abiraterone-acetate and orteronel

We performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mCRPC) that has progressed after docetaxel. Pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel).. We included phase III randomized controlled trials that enrolled patients with mCRPC progressing during or after first-line docetaxel treatment. Trials were identified by electronic database searching. The primary outcome of the review was overall survival. Secondary outcomes were radiographic progression-free survival (rPFS) and severe adverse effects (grade 3 or higher).. Ten articles met the inclusion criteria for the review. These articles reported the results of five clinical trials, enrolling in total 5047 patients. The experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control cohorts (active drug-treated or placebo-treated), the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001), 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001). Pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, P < 0.00001). Androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects linked to elevated mineralocorticoid secretion, compared to placebo (risk ratio for hypokalemia: 5.75, 95% CI 2.08 to 15.90; P = 0.0008; risk-ratio for hypertension: 2.29, 95% CI 1.02 to 5.17; P = 0.05).. In docetaxel-pretreated patients enzalutamide, abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival of patients, compared to placebo or to best of care at the time of study (mitoxantrone-prednisone). Agents targeting the androgen axis (enzalutamide, abiraterone, orteronel) significantly prolonged rPFS, compared to placebo. Further investigation is warranted to evaluate the benefit of combination or sequential administration of these agents. Large-scale studies are also necessary to evaluate the impact of relevant toxic effects observed in a limited number of patients (e.g., enzalutamide-induced seizures, orteronel-induced pancreatitis, and others).

Topics: Abiraterone Acetate; Androstenes; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Evidence-Based Medicine; Humans; Imidazoles; Ipilimumab; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Risk Factors; Survival Analysis; Taxoids; Time Factors; Treatment Outcome

Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Androstenes; Antineoplastic Agents; Benzamides; Benzimidazoles; Combined Modality Therapy; Humans; Imidazoles; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Thiohydantoins

New drugs have recently been developed, through a better understanding of the mechanisms involved in the progression of prostate cancer, including castration-resistant ones (CRPC). This article aims to describe the mechanisms of action of these new hormonal treatments and their major clinical outcomes and development programs.. A bibliographic research in French and English using Medline(®) and Embase(®) using the keywords "castration-resistant prostate cancer", "abiraterone acetate", "orteronel", "enzalutamide", and "clinical trials" was performed.. the androgen signaling pathway remains the cornerstone of advanced cancers management. Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17. Others act as antagonists of the androgen receptor: the enzalutamide, RNA-509 and ODM201. Finally, galeterone combines the two effects.. Progress conferred by these molecules in terms of overall survival and quality of life in patients with metastatic CRPC, suggest that their use at earlier stages of the disease could reduce morbidity and mortality from prostate cancer. Determining the best strategy for sequence or combination therapy to optimize the use of these new molecules should be investigated.

Topics: Abiraterone Acetate; Androgen Antagonists; Androgen Receptor Antagonists; Androstadienes; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Imidazoles; Male; Naphthalenes; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Quality of Life; Steroid 17-alpha-Hydroxylase; Treatment Outcome

• It is >70 years since the responsiveness of symptomatic metastatic prostate cancer to androgen deprivation was first demonstrated. • Since those pivotal studies, progress in hormonal therapy of prostate cancer has been marked by several important developments and the availability of various androgen-suppressing agents. • Treatment guidelines have continued to evolve with clinical and therapeutic progress, but androgen-deprivation therapy (ADT) remains the standard of care for non-localised prostate cancer. • Because of the long-term experience (>20 years) and wealth of evidence from the large number of clinical trials, the luteinizing hormone-releasing hormone (LHRH) agonists are currently the main forms of ADT. • Treatment strategies should be adapted to the individual patient in terms of timing, duration and choice of agent. • Prostate cancer remains the most common type of cancer in men and the development of castration-resistant disease seems inevitable, which together drive the clear and continuing need for new, effective agents for ADT to be used alongside the LHRH agonists.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antineoplastic Agents, Hormonal; Benzamides; Combined Modality Therapy; Humans; Imidazoles; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Treatment Outcome

Topics: Abiraterone Acetate; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; Imidazoles; Kaplan-Meier Estimate; Male; Middle Aged; Naphthalenes; Neoplastic Cells, Circulating; Prednisolone; Prognosis; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome