- Email: [email protected]
MTOR DUAL INHIBITOR IN CASTRATION-RESISTANT PROSTATE CANCER IN VIVO AND EX VIVO
THE JOURNAL OF UROLOGYâ
Vol. 195, No. 4S, Supplement, Sunday, May 8, 2016
and antineoplastic efficacy in metastatic castration resistant prostate cancer (mCRPC) patients. Here we report the combined long-term safety and antitumor activity of ODM-201 in ARADES (phase 1-2, NCT01317641, NCT01429064) and ARAFOR (phase 1 bioavailability, NCT01784757) trials in chemotherapy- and CYP17-inhibitor-naive patients. METHODS: Long-term safety and antitumor activity of ODM201 were analysed with the data combined from the 2 trials at dose levels 600-900 mg twice daily, including 41 patients (600mg n¼30, 700mg n¼9 and 900mg n¼2) with progressive mCRPC who were naive to chemotherapy and CYP17-inhibitor treatment. The results up to data cut-off dates 31 Oct 2014 (ARADES) and 30 Apr 2015 (ARAFOR) are reported. The median follow-up time in the studies was 67 weeks. Initial results of ARADES study (data cut-off date 3 Oct 2013) were reported by Fizazi et al. (Lancet Oncol. 2014) and results of ARAFOR study (data cut-off date 31 Oct 2014) by Massard et al. (Eur Urol. 2015). RESULTS: Baseline demographics were: median age 69 (range 54-86) years, ECOG score of 0 in 73% and ECOG 1 in 27% patients, and median PSA 28 (range 3.5 - 1294) ng/mL. The median time from prostate cancer diagnosis to start of the ODM-201 treatment was 4 years 2 months, and prior LHRH therapy to start of the study was 1 year and 11 months. AEs occurred in 33 (80%) patients. Ten grade 3 AEs were reported; back pain, nausea, bone pain, fall, femoral neck fracture, hypertension, increase in serum alkaline phosphatase, prostate cancer, hyponatraemia, and lung adenocarcinoma (one event each). There were 2 grade 4 AEs; one neuroendocrine carcinoma and one respiratory failure, and two grade 5 AEs; one prostate cancer and one general physical health deterioration. All grade 3 AEs were classified as not related to ODM-201. Treatment-related AEs occurred in 10 (24%) patients; all were grade 1. The most common treatment-related AEs were fatigue (3; 7%) and hot flushes (2; 5%). Median time to PSA progression by Prostate Cancer Working Group (PCWG2) criterion was 54 (95% CI 27-79) weeks. CONCLUSIONS: ODM-201 daily doses between 600-900mg bid showed antitumor activity, and the safety profile remained favorable in patients with mCRPC who were naive for chemotherapy and CYP17inhibitor treatment. A phase 3 ARAMIS trial at a dose of 600 mg twice daily in men with non-metastatic CRPC is currently ongoing. Source of Funding: Orion Corporation Orion Pharma, and Bayer Healthcare Pharmaceutical, Inc.
PD32-07 GALETERONE SHOWS ANTI-TUMOR ACTIVITY IN MULTIPLE PRECLINICAL MODELS THAT EXPRESS ANDROGEN RECEPTOR SPLICE VARIANTS, SUPPORTING CORRELATIVE PATIENT DATA SEEN IN ARMOR2 Vincent Njar*, Baltimore, MD; Amina Zoubeidi, Vancouver, Canada; Eva Corey, Elahe Mostaghel, Seattle, WA; Andrew Kwegyir-Afful, Senthilmurugan Ramalingam, Baltimore, MD; Douglas Jacoby, Boston, MA INTRODUCTION AND OBJECTIVES: Galeterone is a selective, multitargeted, small molecule that disrupts androgen signaling at multiple points in the pathway by enhancing androgen receptor (AR) degradation, inhibiting androgen biosynthesis, and antagonizing androgen binding to the AR. AR splice variant-7 (AR-V7) is a truncated, constitutively active splice variant of the AR that lacks the ligand binding domain (LBD), and has been implicated in castration resistant prostate cancer (CRPC) progression. AR-V7 expression is detected in approximately 12-26% of men with metastatic CRPC (mCRPC) prior to secondgeneration anti-androgens or chemotherapy, and AR-V7 expression has been clinically associated with resistance to enzalutamide (Xtandi) and abiraterone (Zytiga). In this study, multiple experimental approaches examined whether, and by what mechanism, galeterone inhibits the growth of prostate cancer cells or tumors expressing AR splice variants, such as AR-V7.
e763
METHODS: To measure effects of galeterone on prostate tumor cell signaling and growth, we monitored reductions in AR protein levels, and have used in vitro measures of AR-dependent gene expression and tumor cell viability. In addition, we assessed in vivo efficacy of galeterone in mouse xenograft models and clinically by evaluating PSA responses in patients whose CTCs express truncated AR. RESULTS: Our findings show that galeterone attenuates tumor cell proliferation, AR signaling and xenograft tumor growth using cells and tumors that express AR splice variants. Galeterone treatment also causes dose-dependent reductions in AR protein. Reductions in AR splice variant protein were observed in cells that co-express wild-type AR, and in AR negative prostate cancer cells that transiently express AR splice variant protein. These findings support the PSA responses seen clinically with galeterone treatment in men with mCRPC whose tumors contain truncated AR. CONCLUSIONS: Galeterone’s unique mechanism of AR protein downregulation occurs in both splice variant and full-length AR, supporting that galeterone-induced AR downregulation is independent of the AR LBD. Because preclinical and clinical data support an opportunity for treatment in this setting, Tokai is evaluating galeterone in an ongoing global pivotal trial designed to determine whether treatment with galeterone results in a statistically significant increase in radiographic progression-free survival as compared to enzalutamide in approximately 148 treatment-naïve, AR-V7+ mCRPC patients. Source of Funding: Tokai Pharmaceuticals
PD32-08 SYNERGISTIC ANTICANCER EFFECT OF COMBINATION TREATMENT WITH MEK INHIBITOR AND PI3K /MTOR DUAL INHIBITOR IN CASTRATION-RESISTANT PROSTATE CANCER IN VIVO AND EX VIVO Se Young Choi*, Jaeyoon Jung, Jae Hyeon Han, Junghyun Shin, Jeong-Woen Moon, Sang Hoon Song, Dalsan You, Jung Jin Hwang, Choung-Soo Kim, Seoul, Korea, Republic of INTRODUCTION AND OBJECTIVES: PTEN deletion, mutation or reduced expression occurs in 63% of metastatic prostate tumors, resulting in the activation of PI3K and its downstream targets, AKT and mTOR. Inhibition of the PI3K pathway results in upregulation of the MAPK pathway. Therefore, co-administration of inhibitors of both pathways, GSK2126458 as a dual PI3K mTOR inhibitor, and AZD6244 as a MEK inhibitor, is able to overcome resistance and increase antitumor efficacy in castration resistant prostate cancer. This study investigated whether monotherapy with either the dual PI3K/mTOR inhibitor GSK2126458 or the MEK inhibitor AZD6244 might activate other pathways and whether the combination of both drugs might be synergistic in PTEN-deletion/mutated prostate cancer in vivo and ex vivo. METHODS: The human DU145 and PC3 tumor xenograft mouse model and CRPC patient-derived cells were employed to evaluate the in vivo and ex vivo efficacy. Celltiter Gloâ luminescent assay, Western blotting and immunohistochemistry were conducted. Statistical evaluation of the results was performed by one-Way ANOVA. RESULTS: The combination of GSK2126458 and AZD6244 treatment effectively inhibited the growth of tumor in DU145 and PC3 xenograft model. The combination of GSK2126458 and AZD6244 decreased both phosphor-AKT and phosphor-ERK effectively in vivo. Moreover, the combination decreased the level of Ki-67, and increased TUNEL positive cells and cleaved caspase-3 in DU145 xenograft tumors implanted in mice. In addition, this combination treatment inhibited both the PI3K and MEK pathway primary in cultures from CRPC patients harboring PTEN loss, leading to synergistic anti-tumor effect. CONCLUSIONS: The combination with GSK2126458 and AZD6244 blocks both the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathway simultaneously is an effective strategy for the treatment of CRPCs. Source of Funding: none
Vol. 195, No. 4S, Supplement, Sunday, May 8, 2016
and antineoplastic efficacy in metastatic castration resistant prostate cancer (mCRPC) patients. Here we report the combined long-term safety and antitumor activity of ODM-201 in ARADES (phase 1-2, NCT01317641, NCT01429064) and ARAFOR (phase 1 bioavailability, NCT01784757) trials in chemotherapy- and CYP17-inhibitor-naive patients. METHODS: Long-term safety and antitumor activity of ODM201 were analysed with the data combined from the 2 trials at dose levels 600-900 mg twice daily, including 41 patients (600mg n¼30, 700mg n¼9 and 900mg n¼2) with progressive mCRPC who were naive to chemotherapy and CYP17-inhibitor treatment. The results up to data cut-off dates 31 Oct 2014 (ARADES) and 30 Apr 2015 (ARAFOR) are reported. The median follow-up time in the studies was 67 weeks. Initial results of ARADES study (data cut-off date 3 Oct 2013) were reported by Fizazi et al. (Lancet Oncol. 2014) and results of ARAFOR study (data cut-off date 31 Oct 2014) by Massard et al. (Eur Urol. 2015). RESULTS: Baseline demographics were: median age 69 (range 54-86) years, ECOG score of 0 in 73% and ECOG 1 in 27% patients, and median PSA 28 (range 3.5 - 1294) ng/mL. The median time from prostate cancer diagnosis to start of the ODM-201 treatment was 4 years 2 months, and prior LHRH therapy to start of the study was 1 year and 11 months. AEs occurred in 33 (80%) patients. Ten grade 3 AEs were reported; back pain, nausea, bone pain, fall, femoral neck fracture, hypertension, increase in serum alkaline phosphatase, prostate cancer, hyponatraemia, and lung adenocarcinoma (one event each). There were 2 grade 4 AEs; one neuroendocrine carcinoma and one respiratory failure, and two grade 5 AEs; one prostate cancer and one general physical health deterioration. All grade 3 AEs were classified as not related to ODM-201. Treatment-related AEs occurred in 10 (24%) patients; all were grade 1. The most common treatment-related AEs were fatigue (3; 7%) and hot flushes (2; 5%). Median time to PSA progression by Prostate Cancer Working Group (PCWG2) criterion was 54 (95% CI 27-79) weeks. CONCLUSIONS: ODM-201 daily doses between 600-900mg bid showed antitumor activity, and the safety profile remained favorable in patients with mCRPC who were naive for chemotherapy and CYP17inhibitor treatment. A phase 3 ARAMIS trial at a dose of 600 mg twice daily in men with non-metastatic CRPC is currently ongoing. Source of Funding: Orion Corporation Orion Pharma, and Bayer Healthcare Pharmaceutical, Inc.
PD32-07 GALETERONE SHOWS ANTI-TUMOR ACTIVITY IN MULTIPLE PRECLINICAL MODELS THAT EXPRESS ANDROGEN RECEPTOR SPLICE VARIANTS, SUPPORTING CORRELATIVE PATIENT DATA SEEN IN ARMOR2 Vincent Njar*, Baltimore, MD; Amina Zoubeidi, Vancouver, Canada; Eva Corey, Elahe Mostaghel, Seattle, WA; Andrew Kwegyir-Afful, Senthilmurugan Ramalingam, Baltimore, MD; Douglas Jacoby, Boston, MA INTRODUCTION AND OBJECTIVES: Galeterone is a selective, multitargeted, small molecule that disrupts androgen signaling at multiple points in the pathway by enhancing androgen receptor (AR) degradation, inhibiting androgen biosynthesis, and antagonizing androgen binding to the AR. AR splice variant-7 (AR-V7) is a truncated, constitutively active splice variant of the AR that lacks the ligand binding domain (LBD), and has been implicated in castration resistant prostate cancer (CRPC) progression. AR-V7 expression is detected in approximately 12-26% of men with metastatic CRPC (mCRPC) prior to secondgeneration anti-androgens or chemotherapy, and AR-V7 expression has been clinically associated with resistance to enzalutamide (Xtandi) and abiraterone (Zytiga). In this study, multiple experimental approaches examined whether, and by what mechanism, galeterone inhibits the growth of prostate cancer cells or tumors expressing AR splice variants, such as AR-V7.
e763
METHODS: To measure effects of galeterone on prostate tumor cell signaling and growth, we monitored reductions in AR protein levels, and have used in vitro measures of AR-dependent gene expression and tumor cell viability. In addition, we assessed in vivo efficacy of galeterone in mouse xenograft models and clinically by evaluating PSA responses in patients whose CTCs express truncated AR. RESULTS: Our findings show that galeterone attenuates tumor cell proliferation, AR signaling and xenograft tumor growth using cells and tumors that express AR splice variants. Galeterone treatment also causes dose-dependent reductions in AR protein. Reductions in AR splice variant protein were observed in cells that co-express wild-type AR, and in AR negative prostate cancer cells that transiently express AR splice variant protein. These findings support the PSA responses seen clinically with galeterone treatment in men with mCRPC whose tumors contain truncated AR. CONCLUSIONS: Galeterone’s unique mechanism of AR protein downregulation occurs in both splice variant and full-length AR, supporting that galeterone-induced AR downregulation is independent of the AR LBD. Because preclinical and clinical data support an opportunity for treatment in this setting, Tokai is evaluating galeterone in an ongoing global pivotal trial designed to determine whether treatment with galeterone results in a statistically significant increase in radiographic progression-free survival as compared to enzalutamide in approximately 148 treatment-naïve, AR-V7+ mCRPC patients. Source of Funding: Tokai Pharmaceuticals
PD32-08 SYNERGISTIC ANTICANCER EFFECT OF COMBINATION TREATMENT WITH MEK INHIBITOR AND PI3K /MTOR DUAL INHIBITOR IN CASTRATION-RESISTANT PROSTATE CANCER IN VIVO AND EX VIVO Se Young Choi*, Jaeyoon Jung, Jae Hyeon Han, Junghyun Shin, Jeong-Woen Moon, Sang Hoon Song, Dalsan You, Jung Jin Hwang, Choung-Soo Kim, Seoul, Korea, Republic of INTRODUCTION AND OBJECTIVES: PTEN deletion, mutation or reduced expression occurs in 63% of metastatic prostate tumors, resulting in the activation of PI3K and its downstream targets, AKT and mTOR. Inhibition of the PI3K pathway results in upregulation of the MAPK pathway. Therefore, co-administration of inhibitors of both pathways, GSK2126458 as a dual PI3K mTOR inhibitor, and AZD6244 as a MEK inhibitor, is able to overcome resistance and increase antitumor efficacy in castration resistant prostate cancer. This study investigated whether monotherapy with either the dual PI3K/mTOR inhibitor GSK2126458 or the MEK inhibitor AZD6244 might activate other pathways and whether the combination of both drugs might be synergistic in PTEN-deletion/mutated prostate cancer in vivo and ex vivo. METHODS: The human DU145 and PC3 tumor xenograft mouse model and CRPC patient-derived cells were employed to evaluate the in vivo and ex vivo efficacy. Celltiter Gloâ luminescent assay, Western blotting and immunohistochemistry were conducted. Statistical evaluation of the results was performed by one-Way ANOVA. RESULTS: The combination of GSK2126458 and AZD6244 treatment effectively inhibited the growth of tumor in DU145 and PC3 xenograft model. The combination of GSK2126458 and AZD6244 decreased both phosphor-AKT and phosphor-ERK effectively in vivo. Moreover, the combination decreased the level of Ki-67, and increased TUNEL positive cells and cleaved caspase-3 in DU145 xenograft tumors implanted in mice. In addition, this combination treatment inhibited both the PI3K and MEK pathway primary in cultures from CRPC patients harboring PTEN loss, leading to synergistic anti-tumor effect. CONCLUSIONS: The combination with GSK2126458 and AZD6244 blocks both the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathway simultaneously is an effective strategy for the treatment of CRPCs. Source of Funding: none