Docetaxel In Castration-resistant Prostate Cancer Research Articles

Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer

Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

AZGP1P2/UBA1/RBM15 Cascade Mediates the Fate Determinations of Prostate Cancer Stem Cells and Promotes Therapeutic Effect of Docetaxel in Castration-Resistant Prostate Cancer via TPM1 m6A Modification.

Prostate cancer (PCa) is a common malignant tumor with high morbidity and mortality worldwide. The prostate cancer stem cell (PCSC) model provides novel insights into the pathogenesis of PCa and its therapeutic response. However, the roles and molecular mechanisms of specific genes in mediating fate decisions of PCSCs and carcinogenesis of PCa remain to be elusive. In this study, we have explored the expression, function, and mechanism of AZGP1P2, a pseudogene of AZGP1, in regulating the stemness and apoptosis of PCSCs and treatment resistance of docetaxel in castration-resistant prostate cancer (CRPC). We revealed that AZGP1P2 was downregulated in CRPC cell lines and PCSCs, while it was positively associated with progression-free interval. Upregulation of the AZGP1P2 enhanced the sensitivity of docetaxel treatment in CRPCs via inhibiting their stemness. RNA pull-down associated with mass spectrometry analysis, co-immunoprecipitation assay, and RNA immunoprecipitation assay demonstrated that AZGP1P2 could bind to UBA1 and RBM15 as a "writer" of methyltransferase to form a compound. UBA1, an E1 ubiquitin-activating enzyme, contributed to RBM15 protein degradation via ubiquitination modification. Methylated RNA immunoprecipitation assay displayed that RBM15 controlled the mRNA decay of TPM1 in m6A methylation. Furthermore, a xenograft mouse model and patient-derived organoids showed that the therapeutic effect of docetaxel in CRPC was increased by AZGP1P2 invivo. Collectively, these results imply that AZGP1P2 mediates the stemness and apoptosis of PCSCs and promotes docetaxel therapeutic effect by suppressing tumor growth and metastasis via UBA1/RBM15-mediated TPM1 mRNA decay in CRPC.

Continuing enzalutamide with docetaxel in castration-resistant prostate cancer.

In metastatic prostate cancer, several life-prolonging therapeutics, such as novel androgen receptor pathway inhibitors, abiraterone acetate and second-generation antiandrogens, and the chemotherapeutic agent docetaxel, are available for both metastatic castration-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). Similarly, cabazitaxel, radioisotopes, and poly(ADP-ribose) polymerase inhibitors are available for the treatment of mCRPC. There is currently no evidence of a survival benefit of combination therapy in mCRPC, and life-prolonging drugs are administered sequentially for patients with mCRPC. However, the potential ability of combination therapy to delay progression has been shown in the CHEIRON (adding enzalutamide to docetaxel), 1 Caffo O Ortega C Nolè F et al. Docetaxel and prednisone with or without enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer: CHEIRON, a randomised phase II trial. Eur J Cancer. 2021; 155: 56-63 Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar ACIS (adding apalutamide to abiraterone plus prednisone), 2 Saad F Efstathiou E Attard G et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021; 22: 1541-1559 Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar IPATential150 (adding ipatasertib to abiraterone plus prednisone or prednisolone), 3 Sweeney C Bracarda S Sternberg CN et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021; 398: 131-142 Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar and PROpel (adding olaparib to abiraterone plus prednisone or prednisolone) trials. 4 Saad F Armstrong AJ Thiery-Vuillemin A et al. PROpel: phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Proc Am Soc Clin Oncol. 2022; 40: 11 Crossref Google Scholar Additionally, the survival benefit of combinations of androgen receptor pathway inhibitors, including the addition of abiraterone or the second-generation antiandrogen darolutamide to castration plus docetaxel, was shown in the PEACE-1 (adding abiraterone plus prednisone to docetaxel) 5 Fizazi K Foulon S Carles J et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022; 399: 1695-1707 Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar and ARASENS (adding darolutamide to docetaxel) trials. 6 Smith MR Hussain M Saad F et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022; 386: 1132-1142 Crossref PubMed Scopus (80) Google Scholar Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b studyPRESIDE met its primary endpoint and showed that continuing enzalutamide with docetaxel plus androgen deprivation therapy delayed time to progression compared with docetaxel plus androgen deprivation therapy alone, supporting the hypothesis that enzalutamide maintenance could control persistent androgen-dependent clones in men with mCRPC who progress after treatment with enzalutamide alone. Full-Text PDF

Prognostic significance of risk stratification in CHAARTED and LATITUDE studies among Japanese men with castration-resistant prostate cancer.

BackgroundThe CHAARTED and LATITUDE trials demonstrated a survival benefit of docetaxel and abiraterone for hormone-sensitive prostate cancer. In this study, we examined the impact of the risk stratification criteria used in the CHAARTED and LATITUDE trials on the prognosis of castration-resistant prostate cancer (CRPC). We also tested whether these risk stratification criteria could help in selecting effective initial treatment for CRPC.MethodJapanese patients with CRPC who were treated with docetaxel or androgen receptor pathway inhibitors such as abiraterone acetate or enzalutamide between 2014 and 2018 were included in this study. Clinicopathological factors, progression-free survival, and overall survival were investigated.ResultsOf 215 patients, 110 men (51.2%) and 93 men (43.3%) were grouped as high volume by CHAARTED criteria and high risk by LATITUDE criteria, respectively. Median progression-free survival was 10.3/4.5 months (P < 0.0001) for low/high volume (CHAARTED criteria) and 9.9/4.8 months (P = 0.0032) for low/high risk (LATITUDE criteria). The median overall survival was 44.8/17.4 months (P < 0.0001) for low/high volume (CHAARTED criteria) and 37.4/17.4 months (P = 0.0011) for low/high risk (LATITUDE criteria). The prognostic impact of CHAARTED and LATITUDE criteria was comparable between androgen receptor pathway inhibitors and docetaxel as first-line treatment for CRPC.ConclusionThe CHAARTED and LATITUDE criteria were prognostic, but not useful to discriminate the therapeutic outcome between androgen receptor pathway inhibitors and docetaxel for CRPC.

Prognostic impact of prior local therapy in castration-resistant prostate cancer

This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95% confidence interval, 0.40-0.79; P=0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.

Fractionated docetaxel and radium-223 (Ra223) in metastatic castration-resistant prostate cancer (CRPC): A phase I trial.

TPS175 Background: Disease progression following highly-active androgen-axis therapy (HAAT) in CRPC remains bone-dominant and docetaxel-responsive. Combination bone-homing Ra223 isotope therapy with docetaxel would be a logical combination therapy to follow but myelosuppression is dose-limiting. With 3-weekly bolus schedules of docetaxel (D), dose-reduction to 60mg/m2 Q3wkly and Ra223 to every 6 weeks has been required representing a reduction in the dose-intensity of both agents. Fractionated schedules of docetaxel Q2wkly (DQ2) have comparable activity to D 75mg/m2 Q3wkly (DQ3) with mitigated myelosuppression. We hypothesize that a fractionated dose-schedule of DQ2 in combination with standard Ra223 dosing will be feasible without reduction in dose-intensity of Ra-223 or D. Methods: Outcomes: The primary objective is to determine the feasibility and maximal tolerated dose (MTD) of the combination. Secondary objectives include PSA kinetics, objective response, bone marker outcomes, progression free and overall survival, and description of toxicity and quality of life. Eligibility: Progressive bone-metastatic CRPC, ECOG PS 0-2 with no prior Ra223, no prior docetaxel for CRPC, and no bulky visceral disease. Design: Phase I (6+6) design; 4 week lead-in with DQ2. Dose-level 1a: 40mg/m2; 2a: 50mg/m2, both with PEGylated G-CSF on Day 16. If tolerated (≤ Grade 2 toxicity, ANC ≥ 1500, Platelets ≥ 100,000), lead-in is followed by C1D1 of DQ2 plus Ra223 Q4wkly x 6 doses. Dose level 1a has accrued 6 subjects without DLT. Enrollment to Dose Level 2a began in August, 2020. An expansion cohort of 25 subjects is planned after the MTD is determined. Clinical trial information: NCT03737370.

Efficacy and Safety of 4-Weekly Docetaxel for Castration-Resistant Prostate Cancer

We investigated the efficacy and safety profiles of 4-weekly docetaxel for castration-resistant prostate cancer. Patients treated with ≥2 courses of docetaxel chemotherapy (median, 70 mg/m2) between 2008 and 2018 were included. Among 125 Japanese men, 40 (32.0%) and 85 (68.0%) were treated with 3-weekly and 4-weekly regimens, respectively. In the 4-weekly regimen, the risks of progression, treatment failure, and any-cause mortality were comparable to those in the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. These data suggest that the 4-weekly regimen may be an acceptable option for selected patients.

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

γ-Klotho is correlated with resistance to docetaxel in castration-resistant prostate cancer.

The Klotho (KL) gene was first identified as a potent aging suppressor. The KL family currently comprises of three proteins: α-Klotho (KLA), β-Klotho (KLB), and γ-Klotho (KLG). Many studies have shown that KLA and KLB participate in tumor progression or suppression, depending on the type of cancer; however, the relationship between KLG and prostate cancer has not yet been studied. Some studies have claimed that KL is correlated to sensitivity to chemotherapy. Here, we investigated the oncogenic potential of KLG in castration-resistant prostate cancer (CRPC). Immunohistochemical analysis using prostate biopsy specimens revealed that patients with high KLG expression in primary prostate cancer tissue had a significantly poor prognosis for overall survival. In addition, the prostate-specific antigen response rate after docetaxel (DTX) therapy in patients with high KLG expression was lower than that in patients with low KLG expression. To evaluate the potential of KLG as a therapeutic target in human prostate cancer, we generated a xenograft model of human CRPC cell line (PC-3) in male athymic mice. The animals were randomly divided into four groups as follows: i) control group (vehicle only); ii) DTX group (intraperitoneal administration); iii) small interfering RNA targeting KLG (KLG siRNA) group (intratumoral administration); and iv) a combination group (DTX plus KLG siRNA). After 3 weeks of treatment, the tumor weight and tumor Ki-67 labeling index were significantly lower in the KLG siRNA group and the combination group than in the control group. Sensitivity to DTX was increased upon treatment with KLG siRNA. These findings suggest that KLG expression in primary prostate cancer lesions is associated with resistance to DTX in CRPC and has potential as a diagnostic and therapeutic target for patients with CRPC.

No survival benefit found after extended treatment with docetaxel for patients with castration-resistant prostate cancer.

Docetaxel (DOC) has been widely accepted as a therapeutic option for castration-resistant prostate cancer (CRPC). Evidence-based clinical guidelines have stipulated its use up to 10 cycles in most health care systems. There has been a paucity of information regarding potential benefits of its use over 10 cycles. The purpose of this study is to re-examine the rationale for the clinical guidelines concerning cycles of DOC in CRPC. Between July 2007 and July 2016, a total of 122 CRPC patients received at least five cycles of DOC at Jikei University and its affiliate hospitals. Doses of DOC (75 mg/m 2 ) were administered every 3 to 4 weeks. Clinical outcomes between patients receiving extended cycles of DOC (≥11 cycles, extended [ex]-DOC group) were compared to those receiving fewer (≤10 cycles, short-DOC group). A subgroup of patients who had discontinued DOC owing to adverse events, but whose disease did not progress, were also considered for comparison (adverse events [AE] group). Overall survival from the induction of DOC was the primary outcome measure. Univariate and multivariate analyses were conducted to analyze variables associated with overall survival. The ex- and short-DOC groups included 80 and 42 patients, respectively. Most baseline demographics did not differ between groups. However, in the short-DOC group more patients had received abiraterone acetate and/or enzalutamide before chemotherapy, age at DOC induction was younger, and lactate dehydrogenase at DOC induction was higher. Overall survival was significantly longer in the ex-DOC group compared to the short-DOC group (median, 53 and 27 months, respectively; P = .04). A subgroup of 22 patients in AE group was compared to compensate for potential bias. Overall survival from the induction of DOC was comparable between AE group and ex-DOC groups (median, 53 vs 53 months, respectively; P = 0.87). Univariate and multivariate analyses did not show any advantage of extended use of DOC on patient survival. The results of this study failed to show the survival benefit of extended use of DOC over 10 cycles in CRPC patients in the era of innovative drugs such as abiraterone acetate, enzalutamide, and cabazitaxel. Further prospective studies are required to confirm our findings.

Inhibition of TAMs improves the response to docetaxel in castration-resistant prostate cancer.

For men with castration-resistant prostate cancer (CRPC), androgen-deprivation therapy (ADT) often becomes ineffective requiring the addition of docetaxel, a proven effective chemotherapy option. Tumor-associated macrophages (TAMs) are known to provide protumorigenic influences that contribute to treatment failure. In this study, we examined the contribution of TAMs to docetaxel treatment. An increased infiltration of macrophages in CRPC tumors was observed after treatment with docetaxel. Prostate cancer cells treated with docetaxel released more macrophage colony-stimulating factor (M-CSF-1 or CSF-1), IL-10 and other factors, which can recruit and modulate circulating monocytes to promote their protumorigenic functions. Inhibition of CSF-1 receptor kinase signaling with a small molecule antagonist (PLX3397) in CRPC models significantly reduces the infiltration of TAMs and their influences. As such, the addition of PLX3397 to docetaxel treatment resulted in a more durable tumor growth suppression than docetaxel alone. This study reveals a rational strategy to abrogate the influences of TAMs and extend the treatment response to docetaxel in CRPC.

Efficacy of gefitinib‑celecoxib combination therapy in docetaxel‑resistant prostate cancer.

Resistance to docetaxel is a major clinical problem in castration‑resistant prostate cancer (CRPC). We have previously reported that the combined inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase‑2 (COX‑2) led to an increased antitumor activity of docetaxel in CRPC. In the present study, we explored the efficacy of the combination of EGFR inhibition (by gefitinib) and COX‑2 inhibition (by celecoxib) as a potential treatment for docetaxel‑resistant CRPC. We established two docetaxel‑resistant prostate cancer cell lines, PC3/DR and DU145/DR, by culturing PC3 and DU145 cells in docetaxel in a dose‑escalating manner. The EGFR and COX‑2 protein expression levels were determined. The effects of gefitinib and celecoxib on cell proliferation, apoptosis and invasion invitro and invivo were evaluated. Invitro changes in Bcl‑2, FOXM1 and ABCB1 expression were analyzed. The expression of Ki‑67 and cleaved‑caspase‑3 was also examined in DU145/DR tumor tissue. The enhanced expression of EGFR and COX‑2 was observed in docetaxel‑resistant CRPC relative to the parental cell lines. MTT, clone formation and fluorescence‑activated cell sorting (FACS) analyses demonstrated that gefitinib and celecoxib in combination decreased cell viability and enhanced the rate of apoptosis when compared with either drug used alone. Additionally, the combination treatment was superior in inhibiting cell invasion and induced significant decreases in Bcl‑2, FOXM1 and ABCB1 expression levels. Furthermore, the gefitinib‑celecoxib combination inhibited DU145/DR tumor growth to a greater extent than either treatment used individually. The expression of Ki‑67 was reduced, whereas cleaved‑caspase‑3 protein expression was increased in the tumors from the combination therapy group. In conclusion, the combined inhibition of EGFR and COX‑2 by gefitinib and celecoxib may overcome docetaxel resistance in human CRPC. These findings provided a molecular basis for the clinical application of a novel combination therapy for docetaxel‑resistant CRPC.

Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner.

At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive. In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC. Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment. In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim-dependent manner. Furthermore, additionally targeting Cdc20 might be a promising solution for the treatment of the CRPC with docetaxel resistance.

Efficacy of docetaxel in castration-resistant prostate cancer patients with intraductal carcinoma of the prostate.

This study aimed to investigate the efficacy of docetaxel in castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P). We retrospectively identified 79 CRPC patients with distant metastasis at initial diagnosis from June 2002 to January 2014. All patients received initial androgen deprivation therapy and 46 received docetaxel chemotherapy after progressing to CRPC. The primary outcome of interest was cancer-specific survival (CSS) from the time of CRPC diagnosis. The Cox regression model was used to confirm whether IDC-P and docetaxel would act as independent factors for prognosis. IDC-P was found in 62 of 79 patients. The median CSS in the IDC-P-present group was 18.2 versus 45.6months in the IDC-P-absent group (HR 2.67; 95% CI 1.18 to 6.06; P=0.019). Docetaxel was administered to 36 patients with IDC-P and 10 patients without IDC-P, with a median CSS of 20.5 versus 53.2months, respectively (HR 2.98; 95% CI 1.02 to 8.64; P=0.044). Multivariate analysis demonstrated that the presence of IDC-P and docetaxel were independent prognostic factors for CSS (P=0.026 and 0.005, respectively) and overall survival (OS) (P=0.029 and 0.001, respectively). The presence of IDC-P is an independent prognostic factor in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis. Docetaxel may prolong CSS and OS in CRPC patients with distant metastases and IDC-P in needle biopsies at the time of initial diagnosis.

Safety and Efficacy of Docetaxel, Bevacizumab, and Everolimus for Castration-resistant Prostate Cancer (CRPC).

Previous data suggests that co-targeting mammalian target of rapamycin and angiogenic pathways may potentiate effects of cytotoxic chemotherapy. We studied combining mammalian target of rapamycin and vascular endothelial growth factor inhibition with docetaxel in castrate-resistant prostate cancer (CRPC). Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Docetaxel and bevacizumab were given intravenously day 1 with everolimus orally daily on a 21-day cycle across 3 dose levels (75:15:2.5, 75:15:5, and 65:15:5; docetaxel mg/m2, mg/kg bevacizumab, and mg everolimus, respectively). Maintenance therapy with bevacizumab/everolimus without docetaxel was allowed after≥ 6 cycles. Forty-three subjects were treated across all dose levels. Maximal tolerated doses for the combined therapies observed in the phase 1B portion of the trial were: docetaxel 75 mg/m2, bevacizumab 15 mg/kg, and everolimus 2.5 mg. Maximal prostate-specific antigen decline≥ 30% and≥ 50% was achieved in 33 (79%) and 31 (74%) of patients, respectively. Best response by modified Response Evaluation Criteria In Solid Tumors criteria in 25 subjects with measurable disease at baseline included complete or partial response in 20 (80%) patients. The median progression-free and overall survival were 8.9 months (95% confidence interval, 7.4-10.6 months) and 21.9 months (95% confidence interval, 18.4-30.3 months), respectively. Hematologic toxicities were the most common treatment-related grade≥ 3 adverse events including: febrile neutropenia (12; 28%), lymphopenia (12; 28%), leukocytes (10; 23%), neutrophils (9; 21%), and hemoglobin (2; 5%). Nonhematologic grade≥ 3 adverse events included: hypertension (8; 19%), fatigue (3; 7%), pneumonia (3; 7%), and mucositis (4; 5%). There was 1 treatment-related death owing to neutropenic fever and pneumonia in a patient treated at dose level 3 despite dose modifications and prophylactic growth factor support. Docetaxel, bevacizumab, and everolimus can be safely administered in CRPC and demonstrate a significant level of anticancer activity, meeting the predetermined response criteria. However, any potential benefit of combined therapy must be balanced against increased risk for toxicities. Our results do not support the hypothesis that this combination of agents improves upon the results obtained with docetaxel monotherapy in an unselected population of chemotherapy-naive patients with CRPC.

High neutrophil-to-lymphocyte ratio predicts poor clinical outcome in patients with castration-resistant prostate cancer treated with docetaxel chemotherapy.

To evaluate the prognostic significance of the neutrophil-to-lymphocyte ratio in patients receiving chemotherapy with docetaxel for castration-resistant prostate cancer. A total of 57 castration-resistant prostate cancer patients treated between 2009 and 2014 were included in the present retrospective study. All patient data, including clinicopathological factors, were assessed. Univariate and multivariate Cox regression models were used to predict overall survival and progression-free survival after chemotherapy initiation. The median overall survival and progression-free survival were determined as 19.0 months (range 1-61 months) and 10.0 months (range 1-56 months), respectively. The cut-off level of the neutrophil-to-lymphocyte ratio was set as the median value of 3.5 among all patients in this study. In Kaplan-Meier analysis, the median overall survival and progression-free survival were shorter in patients with a high neutrophil-to-lymphocyte ratio compared with those with a low neutrophil-to-lymphocyte ratio (15 vs 20 months, P = 0.0125; and 9.5 vs 15 months, P = 0.0132, respectively). The overall survival and progression-free survival periods in patients with a high neutrophil-to-lymphocyte ratio were significantly shorter than those of patients with a low neutrophil-to-lymphocyte ratio (P = 0.0178 and 0.0176, respectively). In the multivariate analysis, a high neutrophil-to-lymphocyte ratio was an independent predictor of overall survival and progression-free survival (hazard ratio 2.728, 95% confidence interval 1.05-7.09, P = 0.039; and hazard ratio 2.376, 95% confidence interval 1.12-5.06, P=0.024, respectively). The present study results suggest that the neutrophil-to-lymphocyte ratio is a useful prognostic factor in patients with castration-resistant prostate cancer treated by docetaxel chemotherapy. These findings might be useful in determining treatment strategies in the future.

Abstract B16: Combination of docetaxel with histone deacetylase inhibitor inhibits AR signaling synergistically in hormone-independent 22Rv1 prostate cancer cells

Abstract Globally prostate cancer is the sixth leading cause of cancer-related death in men, and it is now the first in the United Kingdom and second in the United States. At the early stage, prostate cancer growth and progression depend on androgen receptor (AR) signaling. Therefore, androgen-deprivation therapy (ADT) is effective to patient with prostate cancer by inhibition of androgen synthesis. With time, however, most patients with prostate cancer eventually lose sensitivity to androgen withdrawal and progress to the development of castration-resistant prostate cancer (CRPC). Though docetaxel is a standard of care therapy in CRPC, most of patients develop resistance to this therapy. Therefore, the novel therapeutic strategies and combination therapy are needed to overcome this resistance. In this study, we examined whether histone deacetylase inhibitor (HDACI), suberoylanilide hydroxamic acid (SAHA) might enhance the effect of docetaxel in CRPC. Hormone-independent 22Rv1 cells harboring AR were treated with docetaxel and/or SAHA. Co-treatment of docetaxel and SAHA inhibited the growth of 22Rv1 cells synergistically. Combination treatment decreased the levels of AR, prostate specific antigen (PSA), and anti-apoptotic Bcl-2 proteins (Mcl-1, Bcl-xl) more efficiently compared with docetaxel or SAHA alone, when it analyzed by Western blot. And combination treatment increased activation of caspase-3 remarkably, while docetaxel or SAHA alone increased it slightly. Moreover, immunocytochemistry and analysis of nuclear fractionated proteins showed that combination treatment induced acetylation and bundling of tubulin, inhibiting nuclear accumulation of AR significantly. These results suggested that docetaxel in combination with SAHA inhibited cell growth efficiently and induced apoptosis by repressing expression and translocation to nucleus of AR in 22Rv1 cells, and this combination can be a useful therapeutics for the treatment of CRPC patients. Citation Format: Ha-Gyeong Kim, Jung Jin Hwang, Choung-Soo Kim. Combination of docetaxel with histone deacetylase inhibitor inhibits AR signaling synergistically in hormone-independent 22Rv1 prostate cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B16.

Abstract IA11: The role of bone microenvironment in the lethal progression of prostate cancer

Abstract Lethal prostate cancer (PCa) is clinically characterized by bone-homing and bone- forming metastases, and bone is frequently the initial organ involved in castrate-resistant progression. These clinical observations led investigators to develop bone-tropic radiopharmaceuticals to treat men with advanced PCa. The ability of the bone-homing alpha emitter (RAD-223) to prolong progression free and overall survival establishes the therapeutic relevance of targeting bone 1. The long accepted paradigm of PCa progression has been dominated by the model of evolution from androgen dependence to androgen independence under the selective pressure of castration. Thus, Src family kinases (SFKs) were investigated experimentally and clinically for the treatment of putative “androgen independent” PCa, as SFKs play a role in both tumor growth and bone turnover. The roles of SFKs in migration, invasion, survival of tumor cells, and osteoclast and osteoblast function in tumor microenvironment were supported by numerous clinical and laboratory observations 2, 3. Despite promising phase I /II reports of dasatinib, a multikinase and potent SFK inhibitor, in men with advanced PCa 4, 5, a phase III trial failed to yield the expected survival advantage 6. The result of this trial highlights the difficulties in translating data from cell line models to biologically heterogeneous clinical PCa and in transitioning from phase I/II to phase III clinical trials. The efficacy of dasatinib was not observed likely due to persistent AR signaling, which remains the primary driver of progression in bone by the transition from paracrine to intracrine androgen signaling 7. Based on these considerations, we are testing the efficacy of an androgen biosynthesis inhibitor in combination with dasatinib to better understand the relevance of mechanism(s). A co–clinical investigational strategy is being applied to better define biomarkers to predict clinical efficacy. These studies also highlight the importance of preclinical work that utilizes models that better reflect the heterogeneity of PCa. This problem is partly overcome by patient- derived xenografts (PDX) 8, 9 10. These models reflect many aspects of PCa in bone and can be used to identify therapy targets and better identify both mechanisms of drug efficacy and development of resistance. Studies in PDX have led to identification of FGF signaling as a therapy target 11. Additional studies in PDX implicated the tumor microenvironment in the striking bone responses observed with cabozantinib 13. These observations led us to propose a model of prostate cancer progression founded on the hypothesis that cancer progresses from being an endocrine-driven cancer (Dihydrotestosterone-dependent) to paracrine/intracrine driven (microenvironment-dependent), and then finally to a cell autochthonous phase 12. Continued studies should lead to decisions on therapy treatment that are based on an understanding of markers that predict disease progression. This new paradigm will also result in more effective therapy combinations.

773P - Multicenter, Randomized, Double-Blind Phase Ii Study of Sorafenib Compared to Placebo with Best Supportive Care After Failure of Docetaxel in Metastatic Castration-Resistant Prostate Cancer

ABSTRACT Aim: In castration- and docetaxel-resistant prostate cancer cells, sorafenib has been shown to cause apoptosis through downregulation of myeloid cell leukemia-1, phosphorylation of Akt and inhibition of androgen receptor (AR) expression as well as of its constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain. We aimed to evaluate whether thus sorafenib may stabilize disease after failure of docetaxel in castration-resistant prostate cancer patients. Methods: In our phase 2, double-blind, placebo-controlled trial, 51 men with castration-resistant, docetaxel-refractory prostate cancer were randomly assigned to receive sorafenib 400mg twice daily or best supportive care for 12 weeks. The primary endpoint was the rate of patients who experienced stable disease (or partial response) for at least 12 weeks of treatment. Secondary efficacy variables were response rate according to RECIST criteria, progression-free survival and evaluation of biomarkers in serum. Results: In 8 (partial response: 2; stable disease: 6) out of 24 patients in the sorafenib group (33.3%) but only 2 (stable disease: 2) out of 27 patients in the placebo group (7.4%) tumor stabilization was observed (p = 0.024). Median progression-free survival and overall survival was in favour of the sorafenib group compared with placebo (100 versus 89 days; p = 0.019 and 369 versus 249 days; p= n.s.). In accordance with clinical results, serum values of M65, a prognostic biomarker of tumor progression, stabilized during sorafenib with a maximum effect at week eight (+5 %) while increasing with placebo (+41%). Rates of fatigue, diarrhea, appetite loss, hand-foot syndrome and hypertension were higher with sorafenib but well manageable. Conclusions: For the first time, sorafenib showed significant antitumor activity in patients with metastatic CRPC in the post-docetaxel setting. With activity against C-terminally truncated, constitutively active AR variants assumed to be present in abiraterone-resistant tumor cell clones it may be an option for new treatment sequences and combinations in future. Disclosure: G. Kramer: honorary fees from Advisory Boards: Amgen, Astellas, Bayer, Janssen, Ipsen, Sanofi-Aventis, Takeda, Roche, GSK, Novartis and research grant by Sanofi-Aventis;S.F. Shariat: Honorary fees for advisory boards for Janssen, Ipsen and Astellas;W. Loidl: Honorary fees for advisory boards for Sanofi-Aventis, GSK, Janssen, Roche, Novartis, Takeda, Astellas, Amgen, Ipsen, Bayer. All other authors have declared no conflicts of interest.

800P - Impact of Body Composition on Treatment Toxicities in Patients with Metastatic Prostate Cancer Treated with Docetaxel

ABSTRACT Aim: Body composition is an important prognostic factor in cancer patients (pts) and evidence for a strong link between low skeletal muscle mass (sarcopenia) and chemotherapy toxicity is increasing. Docetaxel is standard first line treatment for castrate resistant prostate cancer (CRPC). The aim of this study was to correlate body composition (by computed tomography) with toxicity to docetaxel in CRPC. Methods: Pts with CRPC who received docetaxel between 2008 - 2013 were included. Correlations between pt characteristics, body composition and toxicity to chemotherapy were analyzed. Sarcopenia was defined using published cut offs. Toxicity was assessed using Common Terminology Criteria for Adverse Effects v4.0. Results: 62 pts, mean age 69y (SD 7), were included. In total 73% of pts were overweight or obese (BMI > 25kg/m2). Sarcopenia was present in 68% (n = 42) and of these 28 (66.6%) were both sarcopenic and overweight or obese. Sarcopenic pts were older (71 vs. 65y, p 75th centile (89 days vs 159 days, p = 0.056). When we analysed the drug dose according to SMI (cm2/m2), 31% of pts receiving a drug dose >75th centile (1.98mg/SMI) experienced neutropenia in the first 3 cycles vs 0% receiving a dose 25kg/m2:722 days vs 327 days for BMI 75th centile (133mg/dl) having a shorter survival compared to pts with CRP Conclusions: Sarcopenia is highly prevalent in pts with CRPC receiving docetaxel but is masked by excessive adiposity. Very low skeletal muscle mass is associated with less treatment days and poor tolerance to chemotherapy. High BMI is associated with longer survival. Disclosure: All authors have declared no conflicts of interest.