Abstract
Background:
This phase 1/2 study assessed sunitinib combined with docetaxel (Taxotere) and prednisone in chemotherapy-naive metastatic, castration-resistant prostate cancer (mCRPC) patients.
Patients and methods:
To determine the recommended phase 2 dose (RP2D), 25 patients in four dose escalation cohorts received 3-week cycles of sunitinib (2 weeks on, 1 week off), docetaxel and prednisone, preceded by a 4-week sunitinib 50 mg/day lead in. RP2D was evaluated in 55 additional patients. The primary end point was prostate-specific antigen (PSA) response rate.
Results:
One phase 1 dose-limiting toxicity occurred (grade 3 hyponatremia). The RP2D was sunitinib 37.5 mg/day, docetaxel 75 mg/m2 and prednisone 5 mg b.i.d. During phase 2, confirmed PSA responses occurred in 31 patients [56.4% (95% confidence interval 42.3–69.7)]. Median time to PSA progression was 9.8 months. Forty-one patients (75%) were treated >3 months, 12 (22%) completed the study (16 cycles) and 43 (78%) discontinued (36% for disease progression and 27% adverse events). The most frequent treatment-related grade 3/4 adverse events were neutropenia (53%; 15% febrile) and fatigue/asthenia (16%). Among 33 assessable patients, 14 (42.4%) had confirmed partial response. Median progression-free and overall survivals were 12.6 and 21.7 months, respectively.
Conclusion:
This combination was moderately well tolerated, with promising response rate and survival benefit, justifying further investigation in mCRPC.
Keywords: phase 1/2, prostate cancer, sunitinib combination
introduction
Clinical and experimental observations implicate the tumor microenvironment as a critical determinant of prostate cancer progression and therapy resistance [1, 2]. Since prostate cancer is characterized by a unique tropism for bone, therapeutic strategies have focused on bone-relevant stromal- and epithelial-interacting pathways such as endothelin-1, platelet-derived growth factor (PDGF) and Src. Unfortunately, drugs targeting these pathways as single agents have shown disappointing results [3–6]. As docetaxel combined with prednisone is the first treatment to prolong overall survival (OS) in patients with metastatic, castration-resistant prostate cancer (mCRPC) [7], attention has turned to combinations of docetaxel with stroma-targeting agents. Results to date have been sufficiently promising to justify phase 2 and 3 studies.
In prostate cancer, several parameters associated with tumor angiogenesis have been found directly correlated with Gleason score, stage, metastatic progression and survival. High microvessel density, vascular size and irregularity are associated with increased long-term risk of death from prostate cancer [8, 9]. The angiogenic growth factors vascular endothelial growth factor (VEGF)-A and VEGF-C have been implicated in disease progression and bone metastasis [10–12]. Elevated VEGF-A plasma and urine levels act as independent prognostic factors in patients with prostate cancer [13, 14], while VEGF-C (which is capable of mediating both lymphangiogenesis and angiogenesis through binding to vascular endothelial growth factor receptor (VEGFR)-2 or VEGFR-3) has been linked to lymph node metastasis [15]. Platelet-derived growth factor receptor (PDGFR) inhibitors alone or in combination with chemotherapy have also been studied in this disease [16–20], but resulted in increased toxicity and no benefit. Nonetheless, a combined approach with VEGFR/PDGFR inhibition may improve efficacy over either agent alone, as suggested in tumor models [21].
Sunitinib malate (Pfizer Inc, New York, NY) is an oral multitargeted inhibitor of VEGFR, PDGFR and several other kinases that is approved for treatment of advanced renal cell carcinoma and imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor [22]. Sunitinib alone or in combination with docetaxel inhibits growth of hormone-insensitive human prostate cancer xenografts [23, 24]. As part of a broader effort to assess the clinical value of therapeutically targeting different compartments of the tumor microenvironment in prostate cancer, we conducted a phase 1/2 multicenter study of sunitinib combined with docetaxel and prednisone in chemotherapy-naive patients with mCRPC. Here we report safety, the recommended phase 2 dose (RP2D), pharmacokinetic (PK)/pharmacodynamic (PD) profile and efficacy.
patients and methods
patients
Chemotherapy-naïve patients with confirmed progressive mCRPC were enrolled. Progression was defined by either nonmeasurable disease plus elevated prostate-specific antigen (PSA) levels or measurable disease alone (as shown by transaxial imaging with computed tomography or magnetic resonance imaging scans according to RECIST v1.0 [25]). Other key eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of zero to one, testosterone <50 ng/dl and adequate cardiac, renal, hepatic and bone marrow function. Patients were ineligible if previously treated with an antiangiogenic agent, chemotherapy, radioisotope or radiotherapy to ≥25% of bone marrow. Additionally, brain metastases, uncontrolled hypertension or pain, severe hemorrhage <4 weeks before commencing treatment, impending complication from bone metastases, unresolved urinary obstruction or clinically significant cardiovascular event/disease during the preceding 6 months were exclusionary.
Patients provided written informed consent. The protocol was approved by the institutional review board or independent ethics committee at each study site. The trial was carried out in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and applicable local regulatory requirements and laws. This study is registered with ClinicalTrials.gov (NCT00137436).
procedures
Treatment comprised 3-week cycles of oral sunitinib given on a 2-week on, 1-week off dosing regimen (schedule 2/1), docetaxel (Taxotere, Sanofi-aventis, Bridgewater, NJ) as an i.v. infusion every 3 weeks, and continuous oral prednisone 5 mg b.i.d. Patients received oral dexamethasone before docetaxel infusions.
phase 1
A modular trial design was used to address the effect of short exposure to sunitinib on PSA levels. Patients received a sunitinib 50 mg/day lead in for 4 weeks, followed by 2 weeks off, before starting combination therapy. Next, four different combination-treatment dose levels were studied sequentially in cohorts of n = 6. Cohorts 1–3 received docetaxel 60 mg/m2 and sunitinib at 12.5, 37.5 and 50 mg, respectively. Cohort 4 received docetaxel 75 mg/m2 and sunitinib 37.5 mg. During cycle 1, sunitinib was started 1 day after docetaxel to facilitate PK sampling of docetaxel and sunitinib dosing alone. The evaluation period for dose-limiting toxicities (DLTs) was the lead-in period plus the first combination cycle, totaling 9 weeks. If more than two out of six patients in one dose level experienced a DLT, the next lower dose level was considered the RP2D. Patients experiencing significant toxicity during the lead in or who discontinued treatment before completing cycle 1 for reasons other than treatment-related toxic effects were replaced.
PK sampling and assay
PK profiles were obtained for sunitinib (and its active metabolite, SU12662) on day 1 of the lead-in period, docetaxel on day 1 of cycle 1, and the combination on day 1 of cycle 2. PK parameters were estimated using noncompartmental methods. Blood samples for determination of trough sunitinib and SU12662 plasma concentrations were also obtained before dosing.
phase 2
At the RP2D, the primary end point was PSA response rate, defined by the PSA Working Group criteria [26]. Secondary end points included time to PSA progression, objective response rate (ORR), progression-free survival (PFS), OS and safety. Prophylactic use of, or treatment with, hematopoietic growth factors was allowed. For grade 3/4 adverse events (AEs), dose modifications were permitted for sunitinib (in decrements of and to 12.5 mg minimum) and/or docetaxel (to ≤60 mg/m2 in cases of hepatic dysfunction). Treatment continued for up to 16 cycles (∼1 year), after which patients receiving clinical benefit were offered further treatment on a separate extension protocol.
efficacy assessments
Serum PSA concentrations were measured at screening, on day 28 of the lead-in phase, day 1 of each cycle and at end of treatment/withdrawal, with responses (≥50% decrease from baseline) confirmed ≥4 weeks later. Radiographic assessments were carried out at screening, day 1 of cycle 3, every three cycles thereafter and at study end/withdrawal. Responses were evaluated using RECIST and confirmed by repeat imaging ≥4 weeks after initial documentation.
PD sampling (soluble proteins)
Plasma samples were collected on days 1 and 14 of cycles 1 through 3 and stored at −70°C until analyzed. Concentrations of VEGF-C and soluble(s) VEGFR-2 and VEGFR-3 were determined using validated enzyme-linked immunosorption assay kits (R&D Systems, Minneapolis, MN) under Good Laboratory Practice conditions.
statistical analysis
During phase 1, the number of patients enrolled in each dose cohort was dependent upon the observed safety profile.
Phase 2 followed a Simon’s Minimax 2-stage design, using an alpha level of 10% and 90% power to test the null hypothesis that the true PSA response rate was ≤28% versus the alternative hypothesis that the true response rate was ≥45%. If ≥9 PSA responses occurred in the first 31 patients, the study was to be expanded to 54 patients; more than 20 PSA responses were required to reject that null hypothesis.
PSA and ORRs were summarized by the number (%) of patients achieving a response with the corresponding exact two-sided 95% confidence interval (CI) calculated using an F distribution method. Time to PSA progression, PFS and OS were summarized using Kaplan–Meier methods.
results
phase 1
Thirty-two patients were enrolled in phase 1; 7 were replaced during the DLT observation period, unable to complete the lead in due to toxicity, resulting in 25 patients eligible for DLT evaluation: 6 patients each in cohorts 1 (sunitinib 12.5 mg/docetaxel 60 mg/m2), 3 (sunitinib 50 mg/docetaxel 60 mg/m2) and 4 (sunitinib 37.5 mg/docetaxel 75 mg/m2) and 7 in cohort 2 (sunitinib 37.5 mg/docetaxel 60 mg/m2).
Baseline characteristics were similar across all cohorts (supplementary Table S1, available at Annals of Oncology online). Median treatment duration was 5.8 months (range 0.5–23.7 months), with 16 patients (50%) on study ≥6 months. Most study discontinuations were due to AEs (41%), followed by disease progression (28%; Table 1). The most common treatment-related grade 3/4 AEs were neutropenia (34%) and fatigue (13%; Table 2). Three patients died of disease progression on study, one each in cohorts 1, 3 and 4.
Table 1.
Phase 1: patient disposition
| 12.5 mg/60 mg/m2 (n = 7) | 37.5 mg/60 mg/m2 (n = 8) | 50 mg/60 mg/m2 (n = 7) | 37.5 mg/75 mg/m2 (n = 10) | Total (N = 32) | |
| No. (%) | No. (%) | No. (%) | No. (%) | No. (%) | |
| Completed (16 cycles) | 2 (29) | 1 (12) | 0 (0) | 3 (30) | 6 (19) |
| Discontinued | 5 (71) | 7 (88) | 7 (100) | 7 (70) | 26 (81) |
| Adverse event | 2 (29) | 4 (50) | 3 (43) | 4 (40) | 13 (41) |
| Disease progression | 2 (29) | 2 (25) | 3 (43) | 2 (20) | 9 (28) |
| Consent withdrawal | 1 (14) | 0 (0) | 1 (14) | 0 (0) | 2 (6) |
| Other | 0 (0) | 1 (12) | 0 (0) | 1 (10) | 2 (6) |
Table 2.
Phase 1: treatment-related grade 3/4 adverse events observed in >1 patient
| 12.5 mg/60 mg/m2 (n = 7) | 37.5 mg/60 mg/m2 (n = 8) | 50 mg/60 mg/m2 (n = 7) | 37.5 mg/75 mg/m2 (n = 10) | Total (N = 32) | |
| Adverse eventa | No. (%) | No. (%) | No. (%) | No. (%) | No. (%) |
| Neutropenia | 3 (43) | 4 (50) | 2 (29) | 2 (20) | 11 (34) |
| Fatigue | 0 (0) | 0 (0) | 1 (14) | 3 (30) | 4 (12) |
| Leukopenia | 0 (0) | 1 (12) | 2 (29) | 0 (0) | 3 (9) |
| Thrombocytopenia | 1 (14) | 1 (12) | 0 (0) | 0 (0) | 2 (6) |
| Arthralgia | 2 (29) | 0 (0) | 0 (0) | 0 (0) | 2 (6) |
| Diarrhea | 0 (0) | 0 (0) | 1 (14) | 1 (10) | 2 (6) |
| Hand–foot syndrome | 0 (0) | 0 (0) | 1 (14) | 1 (10) | 2 (6) |
| Syncope | 0 (0) | 0 (0) | 0 (0) | 2 (20) | 2 (6) |
Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
determination of the RP2D.
Only one DLT (grade 3 hyponatremia) was observed in cohort 3. Based on overall safety and a favorable PK profile, the cohort 4 combination (sunitinib 37.5 mg/docetaxel 75 mg/m2) was selected as the RP2D. Median relative dose intensities at the RP2D were 81% and 88% for sunitinib and docetaxel, respectively (supplemental Table S1, available at Annals of Oncology online).
PK parameters.
There was a minimal decrease in maximum plasma concentration of the drug (Cmax) (4%) and area under the curve at 24 hours (AUC24) (8%) for sunitinib (and SU12662) when administered with docetaxel and prednisone at the RP2D compared to sunitinib administered alone. Changes in Cmax and AUC∞ for docetaxel were 15% and 20%, respectively, with variability ranging from 25% to 42%. These changes were not considered clinically significant.
phase 2
patient disposition and baseline characteristics.
Fifty-five patients were enrolled in phase 2. At baseline, patients had a median PSA level of 57.6 ng/ml (range, 7.4–417.8 ng/ml; Table 3), and the majority had ECOG performance status 0 (64%), Gleason scores of 8–10 (67%) and bone metastasis (73%). By risk group [27] based on baseline presence of pain, visceral metastases, anemia and bone scan progression, 25 patients (45%) were characterized as good risk, 24 (44%) intermediate, and 6 (11%) poor. Median treatment duration was 5.4 months (range, 0.4–11.8 months), with 41 patients (75%) on study for >3 months. Median number of cycles started was 7 (range, 1–16). Twelve patients (22%) completed the study as planned receiving 16 cycles (∼1 year of treatment). The remaining 43 patients (78%) discontinued due to disease progression (36%), AEs (27%), consent withdrawal (11%) and other reasons (4%; Table 4).
Table 3.
Phase 2: baseline characteristics
| Total (N = 55) | |
| Characteristic | No. (%) |
| Age, years | |
| Median (range) | 66 (47–88) |
| Race | |
| White | 47 (85) |
| Black | 8 (15) |
| ECOG PS | |
| 0 | 35 (64) |
| 1 | 20 (36) |
| Gleason score | |
| ≤7 | 13 (24) |
| 8–10 | 37 (67) |
| Missing | 5 (9) |
| PSA, ng/ml | |
| Median (range) | 57.6 (7.4–417.8) |
| Time since primary diagnosis, years | |
| Mean (range) | 5.6 (0.4–18.4) |
| Prior treatment | |
| Prostatectomy | 49 (89) |
| Radiation Therapy | 26 (47) |
| Hormonal Therapy | 54 (98) |
| Immunotherapy | 4 (7) |
| Disease present at screening | |
| Bone | 40 (73) |
| Lymph nodes only | 4 (7) |
| Visceral metastases | 10 (18) |
| Significant pain | 23 (42) |
| Presence of anemia (Hgb <13.0 g/dl) | 30 (55) |
| Bone scan progression | 22 (40) |
ECOG, Eastern Cooperative Oncology Group; PS, performance status; PSA, prostate-specific antigen.
Table 4.
Phase 2: patient disposition
| Total (N = 55) | |
| No. (%) | |
| Completed (16 cycles) | 12 (22) |
| Discontinued | 43 (78) |
| Disease progression | 20 (36) |
| Adverse event | 15 (27) |
| Death | 2 (4) |
| Fatigue | 2 (4) |
| Infection | 2 (4) |
| Neutropenia | 2 (4) |
| Stomatitis | 2 (4) |
| Diverticuliti | 1 (2) |
| Elevated liver function tests | 1 (2) |
| Febrile neutropenia | 1 (2) |
| Hemoptysis | 1 (2) |
| Hypersensitivity | 1 (2) |
| Consent withdrawal | 6 (11) |
| Other | 2 (4) |
safety.
The most frequently reported treatment-related AEs [by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0] were fatigue/asthenia (80%), diarrhea (73%) and neutropenia (56%; Table 5). The most frequent treatment-related grade 3/4 AEs were neutropenia (53%), fatigue/asthenia (16%) and febrile neutropenia (15%). The main AEs leading to discontinuation included fatigue, infection, neutropenia and stomatitis [each n = 2 (4%); Table 4]. Two patients died while actively on treatment, of pneumonia and urosepsis.
Table 5.
Phase 2: treatment-related adverse events reported by ≥20% of patients
| Total (N = 55) | ||||
| Grade 1/2 | Grade 3 | Grade 4 | All grades | |
| Adverse eventa | No. (%) | No. (%) | No. (%) | No. (%) |
| Fatigue/asthenia | 35 (64) | 8 (15) | 1 (2) | 44 (80) |
| Diarrhea | 39 (71) | 1 (2) | 0 (0) | 40 (73) |
| Neutropenia | 2 (4) | 11 (20) | 18 (33) | 31 (56) |
| Dysgeusia | 30 (55) | 0 (0) | 0 (0) | 30 (55) |
| Alopecia | 30 (55) | 0 (0) | 0 (0) | 30 (55) |
| Nausea | 26 (47) | 1 (2) | 0 (0) | 27 (49) |
| Leukopenia | 10 (18) | 13 (24) | 2 (4) | 25 (45) |
| Stomatitis | 19 (35) | 5 (9) | 5 (9) | 24 (43) |
| Hand–foot syndrome | 15 (27) | 2 (4) | 0 (0) | 17 (31) |
| Vomiting | 16 (29) | 0 (0) | 0 (0) | 16 (29) |
| Anemia | 14 (25) | 0 (0) | 0 (0) | 14 (25) |
| Epistaxis | 13 (24) | 0 (0) | 0 (0) | 13 (24) |
| Lacrimation increased | 13 (24) | 0 (0) | 0 (0) | 13 (24) |
| Dry skin | 12 (22) | 0 (0) | 0 (0) | 12 (22) |
| Dyspnea | 11 (20) | 0 (0) | 1 (2) | 12 (22) |
| Anorexia | 7 (13) | 4 (7) | 0 (0) | 11 (20) |
| Rash | 10 (18) | 1 (2) | 0 (0) | 11 (20) |
| Thrombocytopenia | 10 (18) | 1 (2) | 0 (0) | 11 (20) |
| Febrile neutropeniab | 0 (0) | 7 (13) | 1 (2) | 8 (15) |
Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.
Included due to clinical relevance.
Eighteen patients (33%) had a 1- to 2-week dose delay in either docetaxel or sunitinib (or both) due primarily to neutropenia (including febrile neutropenia). AEs led to sunitinib dose reduction to 25 mg/day in 17 patients (31%); three patients (6%) required a subsequent dose reduction to 12.5 mg/day. The docetaxel dose was reduced to 60 mg/m2 in 18 patients (33%). Colony-stimulating growth factors were administered in 16 patients (29%).
efficacy.
Confirmed PSA responses occurred in 31 patients [56.4% (95% CI 42.3–69.7)]. Median time to PSA progression was 9.8 months. Figure 1 depicts the maximum decrease in PSA from baseline for each patient. Twenty-nine patients (53%) on study >3 months had a ≥30% decline in PSA by that time, including 12 patients (22%) whose PSA decreased to <4.0 ng/ml.
Figure 1.
Phase 2: maximum percentage change from baseline in prostate-specific antigen (PSA) concentrations in each phase 2 patient (N = 55).
Among 33 patients with measurable disease at baseline, 14 [42.4% (95% CI 25.5–60.8)] had a confirmed RECIST-defined partial response (PR), 8 (24%) had stable disease (SD) and 5 (15%) progressed on study. Six patients had nonevaluable assessments. Median PFS was 12.6 months (95% CI 9.8–14.1; Figure 2A). Median OS was 21.7 months (95% CI 17.7–27.7; Figure 2B), with 1-year survival probability of 85.5% (95% CI 73.0–92.4) and 2-year of 44.7% (95% CI 27.5–60.4). By risk group [27], patients in the good category had an ORR of 22% and median OS of 21.5 months (95% CI 16.0–27.7), while those in the intermediate- and poor-risk combined group had an ORR of 67% and median OS of 22.5 months (95% CI 13.9 to not reached, P = 0.9666).
Figure 2.
Phase 2: Kaplan–Meier estimates of (A) progression-free survival and (B) overall survival (intent-to-treat population).
soluble protein biomarkers.
Plasma levels of soluble VEGFR-2 and VEGFR-3 decreased significantly from baseline at all on-treatment time points and returned partially toward baseline in off-drug periods, consistent with the intermittent dosing schedule. In contrast, VEGF-C levels did not change significantly with time.
No significant differences were seen when soluble proteins (either baseline concentrations or ratios to baseline) were compared between RECIST responders and nonresponders or patients with a clinical benefit response (PR or SD ≥3 months) versus no response (SD <3 months or progressive disease). However, patients with baseline VEGF-C concentrations lower than the median value were associated with significantly longer time to PSA progression [hazard ratio = 2.78 (95% CI 0.97–8.01), P = 0.046].
discussion
In this phase 1/2 study, we established the RP2D for sunitinib in combination with docetaxel and prednisone in mCRPC and showed promising evidence of efficacy, with an overall PSA response rate of 56.4%, a RECIST-defined ORR of 42.4% in patients with measurable disease, median PFS of 12.6 months and median OS of 21.7 months. The toxicity profile was moderately well tolerated and predictable, reflecting manageable side-effects expected from sunitinib and docetaxel as single agents.
Based on the single DLT observed in cohort 3 of phase 1, and PK data showing trough plasma concentrations of sunitinib consistently above the predicted threshold for VEGFR/PDGFR inhibition [28] in cohort 4 (with no significant drug–drug interactions between sunitinib and docetaxel/prednisone identified), we selected sunitinib 37.5 mg/day plus docetaxel 75 mg/m2 and prednisone 5 mg b.i.d. as the RP2D. A substantial proportion of patients (22%) completed the planned 16 cycles of the study. The frequency of grade 3/4 neutropenia was 53% (higher than the 32% reported in TAX327 [7] and 30% reported with docetaxel and prednisone plus bevacizumab in CALGB-90401 [29]), and that of febrile neutropenia was 15% (versus 3% in CALGB-90401 with bevacizumab [29]). While only three patients discontinued treatment due to neutropenia or febrile neutropenia, indicating that most events were controllable with dose delays or reductions and/or administration of growth colony-stimulating factors, as a cautionary note, the two deaths in this trial were related to infectious complications in neutropenic patients. This warrants up-front consideration of granulocyte colony-stimulating factor prophylaxis with this combination. There was no obvious increase in nonhematologic toxic effects. Fatigue/asthenia and diarrhea were commonly reported but were generally mild to moderate and did not lead to discontinuation. Longer follow-up with larger numbers of patients is required to more accurately estimate low frequency but potentially severe toxic effects, such as cardiac and hepatic dysfunction.
The encouraging response rate and PFS observed in the patient subset with measurable disease suggest the combination of sunitinib and docetaxel has significant antitumor activity in mCRPC. However, our data should be regarded in context of recent results with bevacizumab in the CALGB-90401 trial [29] and second-line sunitinib with prednisone after failure of docetaxel-based chemotherapy, showing improvement in PFS but not in the primary end point of OS versus prednisone alone [30].
Although cross-study comparisons should be interpreted with care, historical controls for docetaxel-based therapy in first-line treatment of mCRPC such as those in TAX327, where patients received the same doses and schedule of docetaxel plus prednisone as our study, had an ORR of 12% and OS of 19.2 months [7, 31, 32]. Recent data from the CALGB-90401 study of docetaxel and prednisone with or without bevacizumab preliminarily demonstrated an ORR in the control arm of 42.1% and OS of 21.5 months (versus 53.2% and 22.6 months, respectively, with bevacizumab) [29]; however, almost half the patients on that trial were considered good risk [33].
Based on TAX327, Armstrong et al. [27] recently published a risk classification of mCRPC patients based on four independent, clinically well-established pretreatment factors (pain, visceral metastases, anemia and bone scan progression) to predict a ≥30% PSA decline within 3 months of starting chemotherapy and found that the defined groups (good, intermediate and poor) obtained a distinct and not overlapping separation in OS (25.7, 18.7 and 12.8 months, respectively). In the present study, 30 patients (55%) fitted the intermediate- to poor-risk categories and achieved a promising OS of 22.5 months, providing rationale for further development of the sunitinib and docetaxel combination in these patient groups.
Our study additionally showed, with a median of seven treatment cycles, a promising PFS of 12.6 months (relative to 9.9 and 7.5 months in the CALGB-90401 treatment and control arms, respectively) [29]. However, similar to other clinical trials with VEGF inhibitors, this did not translate into a proportionally prolonged OS, suggesting a possible role for extended angiogenesis inhibition, perhaps incorporating further targets. Since we did not monitor our patients after discontinuation, their patterns of progression could not be assessed.
Sunitinib has been shown to affect endothelium and bone in prostate cancer; serum N-telopeptides reflecting osteoclast activity decrease with sunitinib in patients with bone metastasis [34]. In our study, we observed significant on-treatment decreases in sVEGFR-2 and sVEGFR-3, comparable to previous studies of sunitinib in prostate cancer and other malignancies, demonstrating an on-target inhibitory effect of sunitinib that was unaffected by addition of docetaxel. Moreover, low baseline levels of VEGF-C (a VEGFR-2 and VEGFR-3 ligand) were associated with longer time to PSA progression, indicating that VEGF-C might be a useful biomarker to explore in mCRPC.
Though limited by lack of a comparator arm, relatively small size and use of PSA response rate as the primary end point, our findings suggest that the addition of sunitinib to docetaxel and prednisone may increase antitumor activity in mCRPC with a reasonable toxicity profile, especially in patients with intermediate and poor prognostic characteristics. Since the relative contribution of the microenvironment to tumor progression may differ in specific clinical states, sunitinib is being investigated in earlier stages of prostate cancer progression, including primary disease before prostatectomy. Together, the clinical and correlative results of these studies may help us refine the selection of prostate cancer patients for antiangiogenic therapy.
funding
This study was sponsored by Pfizer Inc.
disclosures
DG has received honoraria and consultant fees from Pfizer. GL has received research funding/grants from Pfizer. GW has received research grants from Pfizer. TEH has received honoraria and consultant fees from Pfizer. CSH is an employee of Atrium Inc. and was a paid contractor to Pfizer in the development of this manuscript and the analysis and interpretation of data involving circulating biomarkers of angiogenesis. S-LW is a full-time employee of Pfizer with stock ownership. IC and ECM were previous employees of Pfizer. AJZ, NS, MK, PM and CJL reported no potential conflicts of interest.
Supplementary Material
Acknowledgments
We thank all the patients, their families and caregivers for their participation in this study and the investigators and their staff at participating sites. Editorial assistance was provided by Andy Gannon of ACUMED® (Tytherington, UK) with funding from Pfizer Inc.
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