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Keywords:

  • dasatinib;
  • docetaxel;
  • prostate cancer;
  • metastases;
  • bone

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

BACKGROUND:

To 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.

METHODS:

In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m2 every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m2 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.

RESULTS:

Combination 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.

CONCLUSIONS:

The 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.

Mortality in patients with advanced prostate cancer (PC) is associated with osseous spread of bone-forming metastases.1-4 Clinical observations and mechanistic-based studies implicate signaling by paracrine factors from the tumor microenvironment in PC progression.5-8 These findings suggest that successful therapeutic strategies will require targeting of signaling pathways central to both the tumor and bone microenvironment.

SRC-family kinases are nonreceptor protein tyrosine kinases that are rational therapeutic targets for castration-resistant PC. The SRC-family kinases SRC, LYN, and FYN have established roles in PC growth, invasion, and metastasis.9-14 Elevated SRC-family kinase activity in tumors from patients with PC is associated with a shorter responses to androgen-ablation therapy, metastasis to the bone, and shorter survival.15 SRC also has key roles in regulating osteoclast function and in the pathogenesis of bone metastases.16-20

Dasatinib is a tyrosine kinase inhibitor that potently inhibits SRC-family kinases and also has activity against ABL1, platelet-derived growth factor receptor (PDGFR), KIT,10, 21 EPHA2,22 and focal adhesion kinase.23 In vitro, dasatinib decreased proliferation and migration of PC cells,11, 15 including the hormone-refractory cell line LNCaP-SDM.15 In a mouse model, dasatinib treatment significantly reduced prostate tumor size and number of lymph node metastases compared with control mice.11 In mice with prostate tumor cells injected intratibially, dasatinib significantly lowered serum prostate-specific antigen (PSA) concentrations and increased bone mineral density, and treatment with dasatinib plus docetaxel had greater activity than either agent alone.12 These preclinical studies led to our hypothesis that combining dasatinib with docetaxel would improve treatment of patients with metastatic castration-resistant PC by targeting both the tumor and bone microenvironment.

To test this hypothesis, a phase 1-2 study was conducted to define the toxicity profile, pharmacokinetics (PK), and maximum tolerated dose (MTD) of oral dasatinib combined with docetaxel in patients with metastatic castration-resistant PC. Secondary objectives were to assess tumor responses, PSA responses, progression-free survival (PFS), bone scan changes, and modulation of bone turnover markers.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Patients and Eligibility Criteria

The study was conducted in accordance with institutional and federal regulations including informed consent. Men aged ≥18 years were eligible if they had metastatic PC that had progressed despite castrate levels of serum testosterone (≤50 ng/dL). Progression was defined as increased size or appearance of ≥1 new radiographic lesions, 2 or more new lesions on bone scan or 1 new lesion on bone scan with rising PSA, or 2 consecutive PSA rises (≥5 ng/mL) separated by 2 weeks. Exclusion criteria were brain metastases, clinically significant cardiovascular disease, existing pleural/pericardial effusion, second malignancy (excluding nonmelanoma skin cancer), and prior treatment with >1 chemotherapy (including docetaxel) or course of palliative radiotherapy or any radioisotope. There was no limit on prior hormonal therapy. Bisphosphonate therapy could be continued but could not be initiated immediately before or on study. The registered study number was CA180-086 (clinicaltrials.gov NCT00439270).

Study Design

This was an open-label phase 1-2 study. In phase 1, cohorts of patients were treated with escalating doses of docetaxel and dasatinib. Docetaxel was administered intravenously every 21 days from Day 1 of Cycle 1 with twice daily oral prednisone 5 mg. Oral dasatinib was initiated on Day 3 of Cycle 1 and administered once daily continuously. Coadministered doses of dasatinib (mg once daily)/docetaxel (mg/m2 every 21 days) were: 50/60, 50/75, 70/75, 100/75, and 120/75. To enable accurate evaluation of safety and PK, patients without disease progression or significant toxicity received a minimum of 6 cycles of therapy. Therapy was discontinued for disease progression (defined below) after a minimum of 2 cycles of combination therapy, or earlier for serious adverse events (AEs), rapid progression, or withdrawal of consent. Patients with stable or responding disease after 6 cycles were permitted to receive further dasatinib with or without docetaxel at the investigator's discretion.

Pharmacokinetic Evaluations

Blood samples for PK analysis were collected on Day 1 (Cycle 1) for docetaxel alone, Day 14 (Cycle 1) for dasatinib alone, and Day 21 (Cycle 2, Day 1) for the combination. PK parameters were derived from plasma concentration versus time and included maximum plasma concentration (Cmax), area under curve (AUC) for a dosing interval or from time zero to infinity, time to Cmax, plasma half-life, and clearance. PK interactions were assessed using point estimates and 90% confidence interval (CI) of Cmax and AUC with dasatinib and docetaxel alone or in combination.

Safety Evaluations

AEs were assessed continuously and graded according to National Cancer Institute Common Terminology Criteria (version 3.0). Dose-limiting toxicity was defined between Day 3 (Cycle 1) and Day 42 (Cycle 2, Day 21) as grade 4 neutropenia causing treatment interruption for >14 days, febrile neutropenia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with a bleeding episode requiring platelet transfusion, nausea and/or vomiting despite medical intervention/prophylaxis causing treatment interruption for >14 days, grade 3-4 asthenia/fatigue, any other grade ≥3 nonhematologic toxicity except alopecia or transient arthralgia/myalgia (unless unresponsive to intervention), or interruption of study drug for >14 days due to toxicity.

Efficacy Evaluations

Serum PSA concentrations were determined every 3 weeks. PSA response was defined as ≥50% decrease in PSA concentration from baseline sustained for ≥6 weeks. PSA progression was defined as 3 consecutive PSA increases from baseline/nadir observed at ≥1-week intervals, including PSA increase to ≥5 ng/mL and by ≥50%, as per Prostate Cancer Working Group 1 recommendations.24 Duration of PSA response was measured from the first of 2 consecutive measurements confirming response until the first of 3 consecutive measurements confirming PSA progression, disease progression (defined below), or death. Time to PSA progression was not a specified endpoint and was not determined.

For patients with measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) were used to define patients with a complete response or partial response (PR) or who had not met criteria for response or tumor progression after ≥18 weeks of treatment. Tumor progression was defined as either ≥20% increase in sum of longest diameters of target lesions from nadir, progression of nonmeasurable lesions, or detection of new lesions. As per Prostate Cancer Working Group 2 recommendations, response determination excluded pelvic lymph nodes measuring <2 cm.25 Tumor assessments were performed every 6 weeks.

Pretreatment bone scans were performed within 28 days before treatment and every 6 weeks after starting docetaxel. Bone scans were classified as improved (disappearance of at least 1 lesion and no new lesion or pain), stable (no new lesions/pain), or progressed (at least 2 areas of new focal uptake or new adverse clinical symptoms). Confirmatory bone scans were not required. A subset of patients treated at The University of Texas MD Anderson Cancer Center, Houston, Texas, were categorized as having high (20 or more lesions), intermediate (10-20 lesions), or low (1-9 lesions) bone-lesion volume at baseline.

Concentrations of serum bone alkaline phosphatase (BAP; marker of osteoblast activity/differentiation) and urinary N-telopeptide (NTx; marker of osteoclast activity) were measured before treatment and on study.

Progression was defined as either bone scan progression or at least 2 of the following: tumor progression (RECIST), PSA progression, or investigator-defined clinical progression. The protocol-specified definition of progression therefore differs from recommendations published after the study was initiated.25 As appropriate for an early-phase trial, the protocol did not require that patients should be followed for progression after discontinuing study treatment, due to PFS not being the primary endpoint of the study and the likelihood that patients would receive additional therapies after discontinuing that may have impacted PFS. Because of a relatively high proportion of patients in whom the date of progression could not be obtained and difficulties of data interpretation, PFS could not be accurately ascertained and is not reported.

For patients who remained on single-agent dasatinib for >21 days after discontinuing docetaxel treatment, duration of additional single-agent therapy was measured from the date of last docetaxel dose to the date of progression or death, discontinuation, or last efficacy assessment.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

Patients and Treatment

Forty-six patients were treated (Table 1). Median age was 65 years. Thirty-nine patients (85%) had bone metastases and 30 patients (65%) had RECIST-evaluable disease. Fifteen patients (33%) had received prior chemotherapy, including docetaxel in 8 (17%).

Table 1. Baseline Demographics and Disease Characteristics
CharacteristicPhase 1Phase 2Total
  • Abbreviations: ECOG, Eastern Cooperative Oncology Group; RECIST, Response Evaluation Criteria in Solid Tumors; ULN, upper limit of normal; uNTx, urinary N-telopeptide.

  • a

    Started prior to protocol entry and ongoing during dasatinib and docetaxel treatment.

Treated patients, No.163046
Median age, y [range]6962.565 [48-83]
Age ≥65 years, No. (%)11 (69)12 (40)23 (50)
Median time since diagnosis, mo [range]46 [11-184]44 [6-210]44 [6-210]
ECOG status, No. (%)   
 09 (56)13 (43)22 (48)
 17 (44)15 (50)22 (48)
 20 (0)2 (7)2 (4)
Prior therapy, No. (%)   
 Surgery or radiotherapy14 (88)24 (80)38 (83)
 Chemotherapy11 (69)4 (13)15 (33)
 Docetaxel7 (44)1 (3)8 (17)
Current bisphosphonate use, No. (%)a3 (19)9 (30)12 (26)
Bone metastases, No. (%)14 (88)25 (83)39 (85)
uNTx concentration, No. (%)   
 ≤ULN10 (63)20 (67)30 (65)
 >ULN5 (31)8 (27)13 (28)
 Not reported1 (6)2 (7)3 (7)
Bone-specific alkaline phosphatase concentration, No. (%)   
 Higher than normal range5 (31)12 (40)17 (37)
 Normal2 (13)10 (33)12 (26)
 Lower than normal range1 (6)1 (3)2 (4)
 No normal range defined6 (38)4 (13)10 (22)
 Not reported2 (13)3 (10)5 (11)
RECIST-evaluable disease, No. (%)11 (70)19 (63)30 (65)
Target lesions, No. (%)   
 Lymph node9 (56)17 (57)26 (57)
 Pelvis1 (6)1 (3)2 (4)
 Visceral, liver2 (13)1 (3)3 (7)
 Visceral, lung1 (6)3 (10)4 (9)

In phase 1, 16 patients were treated, comprising 3 per dose cohort except cohort 4, in which 1 patient was withdrawn in Cycle 1 after docetaxel hypersensitivity, requiring an additional patient to be treated. Thirty additional patients were treated in phase 2. At data capture (March 2010), median treatment duration was 6.2 months (range, 0.1-17.2 months) for dasatinib and 6 cycles for docetaxel. Excluding the single patient who had docetaxel hypersensitivity, the range of docetaxel cycles administered was 2 to 24. Thirty-four patients (74%) received ≥6 cycles of docetaxel, including 11 patients (24%) who received ≥10 cycles. Twenty-eight patients (61%) received single-agent dasatinib after discontinuing docetaxel for a median of 2.9 months (range, 0.9-11.7+ months) up to data capture. Nine patients (20%) remain on study: 7 on single-agent dasatinib (current treatment duration, 13.9-17.0 months) and 2 on combination therapy (14.7 and 17.25 months of dasatinib and 22 and 24 cycles of docetaxel). Of 37 patients (80%) who are off study, reasons for discontinuation were protocol-defined disease progression in 20 (43%), investigator decision due to patient not likely to benefit from further treatment in 3 (7%), study drug toxicity in 7 (15%), patient request in 2 (4%), and other reason (unrelated AE, noncompliance, no longer meets study criteria, or not specified) in 5 (11%).

Safety

No dose-limiting toxicities occurred, and MTD was not reached. Combination treatment was generally well tolerated at the dose levels tested, and treatment-related AEs were mostly mild to moderate in severity (Table 2). Thirteen patients (28%) experienced at least 1 grade ≥3 AE, of which only fatigue (n = 3) and pleural effusion (n = 2) occurred in >1 patient. Dose reductions of dasatinib or docetaxel were required in 4 and 5 patients, respectively. Docetaxel was delayed in 13 patients, and dasatinib was interrupted in 30 patients.

Table 2. Treatment-Related Adverse Events (Worst Grade) Occurring in ≥10% of Patients (N = 46)
Adverse EventPatients, No. (%)
Grade 1Grade 2Grade 3Grade 4All Grades
Fatigue16 (35)13 (28)3 (7)32 (70)
Alopecia23 (50)3 (7)26 (57)
Diarrhea20 (43)2 (4)22 (48)
Nausea17 (37)4 (9)21 (46)
Dysgeusia19 (41)1 (2)20 (44)
Peripheral edema11 (24)5 (11)16 (35)
Decreased appetite12 (26)3 (7)15 (33)
Anemia4 (9)6 (13)1 (2)11 (24)
Dyspnea8 (17)2 (4)10 (22)
Vomiting6 (13)3 (7)9 (20)
Dry skin9 (20)9 (20)
Nail disorder8 (17)1 (2)9 (20)
Headache6 (13)1 (2)7 (15)
Hypersensitivity5 (11)2 (4)7 (15)
Pleural effusion2 (4)3 (7)2 (4)7 (15)
Constipation4 (9)2 (4)6 (13)
Hypokalemia6 (13)6 (13)
Insomnia4 (9)1 (2)5 (11)
Peripheral sensory neuropathy2 (4)2 (4)1 (2)5 (11)
Peripheral neuropathy4 (9)1 (2)5 (11)

Pharmacokinetic Analysis

PK parameters for dasatinib and docetaxel given alone or in combination were similar. Figure 1 and Table 3 show data for dasatinib 100 mg once daily and docetaxel 75 mg/m2. Point estimates (90% CI) of Cmax and AUC values for each agent given alone/in combination are 0.96 (0.74-1.24) and 1.08 (0.91-1.29) for dasatinib and 1.02 (0.92-1.14) and 0.97 (0.88-1.06) for docetaxel, respectively, indicating no PK interaction.

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Figure 1. Mean plasma concentrations (+standard deviations) of dasatinib and docetaxel administered alone or in combination are shown.

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Table 3. Pharmacokinetic Parameters of Dasatinib and Docetaxel Given Alone or in Combination
AnalyteTreatmentNo.Cmax, ng/mL, Geomean (% CV)Tmax, h, median [min, max]AUC,a ng/h/mL, Geomean (% CV)T1/2, h, mean {SD}CL, L/h, mean {SD}
  • Abbreviations: AUC, area under the curve; CL, clearance; Cmax, maximum plasma concentration; CV, coefficient of variation; Geomean, geometric mean; NA, not applicable; SD, standard deviation; T½, plasma half-life; Tmax, time to Cmax.

  • a

    The AUC column shows AUC for a dosing interval for dasatinib and AUC from zero to infinity for docetaxel.

DasatinibDasatinib 100 mg2884 (75)2.0 [0.5, 7.0]318 (57)5.0 {2.3}NA
DasatinibDasatinib 100 mg with docetaxel 75 mg/m23176 (69)1.6 [0.5, 24]328 (64)4.9 {2.8}NA
DocetaxelDocetaxel 75 mg/m2332125 (33)NA2664 (44)24.3 {11.2}69.3 {50.5}
DocetaxelDocetaxel 75 mg/m2 with dasatinib 100 mg312159 (30)NA2563 (48)22.5 {9.9}66.6 {22.1}

Dasatinib 100 mg once daily and docetaxel 75 mg/m2 every 21 days were chosen as recommended phase 2 dose based on safety observations and PK analysis, plus prior studies of dasatinib in chronic myeloid leukemia.26

Efficacy

Of 46 treated patients, 37 (80%) had any decrease in PSA from baseline, including 26 (57%) who had a confirmed PSA response (sustained ≥50% decline for ≥6 weeks; Fig. 2A). Median duration of PSA response for the 13 of 26 responding patients who had PSA progression, disease progression, or death on study was 4.9 months (range, 1.4-9.5 months); this median value was not calculated using Kaplan-Meier methodology and does not include patients who remained in PSA response or who discontinued from the study without PSA progression, disease progression, or death.

thumbnail image

Figure 2. Waterfall plots show maximal percentage changes from baseline in individual patients: (A) prostate-specific antigen, (B) tumor size, (C) urinary N-telopeptide, (D) bone alkaline phosphatase. In C and D, patients who were receiving ongoing bisphosphonate therapy are shown by white bars.

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Among RECIST-evaluable patients, 18 of 30 (60%) had a PR, and 5 of 30 (17%) remained on therapy without response or progression for ≥18 weeks, resulting in an overall disease control rate of 77%. PRs occurred in 4 of 8 patients (50%) with visceral metastases and 14 of 22 patients (64%) with target lesions in lymph nodes only. Figure 2B shows maximum changes in tumor size.

Among all 46 patients, bone scan response was improved (disappearance of at least 1 lesion) in 14 patients (30%) and stable (no new bone lesions at ≥18 weeks) in 19 patients (41%). Nine patients (20%) had no new bone lesions at 6 and/or 12 weeks but were not scanned further because of discontinuation from the study. Three patients (7%) showed bone scan progression. One patient was not evaluable. As described in the Materials and Methods section, results on bone scan were not required to be confirmed.

Of patients evaluable for bone markers, 33 of 38 (87%) had a reduction in urinary NTx (Fig. 2C). This included 18 patients (47%) who achieved a ≥35% urinary NTx reduction, of whom 2 were receiving bisphosphonates. Furthermore, 26 of 33 patients (76%) had a reduction in BAP (Fig. 2D), including 9 receiving bisphosphonates. Median decreases from baseline (range) in patients with reductions were 36% (6%-81%) for urinary NTx and 26% (6%-85%) for BAP.

Post hoc analyses were performed to determine if bone effects correlated with antitumor activity. Of evaluable patients with bone scan improvement, 12 of 13 (92%) had a urinary NTx decrease, 10 of 12 (83%) had a BAP decrease, and 13 of 14 (93%) had a PSA decrease. Of evaluable patients with stable bone scan, urinary NTx, BAP, or PSA decrease occurred in 15 of 16 (94%), 12 of 13 (92%), and 17 of 19 (90%), respectively. In patients with low, medium, and high numbers of bone scan lesions at baseline, all 3 biomarkers showed variable decreases (Table 4). In a further analysis, 25 patients were classified as responders based on achievement of PSA response (patients with nonmeasurable disease) or RECIST PR without PSA progression (patients with measurable disease). Of evaluable responders, 19 of 21 (90%) and 16 of 18 (89%) had a decrease in urinary NTx and BAP, respectively, and 23 of 25 (92%) had improved bone scans or no new lesion at ≥18 weeks.

Table 4. Subset Analysis of Best Percentage Changes in uNTx, BAP, and PSA According to Bone Scan Volume at Baseline
 Bone Scan Volume
Low, 1-9 lesions, n = 13Intermediate, 10-20 lesions, n = 6High, >20 lesions, n = 8
  1. Abbreviations: BAP indicates bone alkaline phosphatase; PSA, prostate-specific antigen; uNTx, urinary N-telopeptide.

Median uNTx at baseline, ng/mL (min, max)41 (9, 98)58 (26, 203)104 (46, 238)
Best percentage change in uNTx from baseline, median (min, max)−39 (−77, 10)−47 (−81, −27)−28 (−64, 69)
Median BAP at baseline, ng/mL (min, max)17 (7, 33)17 (10, 584)95 (22, 318)
Best percentage change in BAP from baseline, median (min, max)−25 (−59, 12)−19 (−61, 24)−23 (−85, 62)
Median PSA at baseline, ng/mL (min, max)17 (1, 50)135 (29, 379)96 (19, 700)
Best percentage change in PSA from baseline, median (min, max)−78 (−98, 50)−85 (−100, −34)−20 (−95, 49)

Protocol-defined disease progression was recorded in 23 patients, including 8 defined by bone scan. Of 28 patients who continued on single-agent dasatinib after stopping docetaxel, 16 patients subsequently progressed (after 0.9-8.1 additional months of single-agent dasatinib), including 5 patients who had stabilization of disease for at least 3 months. Six patients discontinued dasatinib without progression due to study drug toxicity (n = 2), AE unrelated to study drug, patient request, investigator decision due to patient not likely to benefit from further treatment, and social reasons (n = 1 each). Six additional patients remained on single-agent dasatinib without progression at data capture and had stabilization of disease for 3.4 + to 11.7 + months after the last docetaxel dose.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

The results of this phase 2 study establish the feasibility and safety of combining dasatinib with docetaxel and prednisone at therapeutically relevant doses in patients with metastatic castration-resistant PC. The high rates of soft tissue responses, bone effects (as captured by bone scanning), and modulation of bone turnover markers are promising and support our hypothesis that cotargeting the tumor and associated microenvironment may increase the efficacy of docetaxel.27, 28

Dasatinib plus docetaxel had a favorable toxicity profile, allowing escalation to dasatinib 120 mg once daily with docetaxel 75 mg mg/m2 every 21 days and prednisone. In conjunction with noninteracting PK profiles, these results strongly suggest that the combination can be given safely without compromising dose or schedule. The rate of fluid retention (pleural effusion, edema) was comparable to experience with docetaxel alone. Only 15% of patients experienced pleural effusion (grade 3 in 4%) and 1 patient (2%) had grade 1 pericardial effusion, whereas in a phase 2 study of 47 patients with castration-resistant PC who received twice daily dasatinib monotherapy, pleural and pericardial effusion occurred in 51% and 23%, respectively.29 Oral prednisone, combined with the improved safety of once daily versus twice daily dasatinib,30 may have minimized fluid retention in our study.

Notwithstanding prior chemotherapy exposure in 33% of patients, the objective tumor response rate (60%), which is higher than those seen with docetaxel every 21 days alone in the TAX327 and SWOG9916 trials (12%-17%), is very encouraging. Furthermore, the PSA response rate of 57% compares favorably with TAX327/SWOG9916 (45%-50%).27, 28 The finding that 33 of 46 patients (72%) had either improved bone scan (disappearance of at least 1 lesion) or stable bone scan during the study was also of interest. These observations might be the result of the antitumor and bone-targeted effects of docetaxel and dasatinib treatment, which have been suggested by preclinical studies.11, 12, 15 Whether dasatinib increases antitumor effects of docetaxel in patients and prolongs survival requires evaluation in a randomized setting.

In this study, 23 of 46 patients had experienced disease progression by last follow-up, defined using radiographic and symptomatic criteria. Nine patients remained on-study at last follow-up. Of patients who discontinued treatment, ⅓ discontinued for reasons other than disease progression (eg, drug toxicity) and were not followed further for progression or survival. Because of the proportion of patients for whom date of progression could not be determined, PFS could not be accurately calculated, and this represents a limitation of the study.

Of particular interest was the duration of stable disease in patients who received maintenance single-agent dasatinib after stopping chemotherapy. Experimental observations in murine PC models suggest that dasatinib inhibits tumor proliferation, invasion, and metastasis, indicating that the antitumor effects of dasatinib are likely to be cytostatic rather than cytotoxic. Supporting these studies, 28 patients (61% of study participants), who responded by PSA or RECIST, continued on single-agent dasatinib after completing docetaxel therapy. Among these patients, durations of stabilization of disease of up to 12 months after docetaxel was stopped were recorded by data cutoff. The median of 6 docetaxel cycles administered was lower than published experience with docetaxel every 21 days alone (9.5 cycles in TAX327),28 and additional cycles of docetaxel might have also resulted in ongoing stabilization of disease. The comparatively shorter duration of docetaxel use in this study likely reflects early cessation of chemotherapy after the protocol-specified minimum of 6 cycles based on investigator/patient choice. The occurrence of ongoing stabilization of disease after discontinuation of docetaxel has been reported infrequently within published literature. In the ASCENT trial of docetaxel with or without calcitriol, patients who had a confirmed 50% PSA response and PSA level ≤4.0 ng/mL were allowed to receive intermittent chemotherapy; that is, docetaxel was suspended until the PSA level rose (by 50% and to ≥2 ng/mL) or other evidence of progression was seen. Among 250 randomized patients, 45 (18%) had their chemotherapy suspended, and median duration until resumption was ∼4.2 months (18 weeks), with a reported range of ∼1 to 16.2 months (4-70 weeks).31 Although these data indicate that patients can experience periods of stabilized disease without continuous docetaxel, in the ASCENT trial only a minority of patients who had achieved relatively stringent response criteria had their therapy suspended. Whether single-agent dasatinib has the potential to prolong responses without ongoing docetaxel therapy warrants further investigation.

Treatment with dasatinib targeted both osteoclastic and osteoblastic components of bone disease, as shown by most patients having decreases in concentrations of urinary NTx and BAP. Interestingly, bisphosphonate-treated patients had additional reductions in bone marker levels, suggesting that SRC inhibition may have bone-targeted effects beyond those achieved with bisphosphonates. Previous studies have assessed bone marker effects of novel agents combined with docetaxel in patients with metastatic PC. In a phase 1-2 trial of docetaxel and atrasentan, an endothelin-A receptor antagonist, concentrations of BAP but not urinary NTx decreased in patients not receiving bisphosphonates.32 In a randomized phase 2 trial of docetaxel plus imatinib, a PDGFR inhibitor, combination treatment was associated with significantly greater declines in urinary NTx compared with docetaxel alone, whereas docetaxel-related declines in BAP were impaired.33 Together with bone marker outcomes with zoledronic acid,34 these results suggest that modulating bone turnover alone is insufficient to meaningfully alter the course of PC bone metastases in most patients.

Post hoc analyses were performed to investigate the correlation between bone scan responses and standard PSA/tumor responses or effects on bone markers. Of patients who responded by PSA and/or RECIST criteria, 92% also had an improved or stable bone scan versus 71% in the overall group. Of those with improved or stable bone scans, the proportions of evaluable patients with decreases in urinary NTx, BAP, or PSA were 93%, 88%, and 91%, respectively, versus 87%, 76%, and 80% in the overall group. No correlation was seen in comparisons between volume of bone scan lesions at baseline and effects of treatment on PSA or bone markers.

In summary, this study demonstrates that dasatinib and docetaxel combination therapy is well tolerated and has encouraging efficacy. Parallel bone scan improvements, urinary NTx/BAP decreases, and tumor effects (RECIST and PSA responses) are consistent with the hypothesis that the efficacy of dasatinib and docetaxel combination therapy is attributable to cotargeting of the tumor and the soft tissue and bone microenvironments. These data have provided the rationale for an ongoing randomized phase 3 study.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES

The study was funded by Bristol-Myers Squibb and conducted in part through the Department of Defense Prostate Cancer Clinical Trials Consortium. Medical writing assistance was provided by Fiona Bolland and Jeremy Gardner of StemScientific (funded by Bristol-Myers Squibb).

CONFLICT OF INTEREST DISCLOSURES

G.C.T. is an employee of and owns stocks in Bristol-Myers Squibb. P.P. and S.A. are employees of Bristol-Myers Squibb. A.J.A. has received research funding from and acted in a consultant/advisory role for Bristol-Myers Squibb, has received research funding and honoraria from Sanofi-Aventis, and has received research funding from ImClone and Medivation. C.J.L. has acted in a consultant/advisory role for and received research funding and honoraria from Bristol-Myers Squibb. J.C.A., P.M., E.L.B., E.P., M.L., and G.E.G. have no conflicts of interest to disclose.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. REFERENCES
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