can be strongly activated. It is hypothesized that abiraterone acetate treatment selects for and increases T878A mutated AR clones because of increased upstream progesterone because of CYP17A1 inhibition. Combination treatment with dutasteride and abiraterone acetate or with a progesterone-suppressing agent has been suggested to inhibit selection of these mutants and delay emerging resistance [40]. AR splice variants encode a truncated AR that lacks the ligand-binding domain and is constitutively active. Recently published data suggest that the presence of ARV7 splice variants detected in circulating tumor cells may associate with resistance to abiraterone [41]. AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P ¼ 0.004) and shorter PSA progression-free survival (median ¼ 1.3 mo vs. not reached; P o 0.001). Moreover, the detection of AR-V7 using this test increased from 10% of patients before abiraterone to more than 50% after treatment. CYP17A1 upregulation or amplification resulting in de novo intratumoral androgen production, independent of circulating androgens, has been suggested as a mechanism of resistance to abiraterone. It has been demonstrated in CRPC xenograft models that enzymes required for de novo
androgen production were present [42]. CYP17A1 upregulation was associated with relapse during abiraterone acetate treatment in VCAP xenograft models, potentially because of increased tumor de novo steroidogenesis, and CYP17A1 expression was increased in tumor biopsies from patients with CRPC who were pretreated with a CYP17A1 inhibitor [43].
Future directions Given the efficacy and tolerability of abiraterone in CRPC, trials have been designed to assess abiraterone in earlier stages of prostate cancer disease. Abiraterone acetate is being assessed in castrate men in both the neoadjuvant setting before radical radiotherapy (NCT02160353) and after biochemical relapse following radical surgery, in combination with salvage radiotherapy (NCT01780220). A number of trials have been designed to assess the tolerability and efficacy of combination treatment strategies of abiraterone acetate and prednisone with enzalutamide. A phase I trial from MD Anderson suggests combination treatment strategies will be well tolerated [44]. PLATO is a multicenter trial evaluating the efficacy of adding abiraterone acetate and prednisone vs. placebo and prednisone to enzalutamide at the point of progression (clinicaltrials.gov NCT01995513) to further suppress AR activation, which may be re-emerging on resistance to enzalutamide. Furthermore, given the tolerability of single-agent abiraterone acetate in phase I trials, its administration without concomitant glucocorticoids is being re-evaluated (NCT02025010). Additionally, abiraterone is undergoing evaluation in combination with other approved (e.g., radium-223, NCT02034552) and multiple experimental agents.
Conclusion The development of abiraterone acetate for treatment of patients with CRPC highlights how better understanding of the biology of a disease can drive drug development. Abiraterone acetate treatment not only prolongs survival but is well tolerated and maintains quality of life. Efforts are being directed toward identifying predictive biomarkers for both primary and acquired abiraterone resistance and optimizing its efficacy through exploring combination treatment strategies to overcome resistance mechanisms.
Conflict of interest The ICR developed abiraterone and therefore has a commercial interest in this agent. G.A. is on the ICR list of rewards to inventors for abiraterone. G.A. has received honoraria, consulting fees or travel support from Astellas, Medivation, Janssen, Millennium Pharmaceuticals, Ipsen,
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Takeda, and Sanofi-Aventis and grant support from Janssen, Arno and AstraZeneca. [18]
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