TAK-700 salt

TAK-700 is an oral, selective, non-steroidal androgen synthesis inhibitor of the 17,20 lyase, which is a key enzyme in the production of steroidal hormones. In preclinical studies, TAK-700 has been shown to bind to and inhibit the enzyme 17,20 lygase in both the testes and adrenal glands. TAK-700 is currently under clinical Phase III studies.

Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5.[Pubmed:25624429]

J Clin Oncol. 2015 Mar 1;33(7):723-31.

PURPOSE: Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. PATIENTS AND METHODS: In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], >/= 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. RESULTS: The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). CONCLUSION: Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.

CYP17 inhibitors in prostate cancer: latest evidence and clinical potential.[Pubmed:27482286]

Ther Adv Med Oncol. 2016 Jul;8(4):267-75.

Since androgen signaling plays a pivotal role in the proliferation and metastasis of prostate cancer, androgen deprivation therapy (ADT) or castration therapy is considered the backbone of treatment for newly diagnosed metastatic prostate cancer. However, almost all men experience disease progression on ADT to a state known as metastatic castration-resistant prostate cancer (mCRPC), which continues to be driven by intratumoral androgen synthesis or androgen receptor signaling. Hence, the extragonadal ablation of androgen synthesis from pregnane precursors holds much promise. An inhibitor of cytochrome P450 17alpha-hydroxy/17,20-lyase (CYP17) enzymes, abiraterone acetate, has already been approved for men with mCRPC. Newer CYP17 inhibitors continue to be developed which are either more selective or have concomitant inhibitory actions on AR signaling. These include VT-464, orteronel, and galeterone. Herein, we focus on the molecular mechanism of action, efficacy, latest evidence, and clinical potential of CYP17 inhibitors in prostate cancer.

Management of castrate resistant prostate cancer-recent advances and optimal sequence of treatments.[Pubmed:23559076]

Curr Urol Rep. 2013 Jun;14(3):174-83.

Until 2010, chemotherapy with docetaxel was the only approved agent for treatment of metastatic castrate resistant prostate cancer (mCRPC). Since then, the therapeutic landscape of mCRPC has changed rapidly. Multiple novel agents have received regulatory approval after demonstrating improved overall survival in separate randomized Phase 3 studies. These include immunotherapeutic agent sipuleucel-T, androgen axis inhibitors abiraterone and enzalutamide, and a novel microtubule inhibitor cabazitaxel. More recently, radium-223, a bone-targeting alpha emitting radiopharmaceutical, was reported to improve skeletal related events, as well as overall survival in a Phase 3 randomized study. Additionally, there are several promising agents in the advanced stages of clinical development. Here, we describe the agents recently shown to improve overall survival, and those that have reached the advanced stages of development in Phase 3 clinical trials. We will also propose a strategy for optimal sequencing of these agents in the treatment of mCRPC.

Integration of Bone and Computed Tomography Scans to Assess Bone Metastasis in Metastatic Castration-Resistant Prostate Cancer.[Pubmed:27338517]

Clin Genitourin Cancer. 2017 Feb;15(1):53-59.

BACKGROUND: Progression of bone metastasis in metastatic castrate-resistant prostate cancer (mCRPC) is assessed using bone scan (BS) and correlates modestly with overall survival (OS). Because of the poor reliability of BS and routinely performed computed tomography (CT) scans, we assessed bone progression by integrating BS and CT. PATIENTS AND METHODS: Data were obtained from patients receiving docetaxel chemotherapy or postdocetaxel orteronel with baseline and on-therapy CT and BS within 90 days. Imaging underwent central radiology review by a single dedicated radiologist. Progressive disease (PD) was defined as >/= 1 new lesion on either BS or CT. Cox proportional hazards regression was used to explore potential prognosticators of OS. RESULTS: Twenty-eight patients were evaluable. The mean age was 71.4 years and median OS was 18.4 (range, 9.7-35.4) months. Four patients (14.3%) had PD on BS and CT scan, and 2 (7.1%) had PD on CT scan but not on BS, and 3 (10.7%) had PD on BS but not CT scan. Patients with PD on BS or CT scan had worse OS (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.04-6.90; P = .041) than those with no PD on either CT or BS. When examining individual lesions, 4 patients had >/= 1 new lesion identified on CT but not BS, and they were associated with worse OS (HR, 3.72; 95% CI, 1.01-13.66; P = .048). No significant difference in OS was observed for 4 patients with new lesions on BS but not CT scan. CONCLUSION: Results of this hypothesis-generating study suggest that the integration of >/= 1 new lesion on CT and/or BS within 90 days in mCRPC might better capture bone progression and predict OS. This composite metric needs to be compared with current criteria.

Emerging molecularly targeted therapies in castration refractory prostate cancer.[Pubmed:23819055]

Prostate Cancer. 2013;2013:981684.

Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.