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Clinical Cancer Research 13, 1208, February 15, 2007. doi: 10.1158/1078-0432.CCR-06-2046
© 2007 American Association for Cancer Research
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Cancer Therapy: Clinical

Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer

Robert Dreicer1, Daniel Petrylak2, David Agus3, Iain Webb4 and Bruce Roth5

Authors' Affiliations: 1 Cleveland Clinic Foundation, Cleveland, Ohio, 2 Columbia Presbyterian Medical Center, New York, New York, 3 Cedars-Sinai Medical Center, Prostate Cancer Center, Los Angeles, California, 4 Millenium Pharmaceuticals, Cambridge, Massachusetts, and 5 Vanderbilt-Ingram Cancer Center, Nashville, Tennessee

Requests for reprints: Robert Dreicer, Department of Solid Tumor Oncology Cleveland Clinic, 9500 Euclid Avenue R35, Cleveland, OH 44195. Phone: 216-445-4623; Fax: 216-445-2360; E-mail: Dreicer{at}ccf.org.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent prostate cancer.

Experimental Design: Two bortezomib doses (1.3 and 1.6 mg/m2/dose) in combination with four docetaxel doses (25-40 mg/m2/dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in Solid Tumors guidelines.

Results: Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (≥50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for ≥4 weeks in 14 patients (21%). According to Response Evaluation Criteria in Solid Tumors guidelines, 11% achieved a partial response, and an additional 67% had stable disease. The degree of proteasome inhibition was similar to that reported with single-agent bortezomib. Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred.

Conclusions: The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m2 bortezomib plus 40 mg/m2 docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.

Recent therapeutic advances have, to some extent, modulated the nihilism historically associated with the management of patients with advanced prostate cancer. Standard first-line treatment of metastatic androgen-independent prostate cancer (AIPC) now includes docetaxel, based on findings from two prospective, randomized phase III trials (SWOG 9916 and TAX 327). These trials showed that patients treated with docetaxel-based chemotherapy had significantly improved survival compared with patients receiving mitoxantrone and prednisone (1, 2). Despite this important clinical advance, median survival in patients treated with docetaxel-based therapies remains in the range of 18 to 19 months.

Various strategies have been investigated in an attempt to augment the therapeutic yield of docetaxel-based therapies. One approach involves combining docetaxel with novel agents that target specific pathways associated with AIPC, including the activation of androgen receptors independently of ligands, activation of the transcription factor nuclear factor-{kappa}B, and activation of growth-signaling pathways, such as phosphatidylinositol-3'-kinase/Akt (3). Of note, constitutive activation of nuclear factor-{kappa}B may be associated with phosphatidylinositol-3'-kinase/Akt activation, leading to protection from apoptosis and more aggressive behavior of prostate tumors (4, 5). Blockade of nuclear factor-{kappa}B in prostate tumors inhibits angiogenesis, cancer cell invasion and metastasis (3), and increases sensitivity to apoptosis induced by tumor necrosis factor {alpha} (6). In addition, in BCL-2–overexpressing tumors such as prostate cancer, targeting transcriptional activation may be a more effective strategy for inducing apoptosis than inhibiting signal transduction pathways (7).

Bortezomib (velcade/PS-341; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceuticals, Research and Development, L.L.C., Raritan, NJ) is a novel dipeptide boronic acid. It is the first clinically studied reversible inhibitor of the 26S proteasome, the degradative enzyme involved in the catabolic pathway for many intracellular regulatory proteins including inhibitor of nuclear factor-{kappa}B (I{kappa}B{alpha}), p53, p21, and p27 (8–10). Based on the results of two phase II trials (11, 12) and a randomized phase III trial versus dexamethasone (13), bortezomib has been approved for the treatment of patients with multiple myeloma who have received at least one prior therapy.

In preclinical studies, single-agent bortezomib at concentrations of 7 to 500 nmol/L induced growth arrest and apoptosis in vitro and in vivo against androgen-dependent (LNCaP) and androgen-independent (PC-3 and DU145) prostate cancer cell lines (14–17). The maximally tolerated dose of bortezomib in vivo was 1 mg/kg. Phase I dose escalation has been guided by biochemical assays of proteasome activity to achieve target inhibition of 70% to 80% (18).

Inhibition of proteasome activity increases sensitivity to chemotherapy and radiotherapy (19–25). In vitro and in vivo studies of prostate cancer and other solid tumors suggest that bortezomib activity is enhanced when given with docetaxel (26–29). Docetaxel stabilizes the ß-subunit of tubulin resulting in cell cycle arrest at M phase and apoptosis. Sequencing these drugs is therefore an important consideration as proteasome inhibition with bortezomib arrests cell cycle in G1 and G2, whereas docetaxel is most effective in M phase (27, 28). Various human cancer cell lines and xenograft models provide conflicting evidence of the ability of bortezomib to antagonize/sensitize taxane-induced apoptosis (26, 30). At the time this clinical trial was written, preliminary preclinical evidence supported the taxane-bortezomib sequence used in this study.

In phase I and II trials, bortezomib administered alone showed minimal antitumor activity in AIPC (31, 32). However, as a component of combination regimens, bortezomib shows potential (33). Initial results from a multicenter phase II trial suggest encouraging antitumor activity and tolerability with weekly docetaxel/bortezomib combination therapy in metastatic AIPC (34).

The primary objectives of the present study were to establish the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of docetaxel in combination with bortezomib administered weekly for 2 out of 3 weeks in patients with AIPC, and to evaluate the effect of the combination on prostate-specific antigen (PSA) levels. Secondary objectives included the assessment of objective response, additional selected variables of clinical benefit, bone resorption markers, and proteasome inhibition (20S assay) following docetaxel/bortezomib combination therapy, and investigation of the relationship between interleukin 6 (IL-6) and PSA levels in patients with AIPC.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
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Eligibility criteria. Eligible patients were required to have pathologic evidence of prostate adenocarcinoma, with documented metastatic disease, having progressed on androgen deprivation therapy following antiandrogen withdrawal if applicable. Progression was defined by one or more of the following: progressive soft tissue or bone metastasis or progressive PSA levels (≥5 ng/mL), as shown by two separate measurements taken at least 1 week apart and confirmed by a larger third or fourth measurement. Patients had to have a Karnofsky performance status ≥60% and be maintained on testosterone-suppressing therapy.

Patients may have received prior chemotherapy. Patients on bisphosphonates therapy were eligible, whereas those not receiving bisphosphonates were not allowed to begin bisphosphonates therapy. Patients with greater than grade 2 peripheral neuropathy, myocardial infarction within 6 months of enrollment, or uncontrolled arrhythmias or heart failure were excluded from enrollment. Men of reproductive potential had to agree to use an effective contraceptive method. All patients were informed of the investigational nature of the study and signed written informed consent in accordance with institutional and federal guidelines. The protocol was approved annually by the institutional review board for each treating institution.

Baseline radiographic and laboratory assessments. A computed tomography scan of the abdomen and pelvis and a bone scan were required at baseline. Radiologic assessment for measurable disease was done within 28 days before enrollment. Other baseline laboratory assessments included an electrocardiogram, serum testosterone, complete blood count (differential and platelets), clinical chemistries, urinalysis, C-reactive protein (CRP), IL-6, and two PSA measurements taken at least 1 week apart.

Efficacy was assessed throughout the study by measuring PSA, tumor response, Karnofsky performance status, CRP, IL-6, and bone resorption markers. PSA levels were measured on (or within 7 days of): day 1 of cycle 1, day 1 of subsequent odd-numbered cycles, and at the end-of-study visit if it had been >1 week since the previous assessment. PSA response was defined as a ≥50% decrease from baseline PSA (35), as determined by two separate measurements at least 4 to 6 weeks apart. Every 4 to 6 weeks during treatment, target and nontarget lesions were measured and overall disease response (confirmed complete response or partial response, or stable disease) was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST; ref. 36). Responses were confirmed 4 to 6 weeks after the first complete response or partial response. Blood samples were obtained from all patients before and 1 h after bortezomib administration during the first two cycles for pharmacodynamic analysis of 20S proteasome inhibition. Adverse events, serious adverse events, and all concomitant medications, procedures, and supportive therapies were also documented throughout the study. Laboratory abnormalities considered by the investigator to be clinically significant were reported as adverse events.

Study design and dose escalation schedule. This open-label, phase I/II, dose escalation study was carried out at four centers in the United States. During each 21-day treatment cycle, eligible patients received two docetaxel infusions (days 1 and 8) with 8 mg of dexamethasone given orally the evening prior, the morning of, and the evening after docetaxel infusion, and two bortezomib injections (days 2 and 9, at least 24 h after docetaxel administration) followed by a 12-day rest period.

Two bortezomib dose levels were investigated: low dose (1.3 mg/m2/dose) and high dose (1.6 mg/m2/dose). Docetaxel dose levels were 25, 30, 35, and 40 mg/m2/dose with low-dose bortezomib (dose levels 1-4, respectively) and 35 and 40 mg/m2/dose with high-dose bortezomib (dose levels 5 and 6, respectively). These doses were selected based on experience with weekly docetaxel in refractory malignancies (37, 38) and phase I clinical experience of bortezomib in AIPC (32).

Initially, three patients were treated at dose level 1. If no DLTs occurred during the first cycle, recruitment continued at the next dose level. If one patient experienced a DLT, the dose level was expanded to include six patients. Dose escalation continued if none of the additional three patients experienced a DLT. If two or three of the first three patients experienced a DLT, no additional patients were treated at that dose and 30 patients were subsequently treated at the previous dose level (the low MTD). If the MTD was not identified at the first three dose levels, an additional 30 patients were enrolled to dose level 4. After the first 10 patients in the expanded cohort had completed one cycle of therapy, enrollment began at dose level 5 and dose escalation continued as appropriate. An additional 30 patients were enrolled to the dose level identified as the high MTD in the same manner as the low MTD.

Identification of the MTD was based on the occurrence of DLTs during the first cycle only. The following hematologic adverse events, graded using National Cancer Institute Common Toxicity Criteria version 2.0 guidelines, were defined as DLTs if considered by the investigator to be related to study drug: grade 3 or 4 thrombocytopenia, febrile neutropenia, grade 4 neutropenia without fever for ≥7 days, or grade 4 anemia. Any grade 3 or 4 nonhematologic adverse event considered by the investigator to be related to study drug, except for bone-derived alkaline phosphatase elevations and inadequately treated nausea, vomiting, or diarrhea was defined as a DLT.

A full treatment course consisted of eight treatment cycles (24 weeks). Intrapatient dose escalation was not allowed. For each study drug, a maximum of two dose reductions (total dose reduction of 50%) was recommended. Patients responding to treatment could continue therapy for up to 16 cycles at the investigator's discretion. Patients experiencing progressive disease or unacceptable toxicity were withdrawn from the study.

Assessment of IL-6, CRP, and bone resorption markers. The proinflammatory molecules CRP and IL-6 have been shown to be associated with PSA and metastatic disease in prostate cancer (32, 39, 40). To further assess the relationship between these markers of chronic inflammation and prostate cancer, blood samples for CRP and IL-6 assessment were collected during screening, before study drug administration on days 1 and 8 of cycles 1, 2, 4, 6, and 8, and at the end-of-therapy and end-of-study visits.

It has been hypothesized that inhibition of nuclear factor-{kappa}B may lead to a reduction in bone resorption (or turnover). Therefore, the rate of bone turnover was assessed in this study by measurement of selected biochemical markers of resorbed bone collagen—N-telopeptide, deoxypyridinoline, bone-specific alkaline phosphatase, and osteocalcin. Urine samples for the assessment of N-telopeptide/creatinine ratio and deoxypyridinoline/creatinine ratio and blood samples for the assessment of serum bone-specific alkaline phosphatase and osteocalcin were collected before study drug administration on day 1 of cycles 1, 2, and 4, and at the end-of-study visit.

Statistical analysis. The sample size in the expanded dose level(s) was 30 additional patients, based on the aim of determining whether the PSA response rate was at least 35%, as indicated by the lower bound of a two-sided 90% confidence interval.

Three analysis populations were used: (a) safety population (all patients who had received any amount of docetaxel and/or bortezomib); (b) MTD evaluable population (all patients who received bortezomib and docetaxel in the MTD phase of the study and who had undergone sufficient safety assessments to determine occurrence of DLTs); (c) PSA response evaluation population (patients who received at least one dose of combination study drug, had baseline PSA levels ≥5 ng/mL, and had at least one post-baseline assessment). Subsets of patients based on prior chemotherapy were used when analyzing changes in PSA levels and tumor response to evaluate the combination in taxane-pretreated patients.

Efficacy analyses were carried out using the PSA response evaluation population and included change in PSA level, as well as the change from baseline levels in tumor lesion size. In addition, change from baseline levels of CRP, IL-6, and bone resorption markers, and the relationship between IL-6 and PSA levels were evaluated. Descriptive statistics were used for all efficacy analyses.


   Results
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 Results
Discussion
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Patient demographics. Between January 2002 and December 2004, 83 patients with measurable or evaluable advanced and/or metastatic AIPC were enrolled, all of whom received at least one dose of docetaxel/bortezomib combination therapy. Demographic and baseline characteristics are summarized in Table 1 . The majority of patients (n = 59, 71%) had previously received radiation therapy, 77 patients (93%) had undergone surgery for prostate cancer. Approximately half of the patients (52%) had previously received chemotherapy (Table 1).


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  		Table 1. Patient demographics and baseline characteristics

 
Exposure to study drug. Of the 83 patients enrolled, 21 (25%) completed eight cycles of treatment. The most common reason for early discontinuation was progressive disease (37 of 62 patients, 60%). Compliance was high throughout the study: only 5% to 11% of patients had a missed or delayed dose during cycles 1 to 8. The mean number of cycles administered was 4.8, median 4.0 (range, 0-15), with 100%, 99%, 69%, 63%, 48%, 41%, 34%, and 31% of patients being treated in cycles 1-8, respectively. Median duration of treatment was 11.4 weeks (range, 0-43 weeks).

Evaluation of MTD. No DLTs occurred at the first four dose levels. Therefore, an additional 30 patients were enrolled at the 1.3/40 mg/m2 dose level, and no DLTs were seen. In the 1.6/35 mg/m2 dose level, one patient experienced grade 3 angina pectoris, and an additional patient was enrolled into this group. At the 1.6/40 mg/m2 dose level, none of the first three patients experienced a DLT. However, as a result of safety concerns noted in one of the patients receiving this dose (grade 3 nausea, vomiting, and diarrhea, which the investigator considered to be related to study drug but which had not been adequately treated with antiemetics), an additional three patients were enrolled at this dose level, none of whom experienced a DLT. Consequently, 31 additional patients were enrolled. No DLTs occurred in this expanded cohort. As no DLTs were observed in the dose escalation phase for either of the bortezomib dose levels, the low MTD and high MTD were not established.

Efficacy. PSA response (50% decline from baseline) was observed in 19 (28%) of 67 evaluable patients (90% confidence interval, 19-39). The response was maintained for at least 4 weeks in 14 patients (21%). PSA response rates are summarized in Table 2 . Subpopulation analyses showed that PSA response was higher in chemotherapy-naïve patients [13 of 34, 38%; 5 of 12 (42%) receiving 1.3 mg/m2 of bortezomib, 8 of 22 (36%) receiving 1.6 mg/m2 of bortezomib] than in patients who had previously received chemotherapy [6 of 33, 18%; 5 of 23 (22%) receiving 1.3 mg/m2 of bortezomib, 1 of 10 (10%) receiving 1.6 mg/m2 of bortezomib], and higher in taxane-naïve patients [4 of 12, 33%; 4 of 10 (40%) receiving 1.3 mg/m2 of bortezomib, 0 of 2 receiving 1.6 mg/m2 of bortezomib] than in taxane-pretreated patients [2 of 21, 10%; 1 of 13 (8%) receiving 1.3 mg/m2 of bortezomib, 1 of 8 (13%) receiving 1.6 mg/m2 of bortezomib].


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  		Table 2. Summary of changes in PSA from baseline and of best tumor response by bortezomib dose level

 
Among the 45 patients evaluable for tumor response according to RECIST, five (11%) achieved a partial response (three receiving the 1.3/40 mg/m2 dose and two receiving the 1.6/40 mg/m2 dose). Partial response was confirmed in three of these patients (7%; two receiving 1.3/40 mg/m2 and one receiving 1.6/40 mg/m2). An additional 30 (67%) patients had stable disease (Table 2). Subpopulation analyses according to prior chemotherapy and taxane exposure revealed similar response rates between chemotherapy-naïve patients (n = 22; 9% partial response, 64% stable disease, 27% progressive disease) and taxane-pretreated patients (n = 14; 7% partial response, 64% stable disease, 29% progressive disease). A greater response among patients who had previously received nontaxane chemotherapy was observed (n = 9; 22% partial response, 78% stable disease, 0% progressive disease), although the small patient numbers involved make meaningful comparison difficult.

Of the 14 patients achieving a PSA response, 7 were also evaluable for tumor response. PSA response was associated with partial response in three patients (two patients in the 1.3/40 mg/m2 and one in the 1.6/40 mg/m2 group) and stable disease in four patients (two patients in the 1.3/40 mg/m2 group, two in the 1.6/40 mg/m2 group). Two other patients achieved a partial response according to RECIST without a PSA response. No significant changes from baseline in CRP and IL-6 levels were observed (data not shown).

Pharmacodynamics. The percentage of inhibition of proteasome activity is depicted in Fig. 1 (n = 52). The degree of inhibition observed with the docetaxel and bortezomib combination was similar to that seen in previous studies after the administration of bortezomib alone (32, 39–43). In patients in the different dose cohorts, mean percentage inhibition of proteasome activity 1 h postdose on day 2 (cycle 1) ranged from 61.9% to 73.6%, and on day 9 (cycle 1) immediately prior to dosing, ranged from 14.4% to 22.5%.


Figure 1
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  		Fig. 1. Percentage of inhibition of 20S proteasome activity relative to baseline. Safety population (n = 52).

 
Safety. All 83 patients experienced at least one adverse event, most commonly fatigue, diarrhea, flushing, and nausea (Table 3 ). Eighty-one patients (98%) experienced at least one adverse event considered by the investigator to be at least possibly related to bortezomib and/or docetaxel. Fatigue (70%) was the most common drug-related adverse event. Drug-related diarrhea and nausea occurred in 60% and 55% of patients, respectively. Grade 3 or 4 adverse events occurred in 47 patients (57%) and were considered drug-related in 28 patients (34%). The most common grade 3 or 4 adverse events are listed in Table 4 . Drug-related grade 3 or 4 adverse events were more common in the high-dose than the low-dose group (39% versus 29%, respectively). The most common drug-related grade 3 or 4 adverse events were diarrhea (7%) and fatigue (6%). Five patients experienced drug-related grade 4 adverse events: anemia and duodenal ulcer, acute myocardial infarction and increased cardiac troponin I levels, acute myocardial infarction and dyspnea, anemia, and hypoglycemia. Overall, 11 patients (13%) discontinued the study drug early because of an adverse event. There was no apparent trend in terms of adverse events from any particular system organ class more frequently leading to early discontinuation.


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  		Table 3. Most common adverse events*

 

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  		Table 4. Most common grade 3 or 4 adverse events*

 
In total, 31% of patients experienced at least one treatment-emergent serious adverse event. Gastrointestinal hemorrhage, urinary retention, and anemia each occurred in three patients; acute myocardial infarction, hematuria, and infection were each reported in two patients. The incidence of serious adverse events was similar in low-dose and high-dose groups (27% versus 30%, respectively). During the study, two deaths were reported, both at dose level 6. One patient died from sepsis 26 days after his last dose of study drug; a secondary complication of a cholecystectomy. The other patient died from disease progression 29 days after his last dose.

Dose reductions were necessary in only eight patients (two in cycle 2, four in cycle 4, one in cycle 5, and one in cycle 8). Only two of these patients were treated at the lower bortezomib dose. The proportion of patients in the low-dose group requiring a dose to be missed, held, or delayed in any cycle was 2% to 14% in cycles 1 to 8. In the high-dose group, 5% to 12% of patients in cycles 1 to 6, and none during cycles 7 and 8, required doses to be missed, held, or delayed.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The recent demonstration of a survival benefit, albeit a modest one, resulting from docetaxel-based therapy has established a new baseline for the management of patients with advanced androgen-resistant metastatic prostate cancer. Many questions, such as the optimal timing of initiation of therapy and its duration, remain. What is clear, however, is the need to build upon this therapeutic advance as essentially all these patients will ultimately progress and die of disease.

Bortezomib is the first clinically studied reversible inhibitor of the 26S proteasome with has shown activity in multiple myeloma. Although bortezomib showed minimal single-agent activity in advanced prostate cancer, preclinical and early clinical experience provided a rationale to further explore the activity of the combination of bortezomib and docetaxel. The results of this phase I/II dose escalation study show that bortezomib/docetaxel combination therapy is feasible in patients with AIPC, whether or not they have previously received chemotherapy. The combination is well tolerated and active, as shown by the response rate according to reduction in PSA levels and RECIST.

No DLTs occurred at any dose level, despite dose escalation to 1.6 mg/m2 of bortezomib plus 40 mg/m2 of docetaxel, and therefore, the MTD of this regimen was not determined. In the phase I dose escalation study of single-agent bortezomib reported by Papandreou et al., diarrhea and hypotension were dose-limiting and the MTD was determined as 1.6 mg/m2 (32). However, a weekly dosing regimen was used, with bortezomib administered for 4 weeks followed by a 1-week rest period. Aghajanian et al. determined a MTD of 1.56 mg/m2 when single-agent bortezomib was administered twice weekly for 2 weeks followed by a 1-week rest period in patients with heavily pretreated advanced solid tumors (44). The study included four patients with prostate cancer. DLTs were diarrhea and painful sensory neuropathy, each in two patients at grade 3 intensity. No hematologic DLTs were observed. Likewise, Dy et al. identified an MTD of 1.5 mg/m2 with single-agent bortezomib twice weekly for 2 out of every 3 weeks in their study in patients with advanced cancer (43).

This schedule of bortezomib plus docetaxel combination therapy was well tolerated, as shown by the lack of DLTs. Fatigue, diarrhea, flushing, and nausea were the most common adverse events, reflecting previous experience of bortezomib alone or in combination with docetaxel (12, 13, 32, 34, 45). The most common grade 3 or 4 drug-related adverse events were diarrhea, asthenia, and fatigue. No cases of febrile neutropenia or neuropathy were reported; these have previously been reported with docetaxel plus bortezomib in patients with anthracycline-pretreated breast cancer (46) and in patients with solid tumors (45). Neutropenic fever, neutropenia, cardiovascular events, diarrhea, and nausea were characteristic of docetaxel-based therapy in recent randomized trials in AIPC (1, 2, 47), yet none of these side effects were sufficiently severe to be classified as a DLT with bortezomib/docetaxel therapy in the present study. This observation may be explained by the dosing schedule of docetaxel (up to 40 mg/m2 twice every 21 days compared with 60-75 mg/m2 every 21 days). Adverse events were more common with high-dose than low-dose bortezomib. This trend was most pronounced for vomiting, hyperglycemia, and grade 3/4 fatigue. However, none of these events was considered dose-limiting with 1.6 mg/m2 of bortezomib.

The bortezomib/docetaxel combination therapy showed antitumor activity in the range of what would be anticipated with docetaxel alone. PSA levels declined by ≥50% in 28% of evaluable patients. The proportion of patients achieving a ≥50% decrease in PSA levels was similar in the high- and low-dose groups (28% versus 29%, respectively). Among patients evaluable for tumor response according to RECIST, 78% achieved partial response or stable disease as best response and 7% had confirmed partial response. Of note, only patients receiving the highest docetaxel dose (40 mg/m2/dose) achieved a clinical response.

The results of this trial are generally consistent with data from other phase I/II studies evaluating bortezomib alone or in combination with docetaxel (32, 34), showing antitumor activity and tolerability. The activity of the combination in patients whose disease had progressed with prior taxane-based therapy was of interest. Although activity in terms of PSA response was lower in taxane-pretreated than taxane-naïve patients (10% versus 33%, respectively), tumor responses based on RECIST were similar in these two subgroups (7% versus 9%, respectively). In the >5 years since this trial was initiated and first presented in abstract form, substantial experience has accumulated, showing that selected taxane-responsive patients may achieve clinically meaningful benefit with retreatment after a drug holiday (48).

In conclusion, bortezomib/docetaxel showed antitumor activity in patients with AIPC and was well tolerated. No DLTs occurred in our trial, and therefore, we were unable to determine the MTD. However, the highest dosing regimen evaluated was feasible and tolerable. The relatively small proportion of patients with evaluable disease makes it difficult to draw firm conclusions about the efficacy of the combination, and therefore, further investigations are warranted to determine and optimize the efficacy of docetaxel and bortezomib combination treatment in prostate cancer. The relatively modest PSA response rates may be ascribed to the somewhat suboptimal doses of docetaxel used (25 and 30 mg/m2/dose) in the subset of patients treated.

This phase II combination study was one of the first trials combining docetaxel with a then novel small molecule, and in the 6 years since its design, many similar trials with a range of agents have been conducted with similar problems in interpretation, i.e., is there a meaningful benefit to the addition of a novel agent to an active cytotoxic agent? Although ongoing trials of bortezomib, in combination with other agents such as mitoxantrone (33), may help to establish how a proteasome inhibitor could be integrated into treatment strategies, the ultimate utility of the bortezomib/docetaxel combination in advanced prostate cancer remains undefined.


   Footnotes
 
Grant support: Millennium Pharmaceuticals, Inc., and Sanofi-Aventis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/17/06; revised 11/ 8/06; accepted 11/21/06.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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