Docetaxel-refractory Prostate Cancer Research Articles

Prognostic role of docetaxel-induced reduction of free testosterone serum levels in metastatic prostate cancer patients.

144 Background: We have recently demonstrated that a salvage therapy with carboplatin plus weekly docetaxel is effective in docetaxel-refractory prostate cancer (PC) and interferes with testosterone biosynthesis (Reuter et al.; Oncol Res & Treat. 2018, 41 (suppl.1): p.10). In this study, the impact of docetaxel monotherapy on free and total testosterone serum levels (fT, TT) and the prognostic role of fT and TT were analyzed in mPC patients. Methods: 62 consecutive mPC patients were treated with at least two cycles of docetaxel (75 mg/m2 q3w; 50 mg/m2 q2w, or 35 mg/m2 q1w) until disease progression, occurrence of intolerable adverse effects or completion of the planned cycle number. Efficacy measures were done following PCWG2 recommendations. FT and TT were measured before and during chemotherapy. Results: At the current analysis (August 31, 2020), the median follow-up time was 21.2 months. Response of prostate-specific antigen (PSAR; ≥50% PSA reduction) was observed in 42/62 (67.7%) and 12/36 (33.3%) patients with measurable disease exhibited a partial remission (PR). Median progression-free survival (PFS) for all patients was 8.1 months (CI 95% 3.6, 12.5) and median overall survival (OS) was 25.7 months (CI 95% 19.4, 32.1). The most common reversible grade 3/4 toxicity was leukopenia/neutropenia (29/33.9%). Median fT and TT serum levels were reduced below the detection limit during docetaxel treatment (fT: from 0.34 pg/mL to < 0.01 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified PSAR > 50%, fT reduction of 100% and number of organs involved as independent prognostic risk factors for PFS. Furthermore, fT reduction of 100% and FT nadir values < 0.01 pg/mL were independent prognostic risk factors for OS (p < 0.05). Conclusions: These data demonstrate that fT is an important prognostic factor for PFS and OS in mPC patients.

Feasibility of metronomic chemotherapy with tegafur-uracil, cisplatin, and dexamethasone for docetaxel-refractory prostate cancer.

Objectives: To evaluate the efficacy of tegafur–uracil (UFT), a prodrug of 5-fluorouracil, plus cisplatin and dexamethasone in patients with docetaxel-refractory prostate cancers.Methods: Twenty-five patients with docetaxel-refractory prostate cancer were administered oral UFT plus intravenous cisplatin (UFT-P therapy) and dexamethasone. Treatment responses were assessed monthly via prostate-specific antigen (PSA) level measurements. Treatment-related adverse events and overall survival were also assessed.Results: UFT-P therapy resulted in decreased PSA levels in 14 (56%) patients and increased PSA levels in 11 (44%). In patients with increased PSA levels, 7 (64%) of the 11 patients displayed decreased PSA doubling times. The UFT-P therapy response rate was 84% (21/25 patients). Imaging studies revealed that tumor shrinkage during UFT-P therapy occurred in 1 patient in whom bilateral hydronephrosis caused by lymph node metastasis improved. The median survival time from docetaxel initiation was 36 months. In UFT-P-treated patients, the median PSA progression and overall survival times were 6 and 14 months, respectively. UFT-P treatment-related adverse events were mild diarrhea, general fatigue, and anorexia. Treatment was not discontinued for any of the patients. UFT-P therapy did not cause serious hepatic or renal dysfunction or pancytopenia.Conclusions: UFT-P therapy is a safe and effective treatment for patients with docetaxel-refractory prostate cancer, although large-scale, multicenter, prospective studies are needed to validate these findings.

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.

Residual Prostate Cancer Cells after Docetaxel Therapy Increase the Tumorigenic Potential via Constitutive Signaling of CXCR4, ERK1/2 and c-Myc

Despite an increasing prevalence of patients with docetaxel-refractory prostate cancer, little is known about the tumor biology of the docetaxel-resistant residual tumor cells compared with primary tumor cells. In this study, tumorigenic potential was increased in the docetaxel-resistant residual prostate cancer cell lines (DRD, 1G7 and PC3DR) compared with parental cells (DU145 or PC3). Enhanced tumorigenic potential was conferred by oncogenic c-Myc, which was stabilized by constitutively activated ERK1/2 in DRD, 1G7, and PC3DR cells. Constitutively activated ERK1/2 was maintained by CXCR4, which was upregulated in DRD, 1G7, and PC3DR cells. In docetaxel-treated DU145 cells, transiently activated ERK1/2 induced CXCR4 expression by stabilizing c-Myc. Furthermore, constitutive activation of CXCR4, ERK1/2, and c-Myc signaling was evident in clinical tissue samples from human patients with docetaxel-resistant prostate cancer. In DTX-resistant residual prostate cancer cells, the enhanced tumorigenic potential was reduced by ERK1/2 inhibition, or by AMD3100, a CXCR4 antagonist. Thus, docetaxel treatment constitutively activated the CXCR4, ERK1/2, and c-Myc signaling loop in docetaxel-resistant residual prostate cancer cells. Constitutive signaling pathways are viable therapeutic targets for residual prostate tumor cells following acquisition of docetaxel resistance.

A phase II study of cabazitaxel in patients with previously treated metastatic gastroesophageal adenocarcinoma.

e15095 Background: Cabazitaxel is a semi-synthetic novel taxane with activity in docetaxel refractory prostate cancer. We sought to determine the response rate of cabazitaxel in patients with advanced gastroesophageal adenocarcinoma that had progressed after at least 1 prior therapy for metastatic disease. Methods: This open label single arm phase II study followed a Simon two-stage design. The study was designed to differentiate between a 10% level of activity and a 30% level of activity and was to be terminated if the response rate was unlikely to be > 10%. Eligibility criteria included patients with gastroesophageal cancer with measurable disease after at least 1 prior regimen for metastatic disease. ECOG PS 0-2; ANC > 1,500/µL, AST/ALT ≤ 3x ULN, total bili ≤ ULN. Pts initially received cabazitaxel 25 mg/m2 IV every 21 days but after 9 patients were entered, the dose was reduced to 20 mg/m2due to toxicity. Results: The data safety monitoring board (DSMB) reviewed data after 13 pts were entered. Pt characteristics included 11 men, 2 women; median age, 70 yrs [range, 55-80]. Nine pts had ≥ 2 prior regimens. Ten pts had previous treatment with a taxane. Of 13 pts, no objective antitumor responses were observed and all 13 developed evidence of disease progression. A median of 2 cycles were given, up to a maximum of 6 cycles in 2 pts. The PFS rate at 3 months was 15%. The DSMB considered cabazitaxel ineffective and terminated the study. The probability of erroneously concluding the treatment was active (p ≥ 0.3) was < 0.0419. Grade 3 or 4 adverse events occurred in 6 pts (46.1%), in which neutropenia (n=4) and pneumonia (n=1) were grade 4. Grade 3 toxicities included ANC (n=1), anemia (n=2), nausea (n=2), weakness (n=2), diarrhea (n=1), pleural effusion (n=1), typhilitis (n=1), vomiting (n=1). Conclusions: Cabazitaxel monotherapy demonstrated no antitumor efficacy in previously treated gastroesophageal cancer. Clinical trial information: NCT01365130.

959 FEASIBILITY OF BIOCHEMICAL MODULATION CHEMOTHERAPY WITH UFT, CISPLATIN, AND DEXAMETHASONE FOR DOCETAXEL-REFRACTORY PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (III)1 Apr 2013959 FEASIBILITY OF BIOCHEMICAL MODULATION CHEMOTHERAPY WITH UFT, CISPLATIN, AND DEXAMETHASONE FOR DOCETAXEL-REFRACTORY PROSTATE CANCER Katsuhiro Fukuta, Hiromichi Naruyama, Masahito Hirose, Hiroki Kubota, Noriyasu Kawai, Keiichi Tozawa, Kenjiro Kohri, and Kenjiro Kohri Katsuhiro FukutaKatsuhiro Fukuta yatomi, Japan More articles by this author , Hiromichi NaruyamaHiromichi Naruyama yatomi, Japan More articles by this author , Masahito HiroseMasahito Hirose yatomi, Japan More articles by this author , Hiroki KubotaHiroki Kubota yatomi, Japan More articles by this author , Noriyasu KawaiNoriyasu Kawai nagoya, Japan More articles by this author , Keiichi TozawaKeiichi Tozawa nagoya, Japan More articles by this author , Kenjiro KohriKenjiro Kohri nagoya, Japan More articles by this author , and Kenjiro KohriKenjiro Kohri nagoya, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.540AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel-based systemic chemotherapy has been shown to be useful for the management of castration-resistant prostate cancer (CRPC). However, reports on drug therapy for docetaxel-refractory prostate cancer are scarce. We evaluated the effectiveness of UFT (a prodrug of 5-fluorouracil [5-FU]), cisplatin, plus dexamethasone in patients with docetaxel-refractory prostate cancer. METHODS Fifty-six patients with CRPC whose serum prostate-specific antigen (PSA) levels had increased on 3 consecutive measurements during docetaxel-based treatment were included in the analysis. Twenty-five patients received oral UFT and dexamethasone plus intravenous cisplatin (UFT-P therapy) and control group (thirty-five patients) were continued docetaxel therapy. PSA levels were measured once a month to evaluate the treatment response. UFT-P therapy related adverse events and overall survival were also assessed. RESULTS The average age was 72.4 years (range, 51-86 years). The mean initial PSA was 720 ng/ml (range, 1.84-9700). Forty-two patients had bone metastases (UFT group had twenty patients, and control group had thirty-five patients) and sixteen patients had lymph node metastases at the start of therapy. The previous treatment was full extraction in fifteen patients and radiotherapy in six patients. The mean observation periods was 592 days (range, 65-1380 days). During UFT-P therapy, PSA levels decreased in 14 of 25 patients (56%). PSA doubling time (PSADT) decreased in 7 of 11 patients, although their PSA levels were increasing. Including these latter patients, the response rate to UFT-P therapy was 84% (21 of 25 patients). The median survival of UFT-P group and control group (docetaxel continued) was 34 and 21 months, respectively. The median time to PSA progression of UFT-P group and control group were 14 and 6 months, respectively. The adverse events of UFT-P therapy were mild diarrhea (20%), general fatigue (100%), and anorexia (44%). However there were not pancytopenia, and adverse events were all grade 1. Treatment by UFT-P could be continued in all patients. Tumor shrinkage during UFT-P therapy was minimal on imaging studies, although hydronephrosis with lymph node metastasis improved in one patient. CONCLUSIONS Our results suggest that UFT-P therapy is effective against docetaxel-refractoly prostate cancer, with minimal adverse events. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e393 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Katsuhiro Fukuta yatomi, Japan More articles by this author Hiromichi Naruyama yatomi, Japan More articles by this author Masahito Hirose yatomi, Japan More articles by this author Hiroki Kubota yatomi, Japan More articles by this author Noriyasu Kawai nagoya, Japan More articles by this author Keiichi Tozawa nagoya, Japan More articles by this author Kenjiro Kohri nagoya, Japan More articles by this author Kenjiro Kohri nagoya, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cetuximab in combination with docetaxel in patients (pts) with metastatic castration resistant (mCRPC) and docetaxel-refractory prostate cancer: A multicenter phase II trial (SAKK 08/07).

4666 Background: No standard treatment options exist for pts with mCRPC who progressed during or shortly after docetaxel (doc) therapy. The epidermal growth factor receptor (EGFR) is overexpressed ...

Metronomic Treatment with Low-Dose Trofosfamide Leads to a Long-Term Remission in a Patient with Docetaxel-Refractory Advanced Metastatic Prostate Cancer

The treatment of metastatic prostate cancer patients refractory to androgen withdrawal and docetaxel therapy is currently discouraging and new therapeutic approaches are vastly needed. Here, we report a long-term remission over one year in a 68-year-old patient with metastatic docetaxel-refractory prostate cancer employing low-dose trofosfamide. The patient suffered from distant failure with several bone lesions and lymph node metastases depicted by a (11) C-Choline positron emission tomography/computerized tomography (PET/CT). After initiation of trofosfamide 100 mg taken orally once a day we observed a steadily decreasing PSA value from initial 46.6 down to 2.1 μg/L. The Choline-PET/CT was repeated after 10 months of continuous therapy and demonstrated a partial remission of the bone lesions and a regression of all involved lymph nodes but one. Taken together we found an astonishing and durable activity of the alkylating agent trofosfamide given in a metronomic fashion. We rate the side effects as low and state an excellent therapeutic ratio of this drug in our patient.

Preliminary report of an open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with docetaxel refractory prostate cancer

5145 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in castrate resistant prostate cancer (CRPC) and contribute to resistance to therapy. AT-101 is a pan-Bcl-2 inhibitor (Bcl-2, Bcl-XL, Bcl-W, and Mcl-1) and potent inducer of proapoptotic proteins. AT-101 is active as a single agent and in combinations with standard therapies in in vitro and in vivo tumor models, as a single agent in a phase II trial in CRPC, and in combination with D/P as first-line therapy in CRPC, as demonstrated by declines in PSA and RECIST responses. Methods: Men ≥18 years of age with docetaxel-refractory CRPC were eligible. Patients (pts) must have PSA progression per the Bubley criteria or documented disease progression while receiving prior D/P therapy. Pts (n = 40) were treated with D (75 mg/m2 day 1), P (5mg b.i.d. on days 1–21) and AT-101 40mg b.i.d. on days 1–3 of each 21-day cycle. Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: Efficacy data was available on 34 pts. Thirty-five percent (12/34) of pts treated had at least a 30% decrease in PSA level and 18% (6/34) of pts achieved a >50% PSA decline. Twenty one of 34 pts included in this analysis had measurable disease. Five pts (24%) with measurable disease had a PR or CR by RECIST criteria and one additional patient had tumor shrinkage of 29%. Two (2) RECIST PRs are unconfirmed. Thus far, 3 pts have been on therapy for 6 months or more and 15 pts remain on study. Safety data was available on 22 pts. The most common (>20%) adverse events (AEs) included fatigue (55%), anorexia, including weight decreased (45%), diarrhea and nausea (27%), vomiting and neutropenia (23%). The grade 3/4 AEs occurring in more than 1 pt were: neutropenia (5), anemia, anorexia, dyspnea and leukopenia (2 pts each). One partial small bowel obstruction was the only related, serious adverse event (SAE) reported to date. Conclusions: This data supports that AT-101 can be administered safely with D/P in pts with CRPC who are docetaxel-refractory. Durable PSA and RECIST responses were observed. [Table: see text]

Phase I and Pharmacokinetic Study of YM155, a Small-Molecule Inhibitor of Survivin

To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin. Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion. Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response. CONCLUSION YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

Clusterin knockdown using the antisense oligonucleotide OGX‐011 re‐sensitizes docetaxel‐refractory prostate cancer PC‐3 cells to chemotherapy

To characterize changes in secretory clusterin (sCLU) expression in prostate cancer cells after treatment with docetaxel and to determine whether sCLU knockdown can re-introduce chemosensitivity in a docetaxel-resistant, androgen-independent human prostate cancer model. A tissue microarray was constructed for 84 radical prostatectomy (RP) specimens from a multicentre Phase II trial of neoadjuvant combined androgen ablation and docetaxel (CUOG-P01a) and assessed for changes in the expression of the cytoprotective chaperone sCLU. The human prostate cancer cell line PC-3 was repeatedly exposed to docetaxel chemotherapy in vitro, and a docetaxel-resistant cell subline (PC-3dR) was developed and analysed. sCLU levels were significantly higher in RP specimens treated with neoadjuvant combined androgen ablation and docetaxel than in untreated specimens. Similarly, sCLU expression increased 2.5-fold in the newly developed docetaxel-refractory PC-3dR cell line compared with parental PC-3 cells. There was a dose-dependent and sequence-specific decrease in sCLU levels in PC-3dR cells using OGX-011, an antisense oligonucleotide against human sCLU. OGX-011 and small-interference RNA both chemosensitized PC-3dR cells to docetaxel and mitoxantrone in vitro and apoptotic rates in PC-3dR cells were significantly increased when OGX-011 was combined with docetaxel. In vivo, growth of PC-3dR xenografts in nude mice was synergistically inhibited by OGX-011 combined with paclitaxel or mitoxantrone (by 76% and 44% compared with their mismatch controls, respectively). The present findings indicate that targeted knockdown of sCLU enhances the effects of cytotoxic chemotherapy in docetaxel-refractory cells, and provide preclinical proof of principle for clinical trials testing OGX-011 in second-line chemotherapy regimens for patients with docetaxel-refractory prostate cancer.