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CYP17 inhibitors in prostate cancer: latest evidence and clinical potential:

CYP17 inhibitors in prostate cancer: latest evidence and clinical potential: 642370 TAM0010.1177/1758834016642370Therapeutic Advances in Medical OncologyAB Alex, SK Pal research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol CYP17 inhibitors in prostate cancer: latest 2016, Vol. 8(4) 267 –275 DOI: 10.1177/ evidence and clinical potential © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ Anitha B. Alex, Sumanta K. Pal and Neeraj Agarwal journalsPermissions.nav Abstract: 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 17α−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. Keywords: abiraterone, androgen biosynthesis, androgen receptors, castration-resistant prostate cancer, cytochrome P450 17α−hydroxy/17,20-lyase inhibitors, galeterone, orteronel, VT-464 Correspondence to: Introduction CYP17 enzymes, CYP17 hydroxylase and Neeraj Agarwal, MD Division of Medical The cytochrome P450 (CYP) superfamily of CYP17,20 lyase, sequentially catalyze the conver- Oncology, Department of enzymes mediates the catalytic conversion of sion of pregnenolone and progesterone to 17α Medicine, University of Utah Huntsman Cancer drugs to reactive products that can bind to mac- hydroxypregnenolone and 17α hydroxyprogester- Institute, 1950 Circle of romolecules, like proteins and DNA. CYP one, which are then further converted to the weak Hope, Salt Lake City, UT 84112, USA enzymes account for approximately 75% of the androgens, dehydroepiandrosterone (DHEA) neeraj.agarwal@hci. total drug metabolism [Guengerich, 2008]. In and androstenedione, respectively (Figure 1) utah.edu addition, they also play a vital role in the synthesis [Poole et al. 2014]. Both DHEA and androsten- Anitha B. Alex, PhD Division of Medical of steroid hormones, cholesterol, and vitamin D edione, are eventually transformed into testoster- Oncology, Department of metabolism. Fifty-seven human CYPs identified one and dihydroxy testosterone (DHT), the most Medicine, University of Utah Huntsman Cancer were classified into 18 families and 43 subfami- potent androgen. Metastatic prostate cancer is Institute, Salt Lake City, lies, of which CYP families 1, 2, and 3 are mainly fueled by the androgen axis, and despite the UT, USA responsible for the metabolism of drugs. androgen ablation therapy, almost all men with Sumanta K. Pal, MD Medical Oncology Evidences support the role of CYPs in tumor for- metastatic prostate cancer progress to having cas- & Experimental mation and inhibition of CYPs has become a key tration-resistant prostate cancer (mCRPC), Therapeutics, City of Hope Comprehensive Cancer area in the treatment of cancer [Lohr et al. 2004; which still maintains its dependence on intratu- Center, Duarte, CA, USA Bruno and Njar, 2007]. CYP17α hydroxy- moral androgen synthesis and androgen receptor lase/17,20 lyase (CYP17), a pivotal enzyme for (AR) signaling for proliferation. Abiraterone ace- androgen synthesis, has been implicated in the tate (AA), a CYP17 inhibitor, is the first US Food pathogenesis of prostate cancer [Vasaitis et  al. and Drug Administration (FDA) approved drug 2011]. In fact, an increased expression of CYP17 of its class for the treatment of mCRPC [Bryce has been demonstrated in prostate carcinoma, and Ryan, 2012]. The next generation CYP17 which correlated positively with a high-stage, high inhibitors currently being evaluated in clinical trials Gleason score, and short relapse-free time disease for metastatic prostate cancer include orteronel [Stigliano et al. 2007]. (TAK 700, Takeda Pharmaceuticals, Deerfield, http://tam.sagepub.com 267 Therapeutic Advances in Medical Oncology 8(4) Figure 1. Cytochrome P450 (CYP) 17 inhibitors targeting androgen synthesis and androgen receptors (ARs), currently approved and those in advanced stages of clinical development in castration-sensitive or -resistant prostate cancer. Thick arrows denote stimulation, flat lines denote inhibition, and thin arrows denote synthesis. DHEA, dehydroepiandrosterone; DHT, dihydroxy testosterone. Table 1. Various cytochrome P450 (CYP) 17 inhibitors and their mechanisms of action. CYP17 inhibitors Mechanism of action Abiraterone and D4A Inhibition of 17α hydroxylase and 17,20 lyase; 17β hydroxysteroid dehydrogenase and steroid 5α reductase; AR antagonism Orteronel (TAK-700) Selective inhibition of 17,20 lyase over 17α hydroxylase Viamet (VT-464) Selective inhibition of 17,20 lyase over 17α hydroxylase; AR antagonism Galeterone (TOK-001) 17α hydroxylase and 17,20 lyase inhibition; AR antagonism; downregulation of AR protein expression CFG920 Dual CYP17/CYP11B2 inhibitor AR, androgen receptor. IL, USA), VT-464 (Viamet Pharmaceuticals, blocks 17β-hydroxysteroid dehydrogenase and Durham, North Carolina, USA), and galeterone steroid 5α reductase, which are required for DHT (TOK-001, Tokai Pharmaceuticals, Boston, MA, synthesis, in addition to CYP17A1 enzymes [Li USA). et al. 2015]. Remarkably, D4A was also shown to have a direct inhibitory effect on AR, comparable to that seen with enzalutamide, a potent AR Molecular mechanisms, efficacy, and latest antagonist. Furthermore, D4A exhibited a higher evidence level of the overall antitumor activity than AA in the xenograft prostate tumors. Abiraterone acetate AA, a pregnenolone analogue, and its metabolite, In the earlier phase I and II trials, AA was found to abiraterone, are selective inhibitors of the CYP17 be safe and effective in lowering serum androgen enzymes, 17α hydroxylase and 17,20 lyase levels [Attard et  al. 2008; Ryan et  al. 2010]. (Table 1). Recently, it has been shown that a However, a sixfold increase in adrenocorticotropic more active form of AA, ∆ abiraterone (D4A), hormone (ACTH) was observed, leading to 268 http://tam.sagepub.com AB Alex, SK Pal et al. secondary mineralocorticoid excess, which precip- 940 placebo) revealed that AA significantly pro- itated in the form of hypokalemia, fluid retention, longed the OS, radiographic PFS, and time to and hypertension. To avoid the mineralocorticoid progression without any evidence of unexpected toxicities, a corticosteroid, prednisone, was added toxicity in patients with mCRPC, regardless of on as a concomitant therapy. However, a miner- prior chemotherapy or not [Zhou et al. 2014]. In alocorticoid receptor antagonist, eplerenone, in addition, an updated analysis of the COU-AA-301 conjunction with AA may preclude the require- and COU-AA-302 trials suggests a strong associ- ment for prednisone [Attard et  al. 2008]. This is ation between PSA kinetics and OS in chemo- especially pertinent in those men who have asymp- therapy-pretreated and naïve patients [Xu et  al. tomatic or minimally symptomatic mCRPC, and 2015]. Thus, the overall evidence supports the in whom long-term use of a corticosteroid may not continued use of AA as a standard therapy for be desirable. A significant increase in the absorp- mCRPC. tion of AA was observed when taken with a high- fat meal [Ryan et al. 2010], and to avoid any dietary variations, the FDA recommends taking AA on an Orteronel empty stomach. Orteronel (TAK-700) is an oral, nonsteroidal 17,20-lyase inhibitor with higher specificity for Based on the results of the COU-AA-301 trial, 17,20 lyase over 17 hydroxylase; hence it is likely the FDA approved the use of AA for the treat- more selective in its mechanism of action com- ment of mCRPC in the post-chemotherapy set- pared with AA. In a phase III study, orteronel was ting in April 2011 [De Bono et  al. 2011]. The evaluated in patients with mCRPC that pro- COU-AA 301 trial observed an overall survival gressed after docetaxel therapy. One thousand (OS) benefit, increase in time to prostate-specific and ninety-nine men were randomly assigned in a antigen (PSA) progression and progression-free 2:1 schedule to receive orteronel 400 mg plus survival (PFS) in patients in the AA group over prednisone 5 mg twice daily or placebo plus pred- the placebo group (median OS, 15.8 versus 11.2 nisone 5 mg twice daily, stratified by region months; median time to PSA progression, 8.5 (Europe, North America, and non-Europe/North versus 6.6 months; median radiologic PFS, 5.6 America) [Fizazi et  al. 2015]. The results indi- versus 3.6 months). The PSA decline was at least cated improved radiographic PFS with orteronel– 50% in 29% of the patients in the AA arm com- prednisone (median, 8.3 versus 5.7 months; HR, pared with 6% in the placebo arm [Fizazi et  al. 0.760; 95% CI, 0.653–0.885; p < 0.001). 2012]. Later studies have demonstrated its effi- Similarly, PSA 50, i.e. 50% reduction in PSA cacy in chemotherapy-naïve patients with (25% versus 10%; p<0.001), and time to PSA mCRPC. In a phase III randomized trial with a progression (median, 5.5 versus 2.9 months; median follow up of more than 4 years, treatment p < 0.001) were also significantly different from with AA prolonged OS compared with pred- the placebo–prednisone arm. The median OS, nisone alone [34.7 versus 30.3 months; hazard the primary endpoint, did not reach statistical sig- ratio (HR), 0.81; 95% confidence interval (CI), nificance in patients with mCRPC post docetaxel 0.70–0.93; p = 0.0033], suggesting its favorable [Fizazi et al. 2014], which could be attributed to efficacy and safety profile in chemotherapy-naive the fact that TAK-700 is a reversible inhibitor. patients as well [Ryan et al. 2015]. However, when men were stratified by regions, a significant improvement in OS was seen in men Though AA is reported to be effective after keto- in the non-Europe/North American regions (15.3 conazole treatment [Danila et al. 2010; Ryan et al. versus 10.1 months, p = 0.019), despite having 2010; Kim et  al. 2014], its efficacy is greater in similar baseline clinical and disease characteris- patients who had not received ketoconazole, tics. This discrepancy in OS by region may have chemotherapy, or enzalutamide, a novel AR been related to the decreased exposure to post- antagonist [Bryce and Ryan, 2012; Cheng et  al. trial treatment with AA and enzalutamide, as 2015; Ryan et al. 2015]. Reports indicate that the these agents were available earlier in North benefits of AA on clinical outcomes were increased American and European regions. with concomitant bone-targeted therapy [Saad et  al. 2015b]. Further, a systematic review and Similarly, the results from a phase III trial in meta-analysis based on the results from 10 trials, chemotherapy naïve patients with mCRPC also including two phase III trials (COU-AA-301 and revealed that treatment with orteronel failed to COU-AA-302), with 2283 patients (1343 AA; improve the OS (31.4 months in the orteronel http://tam.sagepub.com 269 Therapeutic Advances in Medical Oncology 8(4) plus prednisone versus 29.5 months in the pla- 300–600 mg VT-464 twice daily had PSA cebo plus prednisone group; HR, 0.92; 95% CI, responses, ranging from 30% to 90%. More inter- 0.79–1.08; p = 0.31) [Saad et  al. 2015a]. estingly, preliminary PSA responses in patients Nevertheless, the radiographic PFS was pro- with treatment failure indicate a 90% response in longed in the orteronel plus prednisone group. a patient who had prior enzalutamide prechemo- Based on these data, orteronel is no longer being therapy, and a 50% response in patients who had developed in the setting of mCRPC, although an prior enzalutamide and prior chemotherapy. ongoing phase III trial through the National However, no mineralocorticoid excess syndrome Clinical Trials Network continue to explore the and changes in ACTH responses were observed, potential of orteronel in men with new castration- despite not using any supplemental steroids. naïve metastatic prostate cancer. Galeterone VT-464 Galeterone (VN/124-1, TOK-001) is a CYP17 VT-464 is a novel, nonsteroidal CYP17 inhibitor inhibitor with multiple mechanisms of action, and AR antagonist. VT-464 blocks AR variants including CYP17 inhibition, AR antagonism, and F877L and T878A, which have been shown to be decrease in intratumoral AR levels. Preclinical associated with resistance to enzalutamide and results indicate that treatment with VN/124-1 AA, respectively. VT-464 preferentially inhibits caused marked downregulation of AR protein 17,20 lyase over 17α hydroxylase, thus offering expression, in contrast to treatments with bicalu- an advantage over AA from the perspective of not tamide or androgen deprivation therapy (ADT), requiring concomitant therapy with prednisone, which may induce upregulation of AR protein owing to its minimal effects on upstream steroid expression [Vasaitis et al. 2008]. It also caused a levels [Suzman and Antonarakis, 2014]. significant reduction in tumor growth compared with AA [Bruno et  al. 2011]. It has been sug- Results from the studies on castrate-resistant gested that the multifaceted action of galeterone prostate cancer cell lines and xenograft models may assist in overcoming the resistance observed that are either enzalutamide responsive or resist- with other CYP17 inhibitors [Stein et al. 2014]. ant, indicate that VT-464 demonstrated a greater decrease in AR transactivation compared with AA In a phase I study of chemonaïve men with in both enzalutamide-sensitive and -resistant cell mCRPC, galeterone was well tolerated. Of 49 lines [Toren et al. 2015]. At gene and protein lev- patients, 22% demonstrated a decrease in PSA of els, VT-464 suppressed the AR axis to a greater more than 50%, while an additional 26% had extent compared with AA. Further, intratumoral PSA decline of 30–50% after 12 weeks. No evi- androgen levels and PSA decrease trends were dence of adrenal mineralocorticoid excess was significantly lower with VT-464 than with AA, in noted [Montgomery et  al. 2012; Taplin et  al. addition to a more potent tumor growth inhibi- 2012]. A phase II trial is currently being under- tion. These data suggest greater suppression of taken to evaluate the efficacy of galeterone in 144 the AR axis with VT-464 than AA, which is likely patients with progressive castration-resistant due to its superior selective suppression of andro- prostate cancer, stratified to no prior CYP17 gen synthesis and direct AR antagonism. inhibitor or enzalutamide, AA-refractory PC, and enzalutamide-refractory mCRPC. The primary Based on these encouraging data, a phase I/II trial endpoints are reduction in PSA and safety. (INO-VT-464-CL-001) is being conducted in four subgroups of men with mCRPC: treatment naïve, that is with no prior treatment with AA, Clinical potential enzalutamide, or chemotherapy; prior treatment Despite the recent advances in the therapeutic with AA but not with chemotherapy or enzaluta- regimen, the gain in OS had been modest, and mide; prior treatment with enzalutamide but not prostate cancer still remains the second leading with AA or chemotherapy; and prior treatment cause of cancer-related death in men. The impli- with both AA and enzalutamide, or chemother- cations of novel CYP17 inhibitors in nonmeta- apy. Early results from the INO-VT-464-CL-001 static and metastatic prostate cancer are being trial [ClinicalTrials.gov identifier: NCT02012920] explored in ongoing clinical trials (Table 2). in mCRPC are promising [De Bono et al. 2015]. Herein, some of the most pertinent studies have Nineteen of 26 treatment-naïve men who received been highlighted. 270 http://tam.sagepub.com AB Alex, SK Pal et al. Table 2. Selected ongoing clinical trials of cytochrome P450 (CYP) 17 inhibitors in metastatic prostate cancer. Patient population Study phase Intervention/arms Accrual (N) ClinicalTrials. gov identifier Prostate cancer with a II Abiraterone versus Ongoing* (120) NCT01751451 rising PSA or a rising abiraterone + PSA and nodal disease degarelix or degarelix following definitive radical alone prostatectomy Progressive chemotherapy- II Abiraterone + Ongoing* (70) NCT02077634 naïve castration-resistant prednisone + LHRH prostate cancer (SPARE) therapy versus abiraterone + prednisone Metastatic hormone-naïve III ADT ± local RT ± Ongoing* (916) NCT01957436 prostate cancer (PEACE1) abiraterone acetate Newly diagnosed metastatic III ADT + TAK-700 versus Open* (1486) NCT01809691 sensitive prostate cancer ADT + bicalutamide CRPC II Galeterone Ongoing (144) NCT01709734 Patients with metastatic III Galeterone versus Open* (148) NCT02438007 CRPC expressing AR-V7 enzalutamide mRNA Patients with CRPC who I/II CFG920 Ongoing, not NCT01647789 are abiraterone naive or recruiting (31) abiraterone resistant *Currently recruiting. ADT, androgen deprivation therapy; AR-V7, androgen receptor splice variant 7; CRPC, castration-resistant prostate cancer; LHRH, luteinizing hormone releasing hormone; orteronel, TAK-700. Abiraterone acetate A crossover phase II study is ongoing to evaluate A phase II, randomized, three-arm study of whether treatment with ADT in combination AA alone, AA plus degarelix, a Gonadotropin- with AA and prednisone for 8 months controls releasing hormone (GnRH) antagonist, and the disease better than treatment with standard degarelix alone for patients with a rising PSA or ADT alone in patients with prostate cancer who a rising PSA and nodal disease following defini- have PSA progression after prostatectomy or tive radical prostatectomy is currently recruit- radiotherapy [luteinizing hormone releasing hor- ing patients [ClinicalTrials.gov identifier: mone (LHRH) alone versus LHRH plus AA NCT01751451]. One of the most interesting plus prednisone] [ClinicalTrials.gov identifier: questions this trial is addressing is whether AA NCT01786265]. In this crossover study, upon therapy may continue to be efficacious without PSA progression or objective evidence of progres- concomitant gonadal suppression by a GnRH sive disease, the participants who had received agonist. The primary endpoints are PFS and LHRH agonist alone will receive a combination soft tissue complete response (RECIST), while of LHRH agonist and AA plus prednisone, and the secondary outcome measures included those who received the combination therapy will PSA response rate, overall quality of life, nonhe- receive LHRH agonist. The primary outcome matologic adverse events, testosterone and lute- measure is PSA PFS. This trial is expected to inizing hormone recovery rates. Further, a provide insight into the efficacy of an earlier correlative tissue analysis where immunohisto- versus delayed therapy with AA in the setting of chemical markers like AR, Phosphatase and biochemically recurrent prostate cancer after tensin homolog (PTEN), Prostate-specific definitive therapy. membrane antigen (PSMA), fatty acid synthase, Phospho-AMP-activated protein kinase Another interesting question is whether men who (AMPK); Phospho-Acetyl-CoA Carboxylase have treatment with AA can be spared concomi- (phospho-ACC), phospho-S6 kinase, phospho- tant therapy with LHRH agonist in the setting of protein kinase B will be assessed. metastatic disease as well. This is being evaluated http://tam.sagepub.com 271 Therapeutic Advances in Medical Oncology 8(4) by an ongoing trial in men with progressive, has been implicated in the progression of chemotherapy-naïve, castration-resistant prostate mCRPC, and result in diminished response to cancer (SPARE) [ClinicalTrials.gov identifier: treatment with AA, enzalutamide, and taxanes NCT02077634], in which men are randomized [Antonarakis et al. 2014, 2015]. Preclinical stud- (1:1) to either the current standard regimen of ies have demonstrated superior antitumor effi- AA plus prednisone plus LHRH therapy (arm A) cacy of galeterone over bicalutamide, indicating or AA plus prednisone without a concomitant that it is more potent than castration in the in LHRH agonist (arm B). The primary endpoint is vivo LAPC4 xenograft, a prostate cancer cell radiographic PFS. line derived from a lymph node metastasis that expresses wild-type AR and secretes PSA The role of AA is also promising in new hormone- [Vasaitis et al. 2008]. Galeterone (0.15 mmol/kg, naïve metastatic prostate cancer. This is being twice daily) caused a 93.8% reduction in the addressed in one of the arms of the STAMPEDE mean final LAPC4 xenograft volume compared trial being conducted in the UK [Sydes et  al. with the controls. Galeterone exerts its action by 2012], as well as a large, multicenter phase III disrupting AR signaling through CYP17 lyase study in Europe (PEACE 1 study) [ClinicalTrials. inhibition, degradation of AR splice variants, gov identifier: NCT01957436]. The PEACE 1 blocking of nuclear translocation and decreased study is comparing the clinical benefit of ADT expression of AR dependent genes [Njar and with or without local radiotherapy, and with or Brodie, 2015]. Given the multitargeted mecha- without AA and prednisone, in men with new nism of action of galeterone, a phase III, rand- metastatic hormone-naïve prostate cancer. OS omized study is comparing the efficacy of and PFS are the primary outcome measures, galeterone with that of enzalutamide in men with while PSA response rate, as defined by an unde- mCRPC harboring AR splice variant 7 mRNA tectable serum PSA level at 8 months, time to (AR-V7) (ARMOR3-SV) [ClinicalTrials.gov pain progression, and time to chemotherapy are identifier: NCT02438007]. Radiographic PFS is some of the secondary outcomes analyzed. the primary outcome measure, while the second- ary outcome measures include OS and time to the initiation of chemotherapy. Orteronel Although orteronel did not improve OS in phase III trials in a mCRPC setting, given its CFG920 mechanism of action and clinical data, it contin- In the emerging line of CYP17 inhibitors, ues to hold promise in the treatment of men another CYP17A1 inhibitor, CFG920 (Novartis with new metastatic castration-naïve prostate Pharmaceuticals, St. Louis, MO, USA), though cancer. S1216 is a NCTN trial sponsored in early stages of development, is worth men- through Southwest Oncology Group (SWOG) tioning [Yin et al. 2013; Gomez et al. 2015; Gaul [ClinicalTrials.gov identifier: NCT01809691], et al. 2015] CFG920 is currently being evaluated which is going to randomize 1636 men with in a phase I/II multicenter study for its safety and newly diagnosed castration-sensitive metastatic antitumor activity in patients with mCRPC who prostate cancer to ADT plus orteronel versus are AA naïve or AA resistant [ClinicalTrials.gov ADT plus bicalutamide (Table 2). The primary identifier: NCT01647789]. outcome measure is OS. The results of these studies are expected to pro- Conclusion vide evidence for the use of CYP17 inhibitors, In conclusion, abrogating intratumoral androgen early in the course of prostate cancer with bio- synthesis and AR signaling by novel CYP17 chemical recurrence or with castration-sensitive inhibitors, as evidenced by the recently available metastatic disease, along with androgen ablation data, have potential in the therapeutic arena of therapy. advanced prostate cancer. Ongoing studies are expected to establish new treatment paradigms with the existing agents, as well as lead to the Galeterone approval of novel CYP inhibitors, all of which will Increased expression of constitutively active AR hopefully delay the onset of symptomatic mCRPC splice variants lacking the ligand-binding domain and improve survival in a meaningful fashion. 272 http://tam.sagepub.com AB Alex, SK Pal et al. Bruno, R., Vasaitis, T., Gediya, L., Furthermore, it is important to recognize that Purushottamachar, P., Godbole, A., Ates-Alagoz, Z. multiple other classes of therapy may be emerg- et al. (2011) Synthesis and biological evaluations of ing for advanced prostate cancer, which may be putative metabolically stable analogs of VN/124–1 of interest alone or in combination with CYP17 (TOK-001): head to head anti-tumor efficacy inhibitors. Whole exome and transcriptome evaluation of VN/124–1 (TOK-001) and abiraterone sequencing of mCRPC has revealed a high fre- in LAPC-4 human prostate cancer xenograft model. quency of clinically relevant entities [Robinson Steroids 76: 1268–1279. et  al. 2015]. Frequent mutations in the BRCA1 Bryce, A. and Ryan, C. (2012) Development and and BRCA2 genes may suggest a potential role clinical utility of abiraterone acetate as an androgen for PARP inhibitors, and in fact, an ongoing synthesis inhibitor. Clin Pharmacol Ther 91: 101–108. study is exploring the role of abiraterone in com- bination with the poly ADP ribose polymerase Cheng, H., Gulati, R., Azad, A., Nadal, R., Twardowski, P., Vaishampayan, U. et al. (2015) (PARP) inhibitor ABT-888 [ClinicalTrials.gov Activity of enzalutamide in men with metastatic identifier: NCT01576172]. As another exam- castration-resistant prostate cancer is affected by prior ple, patients with PTEN deficiency may be sus- treatment with abiraterone and/or docetaxel. Prostate ceptible to phosphoinositide 3-kinase (PI3K) Cancer Prostatic Dis 18: 122–127. inhibitors [ClinicalTrials.gov identifier: NCT02407054, NCT02215096]. Early phase Danila, D., Morris, M., De Bono, J., Ryan, C., Denmeade, S., Smith, M. et al. (2010) Phase trials are exploring the combination of novel II multicenter study of abiraterone acetate plus endocrine therapy with these agents. 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642370 TAM0010.1177/1758834016642370Therapeutic Advances in Medical OncologyAB Alex, SK Pal research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol CYP17 inhibitors in prostate cancer: latest 2016, Vol. 8(4) 267 –275 DOI: 10.1177/ evidence and clinical potential © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ Anitha B. Alex, Sumanta K. Pal and Neeraj Agarwal journalsPermissions.nav Abstract: 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 17α−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. Keywords: abiraterone, androgen biosynthesis, androgen receptors, castration-resistant prostate cancer, cytochrome P450 17α−hydroxy/17,20-lyase inhibitors, galeterone, orteronel, VT-464 Correspondence to: Introduction CYP17 enzymes, CYP17 hydroxylase and Neeraj Agarwal, MD Division of Medical The cytochrome P450 (CYP) superfamily of CYP17,20 lyase, sequentially catalyze the conver- Oncology, Department of enzymes mediates the catalytic conversion of sion of pregnenolone and progesterone to 17α Medicine, University of Utah Huntsman Cancer drugs to reactive products that can bind to mac- hydroxypregnenolone and 17α hydroxyprogester- Institute, 1950 Circle of romolecules, like proteins and DNA. CYP one, which are then further converted to the weak Hope, Salt Lake City, UT 84112, USA enzymes account for approximately 75% of the androgens, dehydroepiandrosterone (DHEA) neeraj.agarwal@hci. total drug metabolism [Guengerich, 2008]. In and androstenedione, respectively (Figure 1) utah.edu addition, they also play a vital role in the synthesis [Poole et al. 2014]. Both DHEA and androsten- Anitha B. Alex, PhD Division of Medical of steroid hormones, cholesterol, and vitamin D edione, are eventually transformed into testoster- Oncology, Department of metabolism. Fifty-seven human CYPs identified one and dihydroxy testosterone (DHT), the most Medicine, University of Utah Huntsman Cancer were classified into 18 families and 43 subfami- potent androgen. Metastatic prostate cancer is Institute, Salt Lake City, lies, of which CYP families 1, 2, and 3 are mainly fueled by the androgen axis, and despite the UT, USA responsible for the metabolism of drugs. androgen ablation therapy, almost all men with Sumanta K. Pal, MD Medical Oncology Evidences support the role of CYPs in tumor for- metastatic prostate cancer progress to having cas- & Experimental mation and inhibition of CYPs has become a key tration-resistant prostate cancer (mCRPC), Therapeutics, City of Hope Comprehensive Cancer area in the treatment of cancer [Lohr et al. 2004; which still maintains its dependence on intratu- Center, Duarte, CA, USA Bruno and Njar, 2007]. CYP17α hydroxy- moral androgen synthesis and androgen receptor lase/17,20 lyase (CYP17), a pivotal enzyme for (AR) signaling for proliferation. Abiraterone ace- androgen synthesis, has been implicated in the tate (AA), a CYP17 inhibitor, is the first US Food pathogenesis of prostate cancer [Vasaitis et  al. and Drug Administration (FDA) approved drug 2011]. In fact, an increased expression of CYP17 of its class for the treatment of mCRPC [Bryce has been demonstrated in prostate carcinoma, and Ryan, 2012]. The next generation CYP17 which correlated positively with a high-stage, high inhibitors currently being evaluated in clinical trials Gleason score, and short relapse-free time disease for metastatic prostate cancer include orteronel [Stigliano et al. 2007]. (TAK 700, Takeda Pharmaceuticals, Deerfield, http://tam.sagepub.com 267 Therapeutic Advances in Medical Oncology 8(4) Figure 1. Cytochrome P450 (CYP) 17 inhibitors targeting androgen synthesis and androgen receptors (ARs), currently approved and those in advanced stages of clinical development in castration-sensitive or -resistant prostate cancer. Thick arrows denote stimulation, flat lines denote inhibition, and thin arrows denote synthesis. DHEA, dehydroepiandrosterone; DHT, dihydroxy testosterone. Table 1. Various cytochrome P450 (CYP) 17 inhibitors and their mechanisms of action. CYP17 inhibitors Mechanism of action Abiraterone and D4A Inhibition of 17α hydroxylase and 17,20 lyase; 17β hydroxysteroid dehydrogenase and steroid 5α reductase; AR antagonism Orteronel (TAK-700) Selective inhibition of 17,20 lyase over 17α hydroxylase Viamet (VT-464) Selective inhibition of 17,20 lyase over 17α hydroxylase; AR antagonism Galeterone (TOK-001) 17α hydroxylase and 17,20 lyase inhibition; AR antagonism; downregulation of AR protein expression CFG920 Dual CYP17/CYP11B2 inhibitor AR, androgen receptor. IL, USA), VT-464 (Viamet Pharmaceuticals, blocks 17β-hydroxysteroid dehydrogenase and Durham, North Carolina, USA), and galeterone steroid 5α reductase, which are required for DHT (TOK-001, Tokai Pharmaceuticals, Boston, MA, synthesis, in addition to CYP17A1 enzymes [Li USA). et al. 2015]. Remarkably, D4A was also shown to have a direct inhibitory effect on AR, comparable to that seen with enzalutamide, a potent AR Molecular mechanisms, efficacy, and latest antagonist. Furthermore, D4A exhibited a higher evidence level of the overall antitumor activity than AA in the xenograft prostate tumors. Abiraterone acetate AA, a pregnenolone analogue, and its metabolite, In the earlier phase I and II trials, AA was found to abiraterone, are selective inhibitors of the CYP17 be safe and effective in lowering serum androgen enzymes, 17α hydroxylase and 17,20 lyase levels [Attard et  al. 2008; Ryan et  al. 2010]. (Table 1). Recently, it has been shown that a However, a sixfold increase in adrenocorticotropic more active form of AA, ∆ abiraterone (D4A), hormone (ACTH) was observed, leading to 268 http://tam.sagepub.com AB Alex, SK Pal et al. secondary mineralocorticoid excess, which precip- 940 placebo) revealed that AA significantly pro- itated in the form of hypokalemia, fluid retention, longed the OS, radiographic PFS, and time to and hypertension. To avoid the mineralocorticoid progression without any evidence of unexpected toxicities, a corticosteroid, prednisone, was added toxicity in patients with mCRPC, regardless of on as a concomitant therapy. However, a miner- prior chemotherapy or not [Zhou et al. 2014]. In alocorticoid receptor antagonist, eplerenone, in addition, an updated analysis of the COU-AA-301 conjunction with AA may preclude the require- and COU-AA-302 trials suggests a strong associ- ment for prednisone [Attard et  al. 2008]. This is ation between PSA kinetics and OS in chemo- especially pertinent in those men who have asymp- therapy-pretreated and naïve patients [Xu et  al. tomatic or minimally symptomatic mCRPC, and 2015]. Thus, the overall evidence supports the in whom long-term use of a corticosteroid may not continued use of AA as a standard therapy for be desirable. A significant increase in the absorp- mCRPC. tion of AA was observed when taken with a high- fat meal [Ryan et al. 2010], and to avoid any dietary variations, the FDA recommends taking AA on an Orteronel empty stomach. Orteronel (TAK-700) is an oral, nonsteroidal 17,20-lyase inhibitor with higher specificity for Based on the results of the COU-AA-301 trial, 17,20 lyase over 17 hydroxylase; hence it is likely the FDA approved the use of AA for the treat- more selective in its mechanism of action com- ment of mCRPC in the post-chemotherapy set- pared with AA. In a phase III study, orteronel was ting in April 2011 [De Bono et  al. 2011]. The evaluated in patients with mCRPC that pro- COU-AA 301 trial observed an overall survival gressed after docetaxel therapy. One thousand (OS) benefit, increase in time to prostate-specific and ninety-nine men were randomly assigned in a antigen (PSA) progression and progression-free 2:1 schedule to receive orteronel 400 mg plus survival (PFS) in patients in the AA group over prednisone 5 mg twice daily or placebo plus pred- the placebo group (median OS, 15.8 versus 11.2 nisone 5 mg twice daily, stratified by region months; median time to PSA progression, 8.5 (Europe, North America, and non-Europe/North versus 6.6 months; median radiologic PFS, 5.6 America) [Fizazi et  al. 2015]. The results indi- versus 3.6 months). The PSA decline was at least cated improved radiographic PFS with orteronel– 50% in 29% of the patients in the AA arm com- prednisone (median, 8.3 versus 5.7 months; HR, pared with 6% in the placebo arm [Fizazi et  al. 0.760; 95% CI, 0.653–0.885; p < 0.001). 2012]. Later studies have demonstrated its effi- Similarly, PSA 50, i.e. 50% reduction in PSA cacy in chemotherapy-naïve patients with (25% versus 10%; p<0.001), and time to PSA mCRPC. In a phase III randomized trial with a progression (median, 5.5 versus 2.9 months; median follow up of more than 4 years, treatment p < 0.001) were also significantly different from with AA prolonged OS compared with pred- the placebo–prednisone arm. The median OS, nisone alone [34.7 versus 30.3 months; hazard the primary endpoint, did not reach statistical sig- ratio (HR), 0.81; 95% confidence interval (CI), nificance in patients with mCRPC post docetaxel 0.70–0.93; p = 0.0033], suggesting its favorable [Fizazi et al. 2014], which could be attributed to efficacy and safety profile in chemotherapy-naive the fact that TAK-700 is a reversible inhibitor. patients as well [Ryan et al. 2015]. However, when men were stratified by regions, a significant improvement in OS was seen in men Though AA is reported to be effective after keto- in the non-Europe/North American regions (15.3 conazole treatment [Danila et al. 2010; Ryan et al. versus 10.1 months, p = 0.019), despite having 2010; Kim et  al. 2014], its efficacy is greater in similar baseline clinical and disease characteris- patients who had not received ketoconazole, tics. This discrepancy in OS by region may have chemotherapy, or enzalutamide, a novel AR been related to the decreased exposure to post- antagonist [Bryce and Ryan, 2012; Cheng et  al. trial treatment with AA and enzalutamide, as 2015; Ryan et al. 2015]. Reports indicate that the these agents were available earlier in North benefits of AA on clinical outcomes were increased American and European regions. with concomitant bone-targeted therapy [Saad et  al. 2015b]. Further, a systematic review and Similarly, the results from a phase III trial in meta-analysis based on the results from 10 trials, chemotherapy naïve patients with mCRPC also including two phase III trials (COU-AA-301 and revealed that treatment with orteronel failed to COU-AA-302), with 2283 patients (1343 AA; improve the OS (31.4 months in the orteronel http://tam.sagepub.com 269 Therapeutic Advances in Medical Oncology 8(4) plus prednisone versus 29.5 months in the pla- 300–600 mg VT-464 twice daily had PSA cebo plus prednisone group; HR, 0.92; 95% CI, responses, ranging from 30% to 90%. More inter- 0.79–1.08; p = 0.31) [Saad et  al. 2015a]. estingly, preliminary PSA responses in patients Nevertheless, the radiographic PFS was pro- with treatment failure indicate a 90% response in longed in the orteronel plus prednisone group. a patient who had prior enzalutamide prechemo- Based on these data, orteronel is no longer being therapy, and a 50% response in patients who had developed in the setting of mCRPC, although an prior enzalutamide and prior chemotherapy. ongoing phase III trial through the National However, no mineralocorticoid excess syndrome Clinical Trials Network continue to explore the and changes in ACTH responses were observed, potential of orteronel in men with new castration- despite not using any supplemental steroids. naïve metastatic prostate cancer. Galeterone VT-464 Galeterone (VN/124-1, TOK-001) is a CYP17 VT-464 is a novel, nonsteroidal CYP17 inhibitor inhibitor with multiple mechanisms of action, and AR antagonist. VT-464 blocks AR variants including CYP17 inhibition, AR antagonism, and F877L and T878A, which have been shown to be decrease in intratumoral AR levels. Preclinical associated with resistance to enzalutamide and results indicate that treatment with VN/124-1 AA, respectively. VT-464 preferentially inhibits caused marked downregulation of AR protein 17,20 lyase over 17α hydroxylase, thus offering expression, in contrast to treatments with bicalu- an advantage over AA from the perspective of not tamide or androgen deprivation therapy (ADT), requiring concomitant therapy with prednisone, which may induce upregulation of AR protein owing to its minimal effects on upstream steroid expression [Vasaitis et al. 2008]. It also caused a levels [Suzman and Antonarakis, 2014]. significant reduction in tumor growth compared with AA [Bruno et  al. 2011]. It has been sug- Results from the studies on castrate-resistant gested that the multifaceted action of galeterone prostate cancer cell lines and xenograft models may assist in overcoming the resistance observed that are either enzalutamide responsive or resist- with other CYP17 inhibitors [Stein et al. 2014]. ant, indicate that VT-464 demonstrated a greater decrease in AR transactivation compared with AA In a phase I study of chemonaïve men with in both enzalutamide-sensitive and -resistant cell mCRPC, galeterone was well tolerated. Of 49 lines [Toren et al. 2015]. At gene and protein lev- patients, 22% demonstrated a decrease in PSA of els, VT-464 suppressed the AR axis to a greater more than 50%, while an additional 26% had extent compared with AA. Further, intratumoral PSA decline of 30–50% after 12 weeks. No evi- androgen levels and PSA decrease trends were dence of adrenal mineralocorticoid excess was significantly lower with VT-464 than with AA, in noted [Montgomery et  al. 2012; Taplin et  al. addition to a more potent tumor growth inhibi- 2012]. A phase II trial is currently being under- tion. These data suggest greater suppression of taken to evaluate the efficacy of galeterone in 144 the AR axis with VT-464 than AA, which is likely patients with progressive castration-resistant due to its superior selective suppression of andro- prostate cancer, stratified to no prior CYP17 gen synthesis and direct AR antagonism. inhibitor or enzalutamide, AA-refractory PC, and enzalutamide-refractory mCRPC. The primary Based on these encouraging data, a phase I/II trial endpoints are reduction in PSA and safety. (INO-VT-464-CL-001) is being conducted in four subgroups of men with mCRPC: treatment naïve, that is with no prior treatment with AA, Clinical potential enzalutamide, or chemotherapy; prior treatment Despite the recent advances in the therapeutic with AA but not with chemotherapy or enzaluta- regimen, the gain in OS had been modest, and mide; prior treatment with enzalutamide but not prostate cancer still remains the second leading with AA or chemotherapy; and prior treatment cause of cancer-related death in men. The impli- with both AA and enzalutamide, or chemother- cations of novel CYP17 inhibitors in nonmeta- apy. Early results from the INO-VT-464-CL-001 static and metastatic prostate cancer are being trial [ClinicalTrials.gov identifier: NCT02012920] explored in ongoing clinical trials (Table 2). in mCRPC are promising [De Bono et al. 2015]. Herein, some of the most pertinent studies have Nineteen of 26 treatment-naïve men who received been highlighted. 270 http://tam.sagepub.com AB Alex, SK Pal et al. Table 2. Selected ongoing clinical trials of cytochrome P450 (CYP) 17 inhibitors in metastatic prostate cancer. Patient population Study phase Intervention/arms Accrual (N) ClinicalTrials. gov identifier Prostate cancer with a II Abiraterone versus Ongoing* (120) NCT01751451 rising PSA or a rising abiraterone + PSA and nodal disease degarelix or degarelix following definitive radical alone prostatectomy Progressive chemotherapy- II Abiraterone + Ongoing* (70) NCT02077634 naïve castration-resistant prednisone + LHRH prostate cancer (SPARE) therapy versus abiraterone + prednisone Metastatic hormone-naïve III ADT ± local RT ± Ongoing* (916) NCT01957436 prostate cancer (PEACE1) abiraterone acetate Newly diagnosed metastatic III ADT + TAK-700 versus Open* (1486) NCT01809691 sensitive prostate cancer ADT + bicalutamide CRPC II Galeterone Ongoing (144) NCT01709734 Patients with metastatic III Galeterone versus Open* (148) NCT02438007 CRPC expressing AR-V7 enzalutamide mRNA Patients with CRPC who I/II CFG920 Ongoing, not NCT01647789 are abiraterone naive or recruiting (31) abiraterone resistant *Currently recruiting. ADT, androgen deprivation therapy; AR-V7, androgen receptor splice variant 7; CRPC, castration-resistant prostate cancer; LHRH, luteinizing hormone releasing hormone; orteronel, TAK-700. Abiraterone acetate A crossover phase II study is ongoing to evaluate A phase II, randomized, three-arm study of whether treatment with ADT in combination AA alone, AA plus degarelix, a Gonadotropin- with AA and prednisone for 8 months controls releasing hormone (GnRH) antagonist, and the disease better than treatment with standard degarelix alone for patients with a rising PSA or ADT alone in patients with prostate cancer who a rising PSA and nodal disease following defini- have PSA progression after prostatectomy or tive radical prostatectomy is currently recruit- radiotherapy [luteinizing hormone releasing hor- ing patients [ClinicalTrials.gov identifier: mone (LHRH) alone versus LHRH plus AA NCT01751451]. One of the most interesting plus prednisone] [ClinicalTrials.gov identifier: questions this trial is addressing is whether AA NCT01786265]. In this crossover study, upon therapy may continue to be efficacious without PSA progression or objective evidence of progres- concomitant gonadal suppression by a GnRH sive disease, the participants who had received agonist. The primary endpoints are PFS and LHRH agonist alone will receive a combination soft tissue complete response (RECIST), while of LHRH agonist and AA plus prednisone, and the secondary outcome measures included those who received the combination therapy will PSA response rate, overall quality of life, nonhe- receive LHRH agonist. The primary outcome matologic adverse events, testosterone and lute- measure is PSA PFS. This trial is expected to inizing hormone recovery rates. Further, a provide insight into the efficacy of an earlier correlative tissue analysis where immunohisto- versus delayed therapy with AA in the setting of chemical markers like AR, Phosphatase and biochemically recurrent prostate cancer after tensin homolog (PTEN), Prostate-specific definitive therapy. membrane antigen (PSMA), fatty acid synthase, Phospho-AMP-activated protein kinase Another interesting question is whether men who (AMPK); Phospho-Acetyl-CoA Carboxylase have treatment with AA can be spared concomi- (phospho-ACC), phospho-S6 kinase, phospho- tant therapy with LHRH agonist in the setting of protein kinase B will be assessed. metastatic disease as well. This is being evaluated http://tam.sagepub.com 271 Therapeutic Advances in Medical Oncology 8(4) by an ongoing trial in men with progressive, has been implicated in the progression of chemotherapy-naïve, castration-resistant prostate mCRPC, and result in diminished response to cancer (SPARE) [ClinicalTrials.gov identifier: treatment with AA, enzalutamide, and taxanes NCT02077634], in which men are randomized [Antonarakis et al. 2014, 2015]. Preclinical stud- (1:1) to either the current standard regimen of ies have demonstrated superior antitumor effi- AA plus prednisone plus LHRH therapy (arm A) cacy of galeterone over bicalutamide, indicating or AA plus prednisone without a concomitant that it is more potent than castration in the in LHRH agonist (arm B). The primary endpoint is vivo LAPC4 xenograft, a prostate cancer cell radiographic PFS. line derived from a lymph node metastasis that expresses wild-type AR and secretes PSA The role of AA is also promising in new hormone- [Vasaitis et al. 2008]. Galeterone (0.15 mmol/kg, naïve metastatic prostate cancer. This is being twice daily) caused a 93.8% reduction in the addressed in one of the arms of the STAMPEDE mean final LAPC4 xenograft volume compared trial being conducted in the UK [Sydes et  al. with the controls. Galeterone exerts its action by 2012], as well as a large, multicenter phase III disrupting AR signaling through CYP17 lyase study in Europe (PEACE 1 study) [ClinicalTrials. inhibition, degradation of AR splice variants, gov identifier: NCT01957436]. The PEACE 1 blocking of nuclear translocation and decreased study is comparing the clinical benefit of ADT expression of AR dependent genes [Njar and with or without local radiotherapy, and with or Brodie, 2015]. Given the multitargeted mecha- without AA and prednisone, in men with new nism of action of galeterone, a phase III, rand- metastatic hormone-naïve prostate cancer. OS omized study is comparing the efficacy of and PFS are the primary outcome measures, galeterone with that of enzalutamide in men with while PSA response rate, as defined by an unde- mCRPC harboring AR splice variant 7 mRNA tectable serum PSA level at 8 months, time to (AR-V7) (ARMOR3-SV) [ClinicalTrials.gov pain progression, and time to chemotherapy are identifier: NCT02438007]. Radiographic PFS is some of the secondary outcomes analyzed. the primary outcome measure, while the second- ary outcome measures include OS and time to the initiation of chemotherapy. Orteronel Although orteronel did not improve OS in phase III trials in a mCRPC setting, given its CFG920 mechanism of action and clinical data, it contin- In the emerging line of CYP17 inhibitors, ues to hold promise in the treatment of men another CYP17A1 inhibitor, CFG920 (Novartis with new metastatic castration-naïve prostate Pharmaceuticals, St. Louis, MO, USA), though cancer. S1216 is a NCTN trial sponsored in early stages of development, is worth men- through Southwest Oncology Group (SWOG) tioning [Yin et al. 2013; Gomez et al. 2015; Gaul [ClinicalTrials.gov identifier: NCT01809691], et al. 2015] CFG920 is currently being evaluated which is going to randomize 1636 men with in a phase I/II multicenter study for its safety and newly diagnosed castration-sensitive metastatic antitumor activity in patients with mCRPC who prostate cancer to ADT plus orteronel versus are AA naïve or AA resistant [ClinicalTrials.gov ADT plus bicalutamide (Table 2). The primary identifier: NCT01647789]. outcome measure is OS. The results of these studies are expected to pro- Conclusion vide evidence for the use of CYP17 inhibitors, In conclusion, abrogating intratumoral androgen early in the course of prostate cancer with bio- synthesis and AR signaling by novel CYP17 chemical recurrence or with castration-sensitive inhibitors, as evidenced by the recently available metastatic disease, along with androgen ablation data, have potential in the therapeutic arena of therapy. advanced prostate cancer. Ongoing studies are expected to establish new treatment paradigms with the existing agents, as well as lead to the Galeterone approval of novel CYP inhibitors, all of which will Increased expression of constitutively active AR hopefully delay the onset of symptomatic mCRPC splice variants lacking the ligand-binding domain and improve survival in a meaningful fashion. 272 http://tam.sagepub.com AB Alex, SK Pal et al. Bruno, R., Vasaitis, T., Gediya, L., Furthermore, it is important to recognize that Purushottamachar, P., Godbole, A., Ates-Alagoz, Z. multiple other classes of therapy may be emerg- et al. (2011) Synthesis and biological evaluations of ing for advanced prostate cancer, which may be putative metabolically stable analogs of VN/124–1 of interest alone or in combination with CYP17 (TOK-001): head to head anti-tumor efficacy inhibitors. Whole exome and transcriptome evaluation of VN/124–1 (TOK-001) and abiraterone sequencing of mCRPC has revealed a high fre- in LAPC-4 human prostate cancer xenograft model. quency of clinically relevant entities [Robinson Steroids 76: 1268–1279. et  al. 2015]. Frequent mutations in the BRCA1 Bryce, A. and Ryan, C. (2012) Development and and BRCA2 genes may suggest a potential role clinical utility of abiraterone acetate as an androgen for PARP inhibitors, and in fact, an ongoing synthesis inhibitor. Clin Pharmacol Ther 91: 101–108. study is exploring the role of abiraterone in com- bination with the poly ADP ribose polymerase Cheng, H., Gulati, R., Azad, A., Nadal, R., Twardowski, P., Vaishampayan, U. et al. (2015) (PARP) inhibitor ABT-888 [ClinicalTrials.gov Activity of enzalutamide in men with metastatic identifier: NCT01576172]. As another exam- castration-resistant prostate cancer is affected by prior ple, patients with PTEN deficiency may be sus- treatment with abiraterone and/or docetaxel. Prostate ceptible to phosphoinositide 3-kinase (PI3K) Cancer Prostatic Dis 18: 122–127. inhibitors [ClinicalTrials.gov identifier: NCT02407054, NCT02215096]. Early phase Danila, D., Morris, M., De Bono, J., Ryan, C., Denmeade, S., Smith, M. et al. (2010) Phase trials are exploring the combination of novel II multicenter study of abiraterone acetate plus endocrine therapy with these agents. 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Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: Apr 19, 2016

Keywords: abiraterone; androgen biosynthesis; androgen receptors; castration-resistant prostate cancer; cytochrome P450 17α−hydroxy/17; 20-lyase inhibitors; galeterone; orteronel; VT-464

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