Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: Exploratory analysis of data from the COU-AA-301 randomised trial

University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: .
The Lancet Oncology (Impact Factor: 24.69). 11/2012; 13(12). DOI: 10.1016/S1470-2045(12)70473-4
Source: PubMed


Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy.

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Available from: Ethan Basch, Apr 09, 2014
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    • "Most importantly, content validity has been established in this population, a key criterion necessary for FDA acceptance in supporting labeling claims. Furthermore, although evidence of known-groups validity was not identified for this measure, test-retest reliability, construct validity, and responsiveness have all been established in patients with mCRPC [[27],[34]]. Other key strengths of this measure include the brief (24-hour) recall period; the single-item assessment (low burden on patients to complete); the 11-point numeric rating scale, which is well-accepted by patients, clinicians, and the FDA; and information available to assist interpretation of clinical trial results in patients with mCRPC with bone metastases [[31]]. "
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    ABSTRACT: Background Metastatic castration-resistant prostate cancer (mCRPC) and its treatment significantly affect health-related quality of life (HRQOL). Our objectives were to evaluate and compare patient-reported outcome (PRO) claims granted by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for 5 recently approved mCRPC treatments and to examine key characteristics, development, and measurement properties of the PRO measures supporting these claims against current regulatory standards.Methods Five products approved for treatment of mCRPC by the FDA and the EMA (2010¿2013) were examined: enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and radium Ra 223 dichloride. United States (US) drug approval packages and European Public Assessment Reports were reviewed. PRO claims in the US labels and European Summaries of Product Characteristics and supporting measures were identified. For PRO measures supporting claims, a targeted literature review was conducted to identify information on key characteristics and measurement properties; this information was compared against FDA PRO guidance criteria.ResultsNine PRO ¿claims¿ were granted across 4 of 5 products reviewed. The EMA granted more claims (7 claims¿4 for pain, 3 for HRQOL) than the FDA (2 claims, both for pain). The Brief Pain Inventory¿Short Form (BPI-SF) worst pain item supported most pain claims and was the only measure supporting US claims. EMA pain claims were supported by BPI-SF worst pain (n¿=¿2) and average pain (n¿=¿1) items and the McGill Pain Questionnaire Present Pain Intensity component (n¿=¿1). EMA HRQOL claims were supported by the Functional Assessment of Cancer Therapy¿Prostate Module (n¿=¿2) and the EuroQol 5 Dimensions with visual analogue scale (n¿=¿1). Pain and prostate cancer¿specific HRQOL measures supporting claims met US regulatory standards for construct validity, reliability, and responsiveness; these properties were strongest for the BPI-SF worst pain item. Only the BPI-SF worst pain item has documented content validity in mCRPC.ConclusionsPRO label claims were commonly granted across the mCRPC products reviewed. Among the measures reviewed, only the BPI-SF worst pain item supported US label claims. The BPI-SF worst pain item is recommended for pain assessment for the evaluation of new mCRPC treatments.
    Full-text · Article · Jul 2014 · Health and Quality of Life Outcomes
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    • "The natural history of prostate cancer often includes painful bone metastases resulting in a decreased health-related quality of life (HRQoL), increase in skeletal-related events (fractures), and correlating with poor survival data on pain control and skeletal-related events was prospectively collected as part of the randomized, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone after docetaxel chemotherapy, as noted above.60 In this study of 1195 patients, 1068 had bone metastasis and an ECOG performance status of two or less. "
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    ABSTRACT: Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.
    Full-text · Article · Apr 2014 · Asian Journal of Andrology
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    • "Eur Urol (2014), j.eururo.2014.02.013 analgesic consumption reported in 12–29% of patients [14] [15]. Since the pain palliation signal and the reductions in narcotic use observed with cabozantinib substantially exceed these previously reported levels, an effect beyond placebo is likely and justifies the design and conduct of a dedicated pain palliation phase 3 trial towards a formal indication [16] [34]. "
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    ABSTRACT: Pain negatively affects quality of life for cancer patients. Preliminary data in metastatic castration-resistant prostate cancer (mCRPC) suggested a benefit of the oral tyrosine kinase inhibitor cabozantinib to pain palliation. Prospective evaluation of cabozantinib's benefits on pain and narcotic use in mCRPC. This was a nonrandomized expansion (NRE) cohort (n=144) of a phase 2 randomized discontinuation trial in docetaxel-refractory mCRPC patients. Pain and interference of symptoms with sleep and general activity were electronically self-reported daily for 7-d intervals at baseline and regularly scheduled throughout the study. Mean per-patient scores were calculated for each interval. Narcotic use was recorded daily during the same intervals. Open-label cabozantinib (100mg or 40mg). The following stringent response definition was used: clinically meaningful pain reduction (≥30% improvement in mean scores from baseline) confirmed at a later interval without concomitant increases in narcotics. Only patients with moderate or severe baseline pain were analyzed. Sixty-five patients with moderate or severe baseline pain were evaluable. Of these, 27 (42%) experienced pain palliation according to the stringent response definition. Thirty-seven patients (57%) had clinically meaningful pain relief at two consecutive intervals, reported ≥6 wk apart in the majority. Forty-four patients (68%) had palliation at one or more intervals; 36 (55%) decreased narcotics use during one or more intervals. Clinically meaningful pain reduction was associated with significant (p ≤ 0.001) improvements in sleep quality and general activity. A limitation of this study was its open-label design. Cabozantinib demonstrated clinically meaningful pain palliation, reduced or eliminated patients' narcotic use, and improved patient functioning, thus meriting prospective validation in phase 3 studies. We evaluated the potential of cabozantinib to improve symptoms in patients with metastatic prostate cancer that no longer responds to standard therapies. We saw a promising reduction in pain and reduced need for narcotic painkillers. Larger, well-controlled trials are necessary to confirm these findings.
    Full-text · Article · Feb 2014 · European Urology
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