Long-term use of dasatinib in patients with metastatic castration-resistant prostate cancer after receiving the combination of dasatinib and docetaxel.
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ABSTRACT:
SUBMITTER: Araujo JC
PROVIDER: S-EPMC3601649 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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Long-term use of dasatinib in patients with metastatic castration-resistant prostate cancer after receiving the combination of dasatinib and docetaxel.
Araujo John C JC Trudel Geralyn C GC Paliwal Prashni P
Cancer management and research 20130309
Dasatinib is a potent oral tyrosine kinase inhibitor which targets several kinases, including the SRC family kinases. SRC family kinases have been implicated in androgen therapy resistance that often develops in metastatic castration-resistant prostate cancer (mCRPC), which drives the need for non-androgen targeting therapies. This article describes the preclinical rationale for the use of combination dasatinib and docetaxel therapy in mCRPC, and highlights the results of a phase I-II trial in w ...[more]
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Project description:BACKGROUND:Activation of the vascular endothelial growth factor receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of castration-resistant prostate cancer (CRPC) in preclinical models. Cediranib and dasatinib are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of cediranib and dasatinib in CRPC have shown single agent activity. METHODS:Docetaxel-pretreated CRPC patients were randomized to arm A: cediranib alone (20 mg/day) versus arm B: cediranib (20 mg/day) plus dasatinib (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12-week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results A total of 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles =4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A versus 18 % in arm B (p?=?0.03). Median PFS in months (arm A versus B) was: 5.2 versus 2.6 (95 % CI: 1.9-6.5 versus 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in either arm. CONCLUSIONS:Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in patients with CRPC. ClinicalTrials.gov number: NCT01260688.
| S-EPMC4281773 | biostudies-literature
Project description:Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR]=1.61, 95% confidence interval [CI]=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95% CI 0.74-1.46, p=0.8) or PSA response (odds ratio=1.14, 95% CI=0.65-1.99, p=0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.16, 95% CI=0.06-0.46, p<0.001) and PFS (HR=0.31, 95% CI=0.12-0.80, p=0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR=1.93, 95% CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95% CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial. PATIENT SUMMARY: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker.
| S-EPMC6377278 | biostudies-other
Project description:PURPOSE:Preclinical evidence suggests that both docetaxel and enzalutamide target androgen receptor translocation and signaling. This phase Ib study assessed the safety, tolerability, and pharmacokinetics of docetaxel when administered with enzalutamide as first-line systemic chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). EXPERIMENTAL METHODS:Docetaxel-naïve patients received 21-day cycles of docetaxel (75 mg/m(2)). Enzalutamide (160 mg/day) was administered daily starting on day 2 of cycle 1. Patients were allowed to stop and restart docetaxel at any time following cycle 2. Treatment continued indefinitely until unacceptable toxicity or discontinuation due to investigator or patient preference. RESULTS:A total of 22 patients received docetaxel, of whom 21 also received enzalutamide. Docetaxel was administered for a median of 5.0 cycles and enzalutamide for a median of 12.0 months. With concomitant treatment, geometric mean docetaxel exposure decreased by 11.8%, whereas peak concentrations decreased by 3.7% relative to docetaxel alone. The most common toxicities observed during the period of concomitant therapy were neutropenia (86.4%) and fatigue (77.3%). Common toxicities observed with post-docetaxel enzalutamide were constipation (23.8%), decreased appetite (19.0%), fatigue (19.0%), and musculoskeletal pain (19.0%). Treatment with enzalutamide and docetaxel resulted in prostate-specific antigen decreases in almost all patients based on exploratory analysis of available baseline and on-study prostate-specific antigen data. CONCLUSIONS:The combination of docetaxel and enzalutamide is feasible, although higher rates of neutropenia and neutropenic fever than anticipated were observed. Reductions in docetaxel exposure with enzalutamide coadministration were not considered clinically meaningful. This combination warrants further study in a larger mCRPC population. Clin Cancer Res; 22(15); 3774-81. ©2016 AACR.
| S-EPMC5468167 | biostudies-literature
Project description:Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone.In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m(2) intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 ?mol/mol creatinine vs ?60 ?mol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497.Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]).The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients.Bristol-Myers Squibb.
| S-EPMC5478530 | biostudies-literature
Project description:Antiproliferative and antiosteoclastic activity from preclinical models show potential for dasatinib, an oral SRC and SRC family kinase inhibitor, as a targeted therapy for patients with prostate cancer. This phase II study investigated the activity of dasatinib in patients with metastatic castration-resistant prostate cancer (CRPC).Chemotherapy-naive men with CRPC and increasing prostate-specific antigen were treated with dasatinib 100 or 70 mg twice daily. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), and markers of bone metabolism. Following Prostate Cancer Working Group 2 guidelines, lack of progression according to Response Evaluation Criteria in Solid Tumor and bone scan was determined and reported at 12 and 24 weeks.Forty-seven patients were enrolled and received dasatinib (initial dose 100 mg twice daily, n = 25; 70 mg twice daily, n = 22), of whom 41 (87%) had bone disease. Lack of progression was achieved in 20 (43%) patients at week 12 and in 9 (19%) patients at week 24. Of 41 evaluable patients, 21 (51%) patients achieved > or =40% reduction in urinary N-telopeptide by week 12, with 33 (80%) achieving some level of reduction anytime on study. Of 15 patients with elevated urinary N-telopeptide at baseline, 8 (53%) normalized on study. Of 40 evaluable patients, 24 (60%) had reduction in bone alkaline phosphatase at week 12 and 25 (63%) achieved some reduction on study. Dasatinib was generally well tolerated and treatment-related adverse events were moderate.This study provides encouraging evidence of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC.
| S-EPMC3394097 | biostudies-literature
Project description:BackgroundTo determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (PC), the authors conducted a phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.MethodsIn phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m(2) every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m(2) every 21 days. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied.ResultsCombination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3-4 toxicity. Drug-drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26 of 46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone marker assessments, 33 of 38 (87%) and 26 of 34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months.ConclusionsThe high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC. Parallel declines in levels of PSA and bone markers are consistent with cotargeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study. Cancer 2012;. © 2011 American Cancer Society.
| S-EPMC3898168 | biostudies-literature
Project description:BackgroundThe administration of docetaxel chemotherapy is one therapeutic option to delay disease progression and increase overall survival in metastatic castration resistant prostate cancer (mCRPC). However, about 15% of patients are primary resistant to chemotherapy and hence would benefit from an alternative mCRPC treatment. Despite intensive research, there are no robust clinical validated biomarkers to predict mCRPC therapy response. Thus, the aim of the study was to determine KDM5D expression in archival radical prostatectomy specimens of patients medicated with docetaxel at time of mCRPC development in order to correlate KMD5D expression with treatment response.MethodsWe used in situ hybridization (ISH) (RNA scope 2.5 HD) to determine KDM5D expression in tissue samples of 28 prostate cancer patients. KDM5D status was correlated to chemotherapy response (PSA and radiographic response).ResultsData revealed that KDM5D is significantly overexpressed in tumor cells (P<0.0001) but also in benign cells (P<0.02) of those patients who responded to chemotherapy compared to non-responders.ConclusionsTo summarize, KDM5D is a promising novel biomarker predicting response to docetaxel chemotherapy already at the time of localized disease and thus potentially avoiding metastatic biopsies in the mCRPC stage of disease.
| S-EPMC8575572 | biostudies-literature
Project description:Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting.We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (??50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models.One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P?=?0.089). Median TTPP was 7.2 months (95% CI?=?4.5?-?17.2) in the D-naïve group versus 2.6 mo (95% CI?=?1.9?-?3.5) in the D-pretreated group (P?<?0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI?=?2.5?-?4.8) for D-pretreated men (P?<?0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR?=?2.32; 95% CI?=?1.19?-?4.50; P?=?0.013) and marginally significant for PFS (HR?=?1.90; 95% CI?=?0.94?-?3.84; P?=?0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n?=?34), results suggested a trend towards shorter duration of response in D-pretreated patients.The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents.
| S-EPMC4176523 | biostudies-other
Project description:This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naïve and docetaxel-resistant Chinese patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 146 patients with docetaxel-naïve group (103 cases) and docetaxel-resistant group (43 cases) were enrolled from the Shanghai Cancer Center (Shanghai, China) in this retrospective cohort study. The efficacy endpoints were prostate-specific antigen response rate, prostate-specific antigen progression-free survival, clinical/radiographic progression-free survival, and overall survival in response to abiraterone plus prednisone. Significantly higher prostate-specific antigen response rate was found in docetaxel-naïve group (54.4%, 56/103) compared to docetaxel-resistant group (34.9%, 15/43) (P = 0.047). In addition, significantly higher median prostate-specific antigen progression-free survival (14.0 vs 7.7 months, P = 0.005), clinical or radiographic progression-free survival (17.0 vs 12.5 months, P = 0.003), and overall survival (27.0 vs 18.0 months, P = 0.016) were found in docetaxel-naïve group compared to docetaxel-resistant group, respectively. The univariate and multivariate analyses indicated that lower albumin and visceral metastases were independent significant predictors for shorter overall survival. To sum up, our data suggested that abiraterone plus prednisone was efficient in both docetaxel-naïve and docetaxel-resistant Chinese patients. Moreover, higher PSA response rate and longer overall survival were observed in the docetaxel-naïve group, which suggested that abiraterone was more effective for docetaxel- naïve patients than for docetaxel failures.
| S-EPMC6413557 | biostudies-literature
Project description:BackgroundDocetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ?50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort.MethodsPC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response.ResultsPC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1?, IL-4, IL-6, IL-12 and IFN?) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002).ConclusionsIn vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.
| S-EPMC4402456 | biostudies-literature