Effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy

Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy.
Annals of Oncology (Impact Factor: 7.04). 11/2012; 24(4). DOI: 10.1093/annonc/mds585
Source: PubMed


Fatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument.Patients and methodsThe Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes.ResultsA total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155).Conclusions
In patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.

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Available from: Arturo Molina, Nov 30, 2015
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    • "Other symptoms of mCRPC include anorexia, anxiety, constipation, diarrhea, sleep disturbance, mucositis, nausea, peripheral sensory neuropathy, rash, vomiting, and urinary symptoms [[3]]. Fatigue is another dominant PC symptom and the most common adverse event resulting from mCRPC treatment [[4]]. These disease symptoms and noted side effects of treatment can significantly affect health-related quality of life (HRQOL). "
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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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    • "Six drugs with different mechanisms of action have been shown to prolong overall survival (OS) in CRPC patients, namely the tubulin targeting chemotherapies docetaxel and cabazitaxel, the immunotherapy sipuleucel-T , the androgen biosynthesis inhibitor abiraterone, the second generation androgen receptor (AR) antagonist enzalutamide and the alpha-emitting radiopharmaceutical radium-223[Kantoff et al. 2010;Ryan et al. 2013b;de Bono et al. 2011;Scher et al. 2012;Parker et al. 2012Parker et al. , 2013Tannock et al. 2004](see Table 1). Patients with CRPC live longer and maintain better quality of lifeOmlin et al. 2013;Nilsson et al. 2013;Logothetis et al. 2012;Sternberg et al. 2013]. The available preclinical and clinical data regarding treatment sequencing in CRPC are discussed in the following sections. "
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    ABSTRACT: In the last three years, five novel treatments have been shown to improve survival in metastatic castration-resistant prostate cancer (CRPC). These novel treatments have distinct mechanisms of action: tubulin-binding chemotherapy (cabazitaxel); immunotherapy (sipuleucel-T); CYP-17 inhibition (abiraterone); androgen receptor (AR) blockade (enzalutamide); and radioisotope therapy (radium-223). For a number of years, docetaxel was the only treatment with a proven survival benefit for patients with CRPC. Therefore, somewhat artificially, three treatment spaces for drug development in CRPC have emerged: pre-docetaxel; docetaxel combinations; and post-docetaxel. For patients progressing after docetaxel-based chemotherapy, treatment options available outside of clinical trials now include abiraterone, cabazitaxel and enzalutamide. Prospective data on how to best use these novel agents sequentially are not available. Clinicians face the difficult task of choosing between treatment options for individual patients to maximize patient benefit. Treatment evaluation in patients with CRPC remains challenging due to the predominance of bone metastatic disease and the lack of validated surrogate markers for survival. This review summarizes the data available with regards to sequencing of the novel treatments for CRPC.
    Preview · Article · Feb 2014 · Therapeutic Advances in Urology
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    • "In patients with clinically significant fatigue at baseline, abiraterone significantly increased the number of patients reporting an improvement in fatigue intensity (58.1% versus 40.3%; P=0.0001) as well as the time to fatigue palliation (median 59 days versus 194 days; P=0.0155).78 In patients with clinically significant pain at baseline, abiraterone significantly increased the number of patients reporting palliation of pain (45% versus 28.8%; P=0.0005), as well as faster palliation (median time to palliation 5.6 months versus 13.7 months; P=0.0018). "
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    ABSTRACT: Androgen deprivation therapy remains the single most effective treatment for the initial therapy of advanced prostate cancer, but is uniformly marked by progression to castration-resistant prostate cancer (CRPC). Residual tumor androgens and androgen axis activation are now recognized to play a prominent role in mediating CRPC progression. Despite suppression of circulating testosterone to castrate levels, castration does not eliminate androgens from the prostate tumor microenvironment and residual androgen levels are well within the range capable of activating the androgen receptor (AR) and AR-mediated gene expression. Accordingly, therapeutic strategies that more effectively target production of intratumoral androgens are necessary. The introduction of abiraterone, a potent suppressor of cytochrome P450 17 α-hydroxysteroid dehydrogenase-mediated androgen production, has heralded a new era in the hormonal treatment of men with metastatic CRPC. Herein, the androgen and AR-mediated mechanisms that contribute to CRPC progression and establish cytochrome P450 17 α-hydroxysteroid dehydrogenase as a critical therapeutic target are briefly reviewed. The mechanism of action and pharmacokinetics of abiraterone are reviewed and its recently described activity against AR and 3-β-hydroxysteroid dehydrogenase is discussed. The Phase I and II data initially demonstrating the efficacy of abiraterone and Phase III data supporting its approval for patients with metastatic CRPC are reviewed. The safety and tolerability of abiraterone, including the incidence and management of side effects and potential drug interactions, are discussed. The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross-resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an abiraterone withdrawal response are presented. Future directions in the use of abiraterone, including optimal dosing strategies, the role of abiraterone in earlier disease settings, including castration sensitive, biochemically recurrent, or localized disease, and the rationale for combinatorial treatment strategies of abiraterone with enzalutamide and other targeted agents are also discussed.
    Full-text · Article · Jan 2014 · Cancer Management and Research
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