Once-daily Dasatinib: Expansion of Phase II Study Evaluating Safety and Efficacy of Dasatinib in Patients With Metastatic Castration-resistant Prostate Cancer

doi:10.1016/j.urology.2011.01.006

Urology

Volume 77, Issue 5, May 2011, Pages 1166-1171

https://doi.org/10.1016/j.urology.2011.01.006 Get rights and content

Objectives

To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC.

Methods

Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase).

Results

The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia.

Conclusions

Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC.

Section snippets

Patients

Male patients with histologically confirmed CaP, metastasis, and ≥2 serial increases in the PSA level with a castrate serum testosterone level of <50 ng/dL, were eligible. The patients with pleural or pericardial effusion were excluded. Other key inclusion/exclusion criteria have been previously described by Yu et al.¹⁷ Concomitant luteinizing hormone-releasing hormone agonists were continued for patients without surgical castration. The patients already receiving bisphosphonates were allowed

Patient Characteristics

From October 2006 to July 2008, 48 additional patients were enrolled and received 100 mg dasatinib QD. The median therapy duration was 3.98 months (range 0.10-14.7). At the database lock, February 19, 2009, 7 patients were continuing dasatinib. The last patient finished the study in January 2010. The baseline characteristics and demographic data are listed in Table 1. A flow chart is provided in Figure 1.

Efficacy

The original predefined primary endpoint of the composite response/SD rate, which included

Comment

In the present study, dasatinib, administered at a dose of 100 mg QD to patients with chemotherapy-naive metastatic CRPC, produced signals of clinical activity. The PCWG2-defined endpoint of a lack of progression at 12 and 24 weeks was observed in 21 (44%) of 48 and 8 (17%) of 48 patients with QD dosing. The previously reported results were 20 (43%) of 47 and 9 (19%) of 47 patients with BID dosing.¹⁷

The present trial was designed before the publication of the PCWG2 criteria¹⁹ and did not

Conclusions

The final results from the present study have demonstrated the biologic activity and tolerability of dasatinib at a dose of 100 mg QD. The bone and potential antitumor effects of dasatinib support the clinical and preclinical results that dasatinib is a potent inhibitor of Src and other Src family kinases.12, 14, 15 Additionally, the 100 mg QD dose demonstrated activity with a more acceptable toxicity profile than the previously pooled BID doses. Future clinical trials with dasatinib evaluating

Acknowledgment

To Heather Ward, an employee of Bristol-Myers Squibb, who provided professional medical writing assistance.

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Cited by (80)

A Phase 2 Trial of Abiraterone Followed by Randomization to Addition of Dasatinib or Sunitinib in Men With Metastatic Castration-Resistant Prostate Cancer
2021, Clinical Genitourinary Cancer
Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC.
In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety.
From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years.
There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.
Randomized Phase II Trial of Abiraterone Alone or With Dasatinib in Men With Metastatic Castration-resistant Prostate Cancer (mCRPC)
2019, Clinical Genitourinary Cancer
Citation Excerpt :
The phase II clinical trial of Das in men with mCRPC who had not received prior docetaxel treatment documented modest clinical activity. In this study, 43% of men had not progressed at week 12, and 17% had not progressed at week 24.15 Objective responses were seen, both by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for 2 of 14 patients with measurable disease, and by prostate-specific antigen (PSA) declines, although only 1 patient had a confirmed 50% reduction in PSA.
Signaling via the Src pathway is thought to be a mediator of resistance to androgen targeted therapy in prostate cancer. We studied whether adding the Src inhibitor dasatinib to abiraterone would delay progression.
Eligible patients had metastatic castration-resistant prostate cancer (mCRPC), without prior chemotherapy. Abiraterone was prescribed at 1000 mg daily with prednisone 5 mg twice daily in both arms, and dasatinib 100 mg daily was added for Arm B. The primary endpoint was progression-free survival (PFS). The interim analysis was planned after 48 subjects, but the study was terminated early. PFS was evaluated using a 1-sided log rank test. The Fisher exact test was used for other categorical data analyses. Circulating tumor cells (CTCs) were identified with the Epic platform.
With 26 men randomized and a median follow up of 41.8 months, the median PFS was 15.7 months (95% confidence interval, 8.2-49.0+ months) for Arm B and 9.0 months (95% confidence interval, 4.4-30.7 months) for Arm A (P = .15). Response Evaluation Criteria in Solid Tumors responses were seen in 5 (36%) of 14 patients, including 2 complete responses (CRs) on Arm B, and 2 (17%) of 12 responses without CR on Arm A (P = .39). Grade ≥ 3 toxicities more common in Arm B included hypertension, pleural effusion/dyspnea, and gastrointestinal effects. CTCs were detected at baseline in 10 of 19 evaluable patients (median, 2.7/mL blood [range 0.41-59.7]). At week 4, CTCs increased in 1 (10%) of 10 patients on Arm A and 4 (44%) of 9 patients on Arm B.
Dasatinib did not significantly prolong PFS in combination with abiraterone, although power was limited owing to the incomplete study cohort. Treatment with the combination was associated with robust objective responses, including Response Evaluation Criteria in Solid Tumors CRs.
Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management
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Bone metastases (BM) are a common complication of cancer, whose management often requires a multidisciplinary approach. Despite the recent therapeutic advances, patients with BM may still experience skeletal-related events and symptomatic skeletal events, with detrimental impact on quality of life and survival.
A deeper knowledge of the mechanisms underlying the onset of lytic and sclerotic BM has been acquired in the last decades, leading to the development of bone-targeting agents (BTA), mainly represented by anti-resorptive drugs and bone-seeking radiopharmaceuticals. Recent pre-clinical and clinical studies have showed promising effects of novel agents, whose safety and efficacy need to be confirmed by prospective clinical trials.
Among BTA, adjuvant bisphosphonates have also been shown to reduce the risk of BM in selected breast cancer patients, but failed to reduce the incidence of BM from lung and prostate cancer. Moreover, adjuvant denosumab did not improve BM free survival in patients with breast cancer, suggesting the need for further investigation to clarify BTA role in early-stage malignancies.
The aim of this review is to describe BM pathogenesis and current treatment options in different clinical settings, as well as to explore the mechanism of action of novel potential therapeutic agents for which further investigation is needed.
Pyrazolo[3,4-d]pyrimidines-loaded human serum albumin (HSA) nanoparticles: Preparation, characterization and cytotoxicity evaluation against neuroblastoma cell line
2017, Bioorganic and Medicinal Chemistry Letters
Pyrazolo[3,4-d]pyrimidine derivatives 1–5, active as c-Src inhibitors, have been selected to be formulated as drug-loaded human serum albumin (HSA) nanoparticles, with the aim of improving their solubility and pharmacokinetic properties. The present study includes the optimization of a desolvation method-based procedure for preparing HSA nanoparticles. First, characterization by HPLC-MS and Dynamic Light Scattering (DLS) showed a good entrapment efficacy, a controllable particle size (between 100 and 200 nm) and an optimal stability over time, confirmed by an in vitro drug release assay. Then, 1–4 and the corresponding NPs were tested for their antiproliferative activity against neuroblastoma SH-SY5Y cell line. Notably, 3-NPs and 4-NPs were identified as the most promising formulation showing a profitable balance of stability, small size and a similar activity compared to the free drugs in cell-based assays. In addition, albumin formulations increase the solubility of pyrazolo[3,4-d]pyrimidine avoiding the use of DMSO as solubilizing agent.
Multiparameter Analysis of Off-Target Effects of Dasatinib on Bone Homeostasis in Patients With Newly Diagnosed Chronic Myelogenous Leukemia
2016, Clinical Lymphoma, Myeloma and Leukemia
We assessed patients with chronic myelogenous leukemia (CML) for serum calcium (Ca), phosphate (PO₄), bone alkaline phosphatase, N-telopeptide (NTx), osteoprotegerin (OPG) levels, and trabecular bone area (TBA) in bone marrow (BM) specimens before and after treatment with dasatinib. We identified a significant increase in percentage of TBA in postdasatinib BM (P = .022). This suggests that dasatinib therapy can increase TBA without significant changes in bone and mineral metabolism. Interferences with bone homeostasis and mineral metabolism have been described in patients receiving imatinib for CML or gastrointestinal stromal tumors. Dasatinib is a potent second-generation tyrosine kinase inhibitor designed to inhibit ABL and SRC kinases while also interfering with the c-Kit, platelet-derived growth factor receptor, and STAT5 pathways.
We used a multiparameter approach to examine the off-target effects of dasatinib in 30 patients with CML treated between 2009 and 2012. We recorded serum Ca and PO₄ levels, analyzed markers of bone formation (bone alkaline phosphatase/bone-specific alkaline phosphatase [BAP]) and bone resorption (NTx), measured OPG levels, and digitally analyzed changes in TBA in paired BM biopsy specimens before and after treatment. We correlated all findings with each other and with the results of conventional cytogenetic and molecular analyses.
We identified a significant increase in the percentage of TBA in postdasatinib BM biopsy specimens (P = .022) and noted a decrease in serum OPG levels in 75% of patients. Ca, PO₄, BAP, and NTx levels remained steady, without significant changes. There was no correlation between biomarker levels, percentage of TBA, and/or cytogenetic or molecular response.
These findings suggest that dasatinib therapy (within the therapeutic range) can increase trabecular bone, without causing significant changes in bone and mineral metabolism. Nonetheless, monitoring of bone health and skeletal integrity should be included into the long-term management of patients treated with dasatinib to further enhance our understanding of its safety profile and its potential role as a treatment modality for other bone diseases.
Biology of Bone Metastases in Prostate Cancer
2016, Urology
Citation Excerpt :
Dasatinib, a small molecule tyrosine kinase inhibitor, blocks the Src family of tyrosine kinases and certain receptor tyrosine kinases (eg, colony-stimulating factor 1 receptor/c-fms). A phase II trial in treated PCa patients with bone metastasis showed slower disease progression and reduced bone turnover and tumor burden.49 Osteoblastic bone metastases are composed of immature woven bone that is less mechanically competent and, thus, prone to fracture.
Advanced-stage prostate cancer (PCa) patients are often diagnosed with bone metastases. Bone metastases remain incurable and therapies are palliative. PCa cells prevalently cause osteoblastic lesions, characterized by an excess of bone formation. The prevailing concept indicates that PCa cancer cell secrete an excess of paracrine factors stimulating osteoblasts directly or indirectly, thereby leading to an excess of bone formation. The exact mechanisms by which bone formation stimulates PCa cell growth are mostly elusive. In this review, the mechanisms of PCa cancer cell osteotropism, the cancer cell-induced response within the bone marrow/bone stroma, and therapeutic stromal targets will be summarized.

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: The present study was funded by Bristol-Myers Squibb.

: G. C. Trudel is an employee of, and owns stocks in, Bristol-Myers Squibb; and P. Paliwal is an employee of Bristol-Myers Squibb.

: E. Y. Yu, M. A. Carducci, E. M. Posadas, and G. Wilding are members of the Department of Defense-Sponsored Prostate Cancer Clinical Trials Consortium.

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Medical OncologyOnce-daily Dasatinib: Expansion of Phase II Study Evaluating Safety and Efficacy of Dasatinib in Patients With Metastatic Castration-resistant Prostate Cancer

Objectives

Methods

Results

Conclusions

Section snippets

Patients

Patient Characteristics

Efficacy

Comment

Conclusions

Acknowledgment

Clin Genitourin Cancer

Eur J Cancer

Eur J Cancer

J Urol

Ann Oncol

Ann Oncol

Cancer statistics

CA Cancer J Clin

Osteoblasts in prostate cancer metastasis to bone

Nat Rev Cancer

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study

J Clin Oncol

Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates

J Clin Oncol

Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer

J Clin Oncol

Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial

J Urol

Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid

Cancer

Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer

J Natl Cancer Inst

A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer

J Clin Oncol

Medical Oncology
Once-daily Dasatinib: Expansion of Phase II Study Evaluating Safety and Efficacy of Dasatinib in Patients With Metastatic Castration-resistant Prostate Cancer