Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven
Publication: Journal of Clinical Oncology
Abstract
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 ≥ 30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to ≥ 578 days. Radiologic regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in analgesic use were documented.
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.
Accompanying Article
Introduction
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 and Methods
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 was an open-label, dose-escalation study. Capsules of abiraterone acetate powder 250 mg were administered once daily, continuously, in 28-day cycles, to fasted patients in three-patient cohorts that escalated through the preplanned doses of 250, 500, 750, 1,000 and 2,000 mg. Any drug-related grade 3 or 4 toxicity (excluding nausea, vomiting, or diarrhea controlled by standard therapies) that occurred in the first cycle—except the anticipated toxicities that related to a syndrome of secondary mineralocorticoid excess, including hypertension, hypokalemia, and fluid overload—was considered a dose-limiting toxicity (DLT). Toxicity related to elevated mineralocorticoid levels was managed with a mineralocorticoid receptor antagonist (eplerenone 50 to 200 mg/d), and treatment of dexamethasone 0.5 mg daily to suppress ACTH was only utilized if mineralocorticoid antagonism did not reverse these toxicities. Spironolactone was not utilized, as it has been reported to bind and activate the AR.28 Cohort expansion to six patients was required if one DLT was reported. Dose escalation would stop if two DLTs were observed, and the preceding cohort would be expanded to six patients. In the absence of any DLT, a total of nine patients would be treated to complete food-effect pharmacokinetic (PK) studies.
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
Safety evaluations were conducted at baseline, weekly for the first two cycles, and at every cycle thereafter. All patients had a physical examination; complete blood count; clotting, serum creatinine, electrolyte, and liver function tests. An ACTH stimulation test also was performed at baseline. All adverse events were graded according to the US National Cancer Institute common toxicity criteria, version 3.0.
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
PK was analyzed using a noncompartmental model with WINNonlin Software (Model 200; Scientific Consultant, Apex, NC). The food effects were assessed by a bioequivalence crossover model. Rates of PSA decline confirmed by a second reading were reported as recommended by PSAWG criteria on an intention-to-treat basis. CT scans were reported as the best result by Response Evaluation Criteria in Solid Tumors (RECIST)35 at least 3 months after the start of treatment. For ERG gene status, tumors were classified into one of five groups on the basis of the observed FISH patterns, described previously34 (Appendix Table A1).
Results
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
Plasma was collected from all 21 patients for PK analysis. Mean apparent clearance values ranged from 494.3 to 1,347.2 L/h. The area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased with dose but not proportionally (r2 = 0.186 and 0.049, respectively; Figs 2A and 2B). Up to five-fold differences were observed in AUC and Cmax within the 250-mg and 500-mg cohorts, and 2.5-fold variations were observed at 750-mg and 2,000-mg cohorts. In the 1,000-mg cohort, the variation reached nine-fold. The terminal half-life was relatively consistent (mean, 10.3 hours; Fig 2C). When administered with food that had high-fat content, drug exposure was significantly increased (by 4.4-fold) compared with fasting administration (P = .049; Fig 2D). The variability between fed patients was comparable to that observed between fasted patients. There was no significant increase in Cmax, but absorption was significantly extended after food.
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
Greater than 50% declines in PSA confirmed after 1 month that lasted for more than 3 months from the start of treatment were observed in 12 (57%) of 21 patients with CRPC. Fourteen (66%) of 21, nine (42%) of 21, and six (29%) of 21 patients had ≥ 30%, ≥ 75%, and ≥ 90% declines in PSA, respectively, which were confirmed after 1 month and which lasted for more than 3 months from the start of study (lasted between 69 and ≥ 578 days, and censured on September 14, 2007; Table 1). Five (62%) of eight patients with measurable disease at baseline had confirmed partial responses by RECIST. Radiologic regression of pelvic and para-aortic lymphadenopathy was observed in three patients, and regression of soft-tissue metastasis in the pelvis, lungs, and mediastinum was observed in two patients (Fig 4). Resolving bone disease was observed on CT and bone scan in two patients (Fig 4). Eleven patients had pain that required analgesics at baseline, and eight of 11 had symptom improvement that allowed a reduction in dose or cessation of analgesic use. Seven patients had an increased lactate dehydrogenase at baseline that decreased to less than the upper limit of normal in five of seven patients.
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
Tumor tissue was available from 18 of 21 patients and included matched hormone-sensitive and castration-resistant samples (four prostates, one liver metastasis, one para-ureteric tumor) collected from six patients. Six patients had an ERG rearrangement (Table 1). Five (83%) of six patients with an ERG rearrangement had a ≥ 50% decline in PSA (which included patient 21, who had an initial, short-lived ≥ 30% decline in PSA on abiraterone alone but a ≥ 50% decline in PSA after the addition of low-dose dexamethasone to abiraterone). The patient with an ERG rearrangement who did not respond to abiraterone acetate had a class Edel tumor in both his baseline transrectal biopsy of the prostate sample and his liver metastasis. The ERG gene status of the castration-resistant samples, including the two metastatic biopsies, matched the ERG gene status of the baseline hormone-sensitive tumors in all six patient cases studied (one class Edel, one class 2+ Esplit, three class 2N, one class 3N; Appendix Table A1).
Discussion
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.
Authors’ Disclosures of Potential Conflicts of Interest
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
Author Contributions
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
Appendix
Fig A1. Reversal of resistance by addition of dexamethasone.
Graphs of prostate-specific antigen (PSA) versus time for patients (A) 10 and (B) 14 that show an increase in PSA during administration of single-agent dexamethasone before starting abiraterone acetate, an initial decline in PSA after starting single-agent abiraterone acetate and a subsequent rise in PSA by greater than 50%. After addition of dexamethasone, (A) patient 10 had a fall in PSA by greater than 25% that lasted greater than 350 days and is ongoing; (B) patient 14 had a decline in PSA greater than 99% that lasted greater than 200 days and is ongoing. HDAC, histone deacetylase.
| Patient No. | Dose (mg) | Age (years) | Gleason Score at Diagnosis | Previous Systemic Treatments* | Baseline PSA (ng/mL) | PSA Doubling Time Prior to Study Entry | Presence of Measurable Disease on Baseline CT Scan | Presence of Bone Metastasis on Baseline Bone Scan | ERG Gene Class | Baseline DHEA (ng/dL) | Baseline Androstenedione (ng/dL) | Confirmed PSA Decline (%)† | Duration of PSA Decline (days) | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Months | Days | ||||||||||||||
| 01 | 250 | 52 | 4 + 5 | Dex, DES | 34.2 | 0.5 | 16 | No | Yes | 2N | 67 | < 2 | No | — | |
| 02 | 250 | 66 | 4 + 5 | HDACi‡ | 75 | 1.7 | 53 | No | Yes | Edel | 172 | 13 | ≥ 90 | 206 | |
| 03 | 250 | 68 | 3 + 4 | — | 8.8 | 3.7 | 112 | Yes | No | Esplit | 407 | 77 | ≥ 90 | 578§ | |
| 04 | 500 | 72 | 3 + 3 | Dex, DES, antiangiogenic, and pan-CDKi‡ | 354 | 2.2 | 66 | Yes | No | Edel | 221 | 32 | ≥ 75 | 421 | |
| 05 | 500 | 77 | N/A | Dex | 79 | 1.6 | 49 | Yes | Yes | N/A | 285 | 46 | ≥ 90 | 427 | |
| 06 | 500 | 58 | 4 + 4 | Dex, DES | 290 | 2.2 | 67 | Yes | No | Edel¶ | 466 | 23 | No | — | |
| 07 | 750 | 74 | 4 + 5 | — | 28.1 | 2.5 | 75 | None | Yes | 2N¶ | 437 | 52 | No | — | |
| 08 | 750 | 69 | N/A | — | 36.8 | 2.6 | 78 | None | Yes | Edel¶ | 70 | 16 | ≥ 90 | 451§ | |
| 09 | 750 | 85 | 4 + 4 | Dex, DES | 46 | 2.4 | 73 | Yes | Yes | 2N | 192 | 46 | ≥ 90 | 465§ | |
| 10 | 1,000 | 62 | 4 + 4 | Dex, DES, HDACi‡ | 110 | 12.3 | 375 | No | Yes | N/A | 524 | 70 | ≥ 50 | 69 | |
| 11 | 1,000 | 69 | 3 + 3 | — | 34.3 | 11.6 | 354 | Yes | Yes | 2N | 320 | 27 | ≥ 90 | 406§ | |
| 12 | 1,000 | 75 | 3 + 4 | Dex, DES, pamidronate | 58 | 5.5 | 166 | No | Yes | 2N | 320 | 43 | No | — | |
| 13 | 2,000 | 60 | 3 + 4 | Dex | 39.3 | 2 | 61 | No | Yes | 2N¶ | 122 | 15 | ≥ 75 | 351§ | |
| 14 | 2,000 | 82 | 3 + 3 | Dex | 56 | 5.5 | 166 | Yes | Yes | N/A | 227 | 34 | No‖ | — | |
| 15 | 2,000 | 62 | 4 + 5 | — | 35.5 | 22.7 | 81 | Yes | Yes | 3N¶ | 102 | 9 | No | — | |
| 16 | 1,000 | 62 | 3 + 4 | DES | 75 | 1.1 | 34 | No | Yes | 2N | 87 | 8 | No (≥ 30) | — | |
| 17 | 1,000 | 78 | 5 + 3 | Dex, DES | 279 | 0.6 | 19 | No | Yes | 2N | 93 | 19 | No | — | |
| 18 | 1,000 | 72 | 5 + 4 | panERBi‡ | 34.6 | 3 | 91 | No | Yes | 2N¶ | 285 | 51 | ≥ 50 | 70 | |
| 19 | 1,000 | 72 | 5 + 3 | — | 30.2 | 3.5 | 108 | No | No | 2N | 902 | 125 | ≥ 75 | 145 | |
| 20 | 1,000 | 62 | 3 + 5 | — | 28.4 | 0.7 | 20 | No | Yes | 2N | 1310 | 107 | ≥ 50‖ | 84 | |
| 21 | 1,000 | 67 | 3 + 3 | DES | 205 | 1.3 | 41 | No | Yes | 2 + Esplit¶ | 320 | 50 | No (≥ 30)‖ | — | |
Abbreviations: PSA, prostate-specific antigen; CT, computed tomography; DHEA, dehydroepiandrostenedione; Dex, dexamethasone 0.5 mg daily; DES, diethylstilboestrol 1 mg/3 mg daily; HDACi, histone deacetylase inhibitor; pan-CDKi, pan–cyclin-dependent kinase inhibitor; N/A, not assessable; N, normal, characterized by twinned red (3’-ERG) and green (5’-ERG) FISH signals; panERBi, pan-ERB inhibitor.
*
All patients were castrate, and all patients had previously progressed on an antiandrogen therapy.
†
Evaluation of decline ≥ 50%; response of no indicates ≥ 50% decline was not achieved, and ≥ 30% decline is noted additionally.
‡
Experimental agents were administered in the context of a clinical trial.
‖
A ≥ 50% decline in PSA occurred on addition of dexamethasone 0.5 mg/day.
¶
ERG gene status confirmed on castration-resistant prostate cancer sample.
§
PSA and clinical responses continue.
| Adverse Event | Event Grade per Dose | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 250 mg (n = 3) | 500 mg (n = 3) | 750 mg (n = 3) | 1,000 mg (n= 9) | 2,000 mg (n = 3) | |||||||||||||||
| 1 to 2 | 3 | 1 to 2 | 3 | 1 to 2 | 3 | 1 to 2 | 3 | 1 to 2 | 3 | ||||||||||
| Hypokalemia | 0 | 0 | 0 | 1 | 2 | 0 | 5 | 0 | 2 | 0 | |||||||||
| Hypertension | 1 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 2 | 0 | |||||||||
| Peripheral edema | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | |||||||||
| Headache | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |||||||||
| Dyspnea/wheeze (exacerbation of baseline asthma) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |||||||||
| Anorexia | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||||||
| Fatigue | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | |||||||||
| Hot flushes | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | |||||||||
| Testicular atrophy | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||||||
| ALT/AST increased | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||||||
| Skin rash | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||||||
| Dysgeusia | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||||||||
| Class | Description |
|---|---|
| Normal | 2 (2N) or more (3N/4N/5N) unrearranged ERG loci characterized by twinned red (5′-ERG) and green (3′-ERG) FISH signals |
| Esplit | Rearranged ERG locus manifested as separation of the red and green signals |
| Edel | ERG rearrangement with loss of green signal corresponding to 5′-ERG sequences |
| 2+ Edel | Class Edel with more than one copy of the 3′-ERG FISH signal |
| 2+ Esplit | Class Esplit with more than one copy of the 3′-ERG FISH signal |
NOTE. Description of the five classes of ERG gene status observed with the ERG break-apart FISH assay.
Abbreviation: N, normal; FISH, fluorescent in situ hybridization.
Acknowledgments
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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© 2008 by American Society of Clinical Oncology.
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Published in print: October 01, 2008
Published online: September 21, 2016
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Phase I Clinical Trial of a Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven. JCO 26, 4563-4571(2008).
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Journal of Clinical Oncology 2008 26:28, 4563-4571
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