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Originally published as JCO Early Release 10.1200/JCO.2007.15.9749 on July 21 2008 © 2008 American Society of Clinical Oncology.
Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven
From the Royal Marsden NHS Foundation Trust; and The Institute of Cancer Research, Sutton, Surrey, United Kingdom; and Cougar Biotechnology, Los Angeles, CA Corresponding author: Johann S. de Bono, MB ChB, FRCP, MSc, PhD, Section of Medicine, The Institute of Cancer Research and Drug Development Unit, the Royal Marsden NHS Foundation Trust, Downs Rd, Sutton, Surrey, United Kingdom SM2 5PT; e-mail: johann.de-bono{at}icr.ac.uk
Purpose Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate—a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis—was pursued. Patients and Methods Chemotherapy-naïve men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts.
Results Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess—namely hypertension, hypokalemia, and lower-limb edema—were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9). Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all patients. Declines in prostate-specific antigen Conclusion CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.
Prostate cancer is the second leading cause of cancer death in men in the western world1,2; this is a result of castration-resistant prostate cancer (CRPC).3 Castration blocks gonadal testosterone generation, but androgens from nongonadal sources are postulated to drive androgen receptor (AR) signaling. This is supported by recent studies, which report high intratumoral androgens, continued AR signaling,4 and overexpression of enzymes key to androgen synthesis, which suggests that CRPC may synthesize androgens de novo.5-7 Despite this, currently available strategies that target the AR, such as antiandrogens, ketoconazole, estrogens, or glucocorticoids, result in modest benefit.8-13 Cytochrome P (CYP)17 is a microsomal enzyme that catalyzes two independently regulated steroid reactions key to androgen and estrogen biosynthesis (Fig 1A).14-16 Congenital CYP17 deficiency does not result in adrenocortical insufficiency, as corticosterone synthesis is unaffected; CYP17 loss interrupts the negative feedback control of adrenocorticotropic hormone (ACTH), which results in high levels of ACTH and steroid precursors upstream of CYP17.17 Abiraterone is a potent, selective, and irreversible inhibitor of CYP17 (IC50, 2 to 4 nmol/L),18-20 unlike the antifungal ketoconazole, which is a less potent and competitive inhibitor of several CYP enzymes.21-24 In preclinical toxicology studies, it reduced the weights of androgen dependent organs and had minimal side effects in other organs.25 When administered as abiraterone acetate, it has good oral bioavailability. First-in-man studies reported that abiraterone acetate was safe when administered daily for 12 days to men with prostate cancer, and it suppressed testosterone synthesis in noncastrate patients.26 We conducted a phase I study to define the safety, tolerability, and recommended phase II dose of abiraterone acetate when administered once daily to castrate men with CRPC.
Patients This was a single-center study conducted at the Royal Marsden Hospital (RMH), United Kingdom. Castrate patients who had an Eastern Cooperative Oncology Group performance status of 0 to 1, a histologic diagnosis of prostate adenocarcinoma, and progressive disease as defined by Prostate-Specific Antigen Working Group (PSAWG) criteria27 were eligible. Patients were required to have a minimum washout period of 4 weeks after the use of prostate cancer therapy, except gonadotropin-releasing hormone agonists, and 6 weeks after stopping antiandrogens. Patients who had previously received chemotherapy or a radionuclide for their prostate cancer were excluded. Other eligibility criteria included normal serum potassium and adequate bone marrow, renal, and hepatic function. Patients were excluded if they had brain metastases or spinal cord compression, active autoimmune disease that required corticosteroid therapy, uncontrolled hypertension, a history of cardiac failure class III or IV, or a serious concurrent medical illness. The study was approved by the ethics review committees of the RMH, United Kingdom.
Study Design This study also was prospectively designed to allow the addition of dexamethasone (0.5 mg daily) to abiraterone acetate in all patients at disease progression to test the hypothesis that resistance could be reversed by suppressing ACTH and by decreasing upstream androgenic steroids that could activate a mutated, promiscuous AR.29,30 We also hypothesized that harboring the androgen-dependent TMPRSS2-ERG fusion gene31,32 could indicate dependence on AR signaling and could define a tumor subgroup with a higher response rate to abiraterone acetate.
Procedures For the PK analyses of patients who were treated at 250 mg, 500 mg, and 750 mg, a single dose of abiraterone acetate initially was administered 7 days before continuous dosing and after an overnight fast. Venipuncture was carried out for PK measurements at 1, 2, 4, 6, 8, 24, 48, and 72 hours postdose; on days 1, 8, and 15 of cycle 1; and on day 1 of the second and third cycles. Patients in the 1,000-mg and 2,000-mg cohorts were randomly assigned to receive two single doses of abiraterone acetate (one with high-fat content food, the other after an overnight fast) administered 5 days apart on days –7 and –3 before continuous dosing. PK analyses after both doses were done at the same time points as the lower-dose cohorts. Abiraterone levels were measured by liquid chromatography tandem mass spectrometry, using a previously published method.33 Prostate-specific antigen (PSA) was measured at baseline and at the end of every cycle. High-resolution computed tomography (CT) scans and bone scans were performed on all patients at baseline and every 3 months. Serum was collected for the measurement of ACTH, cortisol, deoxycorticosterone (DOC), aldosterone, corticosterone, and testosterone at baseline, weekly for the first two cycles, and at every cycle thereafter; serum also was collected at baseline and at every cycle to measure androstenedione, dehydroepiandrostenedione (DHEA), DHEA sulfate (DHEA-S), and estradiol. Testosterone was measured with a supersensitive assay that utilized liquid chromatography tandem mass spectrometry (Quest Diagnostics, Lyndhurst, NJ). DHEA-S, aldosterone, corticosterone, and DOC were measured by Quest Diagnostics, and ACTH, DHEA, androstenedione and estradiol, were measured by the RMH Academic Biochemistry Laboratories (London, United Kingdom). Fluorescent in situ hybridization (FISH) that used an ERG break-apart assay34 was performed on sections cut from archival tumor tissue, and castration-resistant tumors were biopsied for research purposes before or after starting abiraterone acetate.
Data Analyses
Patient Characteristics Twenty-one patients (median age, 69 years; range, 52 to 85 years) were recruited on to this study between December 13, 2005 and February 22, 2007. All patients were resistant to castration and antiandrogens. Ten (48%) of 21 patients had previously progressed on treatment with continuous steroids; nine (43%) of the 21 had previously progressed on diethylstilboestrol; and seven (33%) of these 21 patients had progressed on treatment with both (Table 1). The median baseline PSA was 46 ng/mL (range, 8.8 to 354 ng/mL). At baseline, 17 (81%) of 21 patients had bone metastasis, and eight (38%) of 21 patients had soft tissue disease (Table 1). Five patients remain on study and have an ongoing clinical response to abiraterone acetate alone; seven patients remain on the combination of dexamethasone and abiraterone acetate.
Safety and Tolerability Dose escalation to the maximum preplanned daily dose of 2,000 mg was achieved. There were no treatment-related grade 3 or 4 toxicities in this study. A plateau of endocrine effects was reported at doses greater than 750 mg, and 1,000 mg was selected as the dose for phase II evaluation. An additional six patients were treated at 1,000 mg to complete PK/pharmacodynamic (PD) studies. Hypertension, hypokalemia, and lower-limb edema were observed in six, 10, and one patient, respectively. These side effects were controlled with eplerenone. The incidence of hypertension (one of three for 250, 500, 750, and 1,000 mg, and two of nine for 1,000 mg doses) appears similar across all doses (Table 2).
One patient in the 1,000-mg cohort who had a history of migraines developed daily grade 2 migrainous headaches after 8 weeks of treatment, which necessitated interruption of treatment. Physical examination and magnetic resonance imaging of the brain found no abnormalities. Serial serum potassium levels were less than 3 mmol/dL, which were in keeping with a syndrome of secondary mineralocorticoid excess. Dexamethasone 0.5 mg daily was initiated to suppress ACTH, and the patient's headaches resolved, which allowed the recommencement of abiraterone acetate in combination with dexamethasone. The cause of headache in this patient remains unknown, but a causal relationship with abiraterone acetate could not be excluded. Another patient treated at 1,000 mg who had a history of asthma that was controlled on inhaled β2 agonists developed an acute exacerbation of asthma that was associated with a decline in peak expiratory flow rate (PEFR), hypereosinophilia, an increase in inflammatory markers, and a seven-fold increase in PSA 7 weeks after starting abiraterone acetate. High doses of steroids were initiated. After control of the patient's symptoms, PEFR and eosinopilia normalized, and the PSA returned to the pre-exacerbation level. Subsequently, he was maintained on a combination of abiraterone acetate and dexamethasone 0.5 mg daily for 22 weeks with no recurrent increase in PSA. No other adverse effects that required intervention were reported in this study. Grade 2 fatigue and anorexia were both reported in two patients, and three patients complained of grade 1 hot flushes. A grade 1 increase in liver transaminases was reported in one patient; this abnormality resolved without treatment interruption (Table 2).
Plasma PK
PD: Endocrine Studies Circulating testosterone levels were in the castrate range (median, 7 ng/dL; range, < 1 to 34) at baseline in all patients, and they rapidly became undetectable (< 1 ng/dL) within 8 days at all doses tested (Fig 3A). The median value of DHEA at baseline was 282.4 ng/dL (range, 66 to 1,299 ng/dL), at day 28 was 83.6 ng/dL (range, 60.5 to 174.6 ng/dL), and at day 56 was 79.2 ng/dL (range, 40.3 to 103.7 ng/dL; Fig 3B). The median baseline value for androstenedione was 33.5 ng/dL (range, < 2 to 124.6 ng/dL); androstenedione was suppressed to less than 2 ng/dL at day 28 in all patients (Fig 3C; Table 1). The median baseline value of DHEA-S was 39 µg/dL (range, < 15 to 117 µg/dL), and nine of 21 patients had undetectable DHEA-S at baseline; all patients had undetectable DHEA-S (< 15 µg/dL) at day 28. There was no increase in testosterone, androstenedione, DHEA, or DHEA-S levels during treatment, including at PSA or radiologic progression. Estradiol was suppressed to less than 80 pg/dL at day 28 in all patients (median at baseline, 196 pg/dL; range, 117 to 548 pg/dL).
At all dose levels, treatment was associated with an up to six-fold increase in ACTH levels and increased steroid precursor levels upstream of CYP17, including a median 10-fold (range, four-fold to 50-fold) increase in DOC and a median 40-fold (range, 10-fold to 95-fold) increase in corticosterone (Fig 1B). The median corticosterone level at baseline was 133 ng/dL (range, 31 to 468 ng/dL) and at day 86 was 6,514 ng/dL (range, 1,390 to 17,921 ng/dL; Fig 3D). The median DOC level at baseline was 6.5 ng/dL (range, 2 to 64 ng/dL) and at day 86 was 68.5 ng/dL (range, 15 to 176 ng/dL; Fig 3E). The increases in corticosterone and DOC increased with dose escalation from 250 mg to 750 mg before they reached a plateau,and no significant difference in levels was observed between patients treated at 750 mg to 2,000 mg (Fig 3F). Administration of dexamethasone to patients who received abiraterone acetate resulted in suppression of ACTH and a decrease in upstream steroids to less than baseline levels (Fig 1C).
Antitumor Activity
Reversal of Resistance The addition of dexamethasone 0.5 mg/d resulted in successful salvage in four of 15 patients who had progressed by PSAWG criteria on abiraterone acetate alone (PSA decrements by 36% [patient 10],  99% [patient 14], 68% [patient 19], and 73% [patient 21] that lasted 349, 265, 49, and 81 days, respectively; all four patients have an ongoing response). Two of these four patients previously had progressive disease on the same dose and schedule of single-agent dexamethasone (Appendix Fig A1).
ERG Gene Status
This is the first study to demonstrate that selective and continuous inhibition of CYP17 is safe and results in durable tumor responses. As predicted from congenital CYP17 deficiency, no patients developed clinical adrenocortical insufficiency.17 The toxicities observed in this study were predominantly caused by secondary mineralocorticoid excess. PSA declines were observed at all dose levels studied. Overall, 66% of the patients with CRPC who were treated on this study had a 30% decrease in PSA; a 30% decrease in PSA at 3 months has recently been associated with a decreased risk of death from prostate cancer.36,37 Declines in PSA were frequently associated with normalization of elevated lactate dehydrogenase levels, partial responses by RECIST, and symptomatic improvement, including reduction or discontinuation of analgesic (including opiate) use by several patients. Importantly, tumor responses to abiraterone acetate were observed in castrate patients who had failed several lines of AR-targeting therapy. Although prior ketoconazole administration was not an exclusion criterion for this trial, all the patients on this study were ketoconazole-naïve, because its use is not recommended in this institution, as it has limited clinical benefit and toxicity. Nevertheless, unlike ketoconazole, CRPC that progresses on abiraterone acetate is not associated with increased androgenic steroids downstream of CYP17 blockade.10 This study was not designed to compare antitumor activity at different doses. In view of the clinical responses observed at all dose levels and of the absence of DLTs, we have recommended a phase II dose of 1,000 mg daily on the basis of a plateau in the increase of upstream steroids at doses greater than 750 mg daily (Fig 3F). Once-daily dosing is supported by the results of PK and PD analyses. No increase in steroids downstream of CYP17 was observed at disease progression, which indicates durable, irreversible CYP17 inhibition. Nonetheless, the suppression of steroid synthesis upstream of CYP17 by decreasing the ACTH drive through the addition of dexamethasone reinduced sensitivity to abiraterone acetate in four (26%) of 15 patients. These data indicate the continued addiction of this disease to promiscuous AR activation by high levels of upstream steroids.29 The antitumor activity reported with abiraterone acetate could be explained by durable and profound suppression of serum androstenedione, DHEA, testosterone, and estradiol. Fusion of TMPRSS2 with ERG occurs in up to 60% of prostate cancers and appears to account for the majority of rearrangements that involve ETS proto-oncogenes.31,32,38 The PSA decline rate appears higher in patients with an ERG rearrangement, although these analyses require confirmation in a larger cohort, which is ongoing. Because of ETS gene rearrangement heterogeneity39 investigation of transrectal biopsy of the prostate cores may miss areas with ERG rearrangements, which possibly may explain the observation in this study of rearrangements in only 33% of patients. The results of this study have led to the phase II evaluation of abiraterone acetate in both chemotherapy-naïve and docetaxel-treated patients who have CRPC, and data from this evaluation will be reported soon. Abiraterone acetate could prove an efficacious treatment in docetaxel-resistant disease,40,41 which is an area of unmet medical need, and a rapid route to drug approval. Because the combination of corticosteroids with abiraterone acetate prevents the syndrome of secondary mineralocorticoid excess and may maximize efficacy, placebo-controlled, randomized, phase III studies will compare steroids with a combination of steroids and abiraterone acetate.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Florence Raynaud, The Institute of Cancer Research (C); Christopher Parker, The Institute of Cancer Research (C); Vanessa Martins, The Institute of Cancer Research (C); Elizabeth Folkerd, The Institute of Cancer Research (C); Jeremy Clark, The Institute of Cancer Research (C); Colin S. Cooper, The Institute of Cancer Research (C); Stan B. Kaye, The Institute of Cancer Research (C); David Dearnaley, The Institute of Cancer Research (C); Gloria Lee, Cougar Biotechnology (C); Johann S. de Bono, The Institute of Cancer Research (C) Consultant or Advisory Role: Johann S. de Bono, Cougar Biotechnology (U) Stock Ownership: None Honoraria: None Research Funding: Florence Raynaud, Cougar Biotechnology; Vanessa Martins, Cougar Biotechnology Expert Testimony: None Other Remuneration: None
Conception and design: Gerhardt Attard, Johann S. de Bono Administrative support: Gloria Lee Provision of study materials or patients: Gerhardt Attard, Alison H.M. Reid, Timothy A. Yap, Sarah Settatree, Mary Barrett, Christopher Parker, Stan B. Kaye, David Dearnaley, Johann S. de Bono Collection and assembly of data: Gerhardt Attard, Alison H.M. Reid, Timothy A. Yap, Florence Raynaud, Mitch Dowsett, Vanessa Martins, Elizabeth Folkerd, Jeremy Clark, Gloria Lee, Johann S. de Bono Data analysis and interpretation: Gerhardt Attard, Florence Raynaud, Mitch Dowsett, Vanessa Martins, Elizabeth Folkerd, Colin S. Cooper, Stan B. Kaye, Gloria Lee, Johann S. de Bono Manuscript writing: Gerhardt Attard, Florence Raynaud, Mitch Dowsett, Elizabeth Folkerd, Johann S. de Bono Final approval of manuscript: Gerhardt Attard, Alison H.M. Reid, Timothy A. Yap, Florence Raynaud, Mitch Dowsett, Sarah Settatree, Mary Barrett, Christopher Parker, Vanessa Martins, Elizabeth Folkerd, Jeremy Clark, Colin S. Cooper, Stan B. Kaye, David Dearnaley, Gloria Lee, Johann S. de Bono
We thank the sponsors of the 7th Joint Federation of European Cancer Societies, American Association of Cancer Research, and American Society of Clinical Oncology Workshop on Methods in Clinical Cancer Research, June 18-24, 2005, Flims, Switzerland, where study protocol was developed; Richard Auchus, MD, PhD, for expert endocrinologic advice; Ruth Riisnaes, for processing of tumor samples; Gal Maier, Bridgid Patrick, and Laurent Britton, for data management and assistance with collection of tumor samples; and Barbara Smith, for help with formatting the manuscript.
published online ahead of print at www.jco.org on July 21, 2008 Supported by Cougar Biotechnology; the Section of Medicine is supported by a program grant from Cancer Research UK, who also fund the Centre for Cancer Therapeutics, where the pharmacokinetic studies were conducted. The authors were also supported by the Medical Reserach Council, the Prostate Cancer Research Foundation, the Royal Marsden Hospital Research Fund, an Experimental Cancer Medicine Centre grant, and the Bob Champion Cancer Trust. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
-hydroxylase (crossed out in red), which results in a reduction in serum cortisol and a consequent increase in adrenocorticotropic hormone (ACTH) that drives the steroid biosynthesis pathway: levels of deoxycorticosterone and corticosterone increase by a median of 10- and 40-fold, respectively. Up to a four-fold increase in 11-deoxycortisol is observed, but there is complete inhibition of C17,20-lyase (crossed out in red) and significant suppression of dehydroepiandrostenedione (DHEA), androstenedione, and testosterone. (C) Addition of dexamethasone 0.5 mg/d to abiraterone acetate results in suppression of ACTH to three-fold less than baseline levels, a consequent decrease in deoxycorticosterone levels to less than the limit of sensitivity of the assay used (< 5 ng/dL), and a consequent decrease in corticosterone levels by two-fold. Similarly, 11-deoxycortisol levels decrease. Downstream steroid levels remain suppressed.
