Namphuong Tran

Impact of Baseline Corticosteroids on Survival and Steroid Androgens in Metastatic Castration-resistant Prostate Cancer: Exploratory Analysis from COU-AA-301

BACKGROUND Corticosteroids have been used to mitigate mineralocorticoid-related effects and restore sensitivity to abiraterone acetate. Corticosteroids may also mediate glucocorticoid receptor or mutated androgen receptor activation and adversely influence outcome. OBJECTIVE This post hoc exploratory analysis investigated whether baseline corticosteroids were an independent prognostic factor and its level of contribution in the presence of other prognostic factors for overall survival (OS) in study COU-AA-301. DESIGN, SETTING, AND PARTICIPANTS COU-AA-301 was a randomised study of abiraterone plus prednisone versus prednisone in metastatic castration-resistant prostate cancer patients after docetaxel. INTERVENTION Patients were randomised 2:1 to abiraterone 1000 mg plus prednisone 5mg by mouth twice daily versus prednisone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Association of OS with baseline corticosteroids was determined by univariate and multivariate Cox models. RESULTS AND LIMITATIONS At study entry, 33% of patients received corticosteroids, had worse disease characteristics (p<0.05 except liver metastases), and were more likely to have testosterone levels below the median (odds ratio: 2.92; chi-square p<0.0001). Associations between prostate-specific antigen response as well as circulating tumour cell decline and higher baseline androgen levels were demonstrated. Patients taking baseline corticosteroids had inferior OS in univariate analysis (hazard ratio: 1.48; p<0.0001); however, in multivariate stepwise selection modelling, baseline corticosteroids did not add substantially to the model. This analysis is limited as a retrospective analysis and restricted to patients after docetaxel. CONCLUSIONS In the COU-AA-301 study, baseline corticosteroids were associated with adverse prognostic features, inferior OS, and lower baseline androgen levels but did not add substantial information to the final prognostic model. Thus in these data from study COU-AA-301, concurrent baseline corticosteroids did not have an independent impact on OS. PATIENT SUMMARY Baseline corticosteroids did not adversely affect abiraterone clinical benefit in metastatic castration-resistant prostate cancer. Their use was associated with patients having worse disease characteristics.

A phase I, open-label, single-dose, mass balance study of 14C-labeled abiraterone acetate in healthy male subjects

1. Metabolic disposition of 14C-abiraterone acetate (AA), a prodrug of abiraterone was assessed in a phase I, open-label, single-dose (1000 mg, approximately 100 μCi) study in healthy males (18–55 years, N = 8). Blood, urine, and faecal samples were obtained at specified timepoints for determination of abiraterone concentrations in the plasma, total radioactivity (TR), and the metabolite profile. 2. Most plasma AA concentrations were below the limit of quantification. The mean maximum plasma concentration (Cmax) of abiraterone was 10.4 ng/mL, mean area under the plasma concentration-time curve (AUC) from 0 to the last measurable plasma concentration (AUC0–last) was 74.8 ng·h/mL. The exposures for TR in plasma (Cmax = 3429 ng·eq/mL; AUC0–last = 26,683 ng eq·h/mL) and whole blood (Cmax = 1836 ng·eq/mL; AUC0–last = 12,162 ng·eq·h/mL) were >300-fold higher than abiraterone exposure in plasma. The majority of TR resided in the plasma compartment of blood. 3. Main circulating metabolites were abiraterone sulfate and N-oxide abiraterone sulfate. The main metabolite excreted in urine was N-oxide abiraterone sulfate (4.22% of TR). Major components of TR in faeces were unchanged AA (55.3% of TR) and abiraterone (22.3% of TR). Mean recovery of TR in faeces was 87.9%, indicating faeces as primary route of excretion.

Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis

Background There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. Methods Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III–IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. Findings We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53–0.71, p = 0.55 × 10−10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40–0.51, p = 0.66 × 10−36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III–IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. Interpretation Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.

Impact on abiraterone pharmacokinetics and safety: Open-label drug–drug interaction studies with ketoconazole and rifampicin

We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of abiraterone in two studies in healthy men. All subjects received 1,000 mg of abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11–16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8–13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, abiraterone exposure increased by 9% for maximum plasma concentration (Cmax) and 15% for area under the plasma concentration–time curve from 0 to time of the last quantifiable concentration (AUClast) and AUC from time 0 to infinity (AUC∞) compared to abiraterone acetate alone. Study B: When given with rifampicin, abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on abiraterone exposure. Rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with abiraterone acetate.

Single‐dose pharmacokinetic studies of abiraterone acetate in men with hepatic or renal impairment

Three open‐label, single‐dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non‐cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end‐stage renal disease (ESRD), and age‐, BMI‐matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125‐ and 2,000‐mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4‐fold in patients with moderate hepatic impairment. Despite a 16‐fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single‐dose administration of abiraterone acetate was well‐tolerated.

Phase 1b Study of Abiraterone Acetate Plus Prednisone and Docetaxel in Patients with Metastatic Castration-resistant Prostate Cancer

Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action. COU-AA-206 was a phase 1b study to determine the safe dose combination of docetaxel and AA + P in three cohorts of chemotherapy-naïve mCRPC patients. Twenty-two patients received escalating doses of docetaxel plus AA + P. The primary endpoint was the proportion of patients with a dose-limiting toxicity (DLT) between weeks 2 and 7. The recommended phase 2 dose (RP2D) was the highest safe combination of docetaxel plus AA + P. Prostate-specific antigen (PSA) changes and intensive pharmacokinetic parameters for each drug were evaluated. Docetaxel 75mg/m2 + AA 1000mg + P 10mg was deemed the RP2D, with DLT in one of six patients. PSA declines from baseline of ≥50% and ≥90% were observed for 85.7% and 66.7% of patients, respectively. During median follow-up of 14.5 mo, eight patients had PSA progression and six had radiographic progression or died. Systemic exposure was comparable for docetaxel and abiraterone when given alone or in combination. Studies are ongoing to confirm the efficacy of potent androgen receptor-targeted therapy plus taxane in early mCRPC. PATIENT SUMMARY The combination of hormonal therapy and chemotherapy may improve outcomes in men with metastatic prostate cancer. This study demonstrates the ability to combine the hormonal therapy agent abiraterone acetate, plus prednisone, and the chemotherapy drug docetaxel with an acceptable side effect profile. A high rate of prostate-specific antigen decline was seen, but the study was small and additional research is needed before this becomes a standard approach.

Efficacy and safety of abiraterone acetate plus prednisone in Japanese patients with newly diagnosed, metastatic hormone-naïve prostate cancer: a subgroup analysis of LATITUDE, a randomized, double-blind, placebo-controlled, Phase 3 study

Abiraterone acetate plus prednisone in addition to androgen-deprivation therapy (ADT) was efficacious versus ADT alone in Japanese men with metastatic hormone-naïve prostate cancer. No new safety concerns were identified.

665 EFFECT OF NEOADJUVANT ABIRATERONE ACETATE PLUS LEUPROLIDE ACETATE ON PSA, PATHOLOGIC RESPONSE, AND INTRAPROSTATIC/SERUM ANDROGEN LEVELS IN LOCALIZED HIGH-RISK PROSTATE CANCER: RESULTS OF A RANDOMIZED PHASE 2 STUDY

Jerome P. Richie*, Boston, MA; Robert B. Montgomery, Seattle, WA; Christopher J. Logothetis, Houston, TX; Glenn J. Bubley, Boston, MA; Bruce L. Dalkin, Seattle, WA; Martin G. Sanda, Massimo F. Loda, Rosina T. Lis, Boston, MA; Lawrence D. True, Seattle, WA; Patricia Troncoso, Houston, TX; Elizabeth M. Genega, Steven P. Balk, Boston, MA; Elahe A. Mostaghel, Seattle, WA; Trevor M. Penning, Philadelphia, PA; Peter S. Nelson, Seattle, WA; Wanling Xie, Boston, MA; Christopher M. Haqq, NamPhuong Tran, Weimin Peng, Los Angeles, CA; Daniel Tamae, Philadelphia, PA; Thian Kheoh, Arturo Molina, Los Angeles, CA; Philip W. Kantoff, Mary-Ellen Taplin, Boston, MA

Abstract A194: A QT/QTc and multi-dose pharmacokinetic (PK) study of abiraterone acetate (AA) plus prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Background: AA is the prodrug of abiraterone (A), an androgen biosynthesis inhibitor that selectively inhibits CYP17, thereby blocking testicular, adrenal, and prostatic intratumoral androgen biosynthesis. In a phase 3 study, AA+P demonstrated survival improvements in post-docetaxel mCRPC pts (De Bono ESMO 2010). ADT with an LHRH analog (LHRHa) has been associated with median QTc interval prolongation of 9–21 msec (Garnick ASCO 2004). Primary objective: effects of AA+P on QT/QTc interval duration in mCRPC pts receiving LHRHa. Secondary objectives: pharmacokinetics (PK) of AA and abiraterone (A) after single/multiple doses of AA. Methods: In this open-label, single-arm phase 1b study (COU-AA-006/NCT00910754), 33 mCRPC pts with disease progression after failure of GnRH hormone therapy, a PSA ≥2 ng/mL and ≤1 course of prior chemotherapy, received AA 1000mg orally QD + P 5mg orally BID. ECGs were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle (C)1 Day (D)-1. Serial ECG recordings and time-matched PK blood samples were collected over 24 hrs on C1D1 and C2D1. Serial PK blood samples were also collected over 24 hrs on C1D8. Results: After AA administration, the upper bound of the 2-sided 90% CI for the mean baseline-adjusted QTcF change was Conclusions: There is no significant effect of AA+P on the cardiac QT/QTc interval in mCRPC pts. No relationship between change in QTcF and A plasma concentration was observed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A194.