Most cases occur in men aged 70 years and older. Indeed, age is the biggest risk factor for prostate cancer. Risk is also increased in families with a history of the disease, especially where onset was before 60 years of age. Although there have been major improvements in survival rates over the past 20 years, in many Western countries it remains the second most common cause of cancer-related death in men. New drugs are needed to address significant treatment gaps in advanced prostate cancer, notably in hormone refractory prostate cancer HRPC.
Hormone therapy has an important place in the treatment of prostate cancer, predicated on the basis that androgens testosterone fuel the growth of prostate cancer cells. While surgical castration is used in some cases, most patients today receive drug-based hormone therapy with either pituitary down regulators LHRH agonists or anti-androgens medical castration.
Luteinising hormone releasing hormone LHRH agonists act via the pituitary gland to suppress testosterone production, while anti-androgens act on testosterone production in the testes. These drugs are usually administered alone but may be given concomitantly to prevent tumour flare or if the cancer is becoming resistant to single-agent therapy.
Abiraterone is a new hormonal therapy. Administered orally, it blocks cytochrome p17, a steroidal enzyme that is essential to testosterone production.
By blocking the action of CYPc17, abiraterone not only inhibits testosterone production in the testes but also in other testosterone-producing tissues such as the adrenal glands and in the tumour cells as well. In this respect it differs from currently available hormone therapies, which suppress testosterone production in the testes. Evidence that abiraterone may be an effective hormonal treatment for prostate cancer first emerged from a phase I trial in 21 men with HRPC.
These changes were also accompanied by symptomatic improvements, such as reduced pain. Castration-resistant prostate cancer CRPC may develop regardless of surgical or pharmacological castration therapies.
It is also being studied in patients with earlier-stage prostate cancer and in women with metastatic breast cancer. Abiraterone acetate is converted to abiraterone in vivo. DHEA and androstenedione are precursors of testosterone. The administration of abiraterone may potentiate mineralocorticoid production by the adrenal glands via inhibition of CYP Increased mineralocorticoid synthesis occurs as a result of enhanced deoxycorticosterone conversion from pregnenolone.
This may potentially lead to fluid retention, hypertension, and hypokalemia. The pharmacokinetic properties of abiraterone acetate have been studied in healthy subjects and in patients with CRPC.
In dose-ranging studies, the median time to reach maximum plasma concentrations C max of abiraterone was 2 hours. There is significant variability in the absorption of abiraterone acetate, depending on whether it is administered with or without food. In clinical trials, patients taking abiraterone with high-fat meals had a 4. Based on the extent of variability in exposure when abiraterone is taken with a high-fat food content, and given the normal variations in the content and composition of meals that cannot be controlled outside of the clinical trial setting, the FDA has requested that the product labeling reflect that abiraterone has to be administered 2 hours before meals.
Abiraterone acetate has been studies in phase 2 and phase 3 clinical trials. Of 47 patients, 45 had bone metastases at trial initiation. All patients in the study previously received luteinizing hormone—releasing hormone LHRH agonists and experienced disease progression. Patients received abiraterone acetate 1, mg four capsules of mg each in day cycles. Because of an accumulation of mineralocorticoids, some patients experienced hypertension, hypokalemia, and fluid retention.
These patients were managed with eplerenone Inspra, Pfizer 50 to mg or with low-dose glucocorticoids. Bone scans and computed tomography CT were performed at baseline and at 3 and 6 months. PSA, albumin, liver and renal function tests, and alkaline phosphatase levels were monitored at baseline and then every 4 weeks. The median time to PSA progression was 24 weeks.
Most of the patients received the study drug for 12 to 48 weeks. Three patients died during the study, but these deaths were not attributed to the medication. The promising results of this trial led to the development of a phase 3 clinical study. The second phase 2 trial was a multicenter, open-label, single-arm study of abiraterone plus prednisone in patients with docetaxel-treated CRPC.
The investigators anticipated phase 3 progression of abiraterone acetate and designed the trial to address the outcome of the number and type of prior hormone treatments, mainly ketoconazole Nizoral, Janssen.
Patients received abiraterone acetate 1, mg four mg tablets in the morning on an empty stomach plus prednisone 5 mg by mouth twice daily for day cycles a minimum of 12 cycles. Complete blood count, basic metabolic panel, and PSA and androgen levels were evaluated monthly.
Men were enrolled in seven study centers from June to November In the ketoconazole subgroup, the median time to PSA progression was approximately No deaths or major adverse reactions were reported throughout the study period. As with the previous phase 2 study, it was concluded that there was enough evidence to progress to a phase 3 trial.
The investigators also determined that co-administration of prednisone 5 mg twice daily with abiraterone acetate decreased mineralocorticoid-related adverse events. The phase 3 trial was a randomized, double-blind, placebo-controlled study of abiraterone acetate plus prednisone or placebo that evaluated prolongation of overall survival among patients with metastatic CRPC.
Enrollees received abiraterone acetate for day cycles until the PSA level, radiography, or clinical findings showed disease progression. The median age of the patients was 69 years. Patients received treatment for a median time of 8 months and 4 months in the abiraterone acetate and placebo groups, respectively. N Engl J Med ;— Abiraterone acetate therapy resulted in increased survival in all treatment groups, compared with placebo, and was associated with a low frequency of treatment-related adverse events.
There were no significant differences in fatal cardiac events between the two groups. The publisher's final edited version of this article is available at N Engl J Med. This article has been corrected. See the correction in volume on page See other articles in PMC that cite the published article. Associated Data Supplementary Materials Abstract Background Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival OS in metastatic castration-resistant prostate cancer mCRPC post-chemotherapy.
Methods In this double-blind study, patients were randomized to abiraterone acetate mg plus prednisone 5 mg twice daily or placebo plus prednisone. Keywords: Abiraterone acetate, prednisone, metastatic castration-resistant prostate cancer, androgen, CYP Table 1 Demographics and Baseline Disease Characteristics. Open in a separate window.
Figure 1. Radiographic Progression-free Survival B. Note: Hazard ratio is based on a nonstratified proportional hazards model C. Overall Survival D. Secondary End Points Secondary end points are summarized in Table 2. Figure 2. Time to Initiation of Cytotoxic Chemotherapy C. Time to Prostate-specific Antigen Progression. Other End Points Time to pain progression was Supplementary Material 01 Click here to view. Global cancer statistics.
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