Prostate cancer (PCa) is the second most common cause of cancer‐related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to ...the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand‐binding domain LBD, DNA‐binding domain DBD, and transactivation domain TAD) in its structure. All clinically approved drugs for PCa ultimately target the AR‐LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR‐TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge–derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies.
Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New ...treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.
In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.
The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval CI, 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.
Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
Androgen receptor (AR) is an effective therapeutic target for the treatment of prostate cancer. We report herein the design, synthesis, and biological evaluation of highly effective proteolysis ...targeting chimeras (PROTAC) androgen receptor (AR) degraders, such as compound A031. It could induce the degradation of AR protein in VCaP cell lines in a time-dependent manner, achieving the IC 50 value of less than 0.25 μM. The A031 is 5 times less toxic than EZLA and works with an appropriate half-life (t 1/2) or clearance rate (Cl). Also, it has a significant inhibitory effect on tumor growth in zebrafish transplanted with human prostate cancer (VCaP). Therefore, A031 provides a further idea of developing novel drugs for prostate cancer.
Androgen receptor (AR) is an effective therapeutic target for the treatment of prostate cancer. We report herein the design, synthesis, and biological evaluation of highly effective proteolysis targeting chimeras (PROTAC) androgen receptor (AR) degraders, such as compound A031. It could induce the degradation of AR protein in VCaP cell lines in a time-dependent manner, achieving the IC50 value of less than 0.25 μM. The A031 is 5 times less toxic than EZLA and works with an appropriate half-life (t1/2) or clearance rate (Cl). Also, it has a significant inhibitory effect on tumor growth in zebrafish transplanted with human prostate cancer (VCaP). Therefore, A031 provides a further idea of developing novel drugs for prostate cancer. Display omitted
Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is ...important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers.
Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer cell lines. Pharmacokinetic and xenograft studies were performed in immunocompromised rats and mice.
UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the
proliferation and
growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-protein-coupled receptor kinase and nuclear receptor family members.
Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.
Purpose
Seviteronel (INO-464) is an oral, selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor inhibitor with in vitro and in vivo anti-tumor activity. This open-label ...phase 1 clinical study evaluated safety, tolerability, pharmacokinetics (PK), and activity of once-daily (QD) seviteronel in women with locally advanced or metastatic TNBC or ER+ breast cancer.
Methods
Seviteronel was administered in de-escalating 750, 600, and 450 mg QD 6-subject cohorts. The 750 mg QD start dose was a phase 2 dose determined for men with castration-resistant prostate cancer in (Shore et al. J Clin Oncol 34, 2016). Enrollment at lower doses was initiated in the presence of dose-limiting toxicities (DLTs). The primary objective of this study was to determine seviteronel safety, tolerability, and MTD. The secondary objectives included description of its PK in women and its initial activity, including clinical benefit rate at 4 (CBR16) and 6 months (CBR24).
Results
Nineteen women were enrolled. A majority of adverse events (AEs) were Grade (Gr) 1/2, independent of relationship; the most common were tremor (42%), nausea (42%), vomiting (37%), and fatigue (37%). Four Gr 3/4 AEs (anemia, delirium, mental status change, and confusional state) deemed possibly related to seviteronel occurred in four subjects. DLTs were observed at 750 mg (Gr 3 confusional state with paranoia) and 600 mg (Gr 3 mental status change and Gr 3 delirium) QD, with none at 450 mg QD. The recommended phase 2 dose (RP2D) was 450 mg QD, and at the RP2D, 4 of 7 subjects reached at least CBR16 (2 TNBC subjects and 2 ER+ subjects achieved CBR16 and CBR24, respectively); no objective tumor responses were reported.
Conclusions
Once-daily seviteronel was generally well tolerated in women with and 450 mg QD was chosen as the RP2D.
Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an ...estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.
Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis ...and death in men with nonmetastatic, castration-resistant prostate cancer.
We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg two 300-mg tablets twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks.
In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P<0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo.
Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).
Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to ...testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.
In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.
A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval CI, 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.
Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).
PDF
