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Intermittent Chemotherapy as a Platform for Testing Novel Agents in Patients With Metastatic Castration-Resistant Prostate Cancer: A Department of Defense Prostate Cancer Clinical Trials Consortium Randomized Phase II Trial of Intermittent Docetaxel With Prednisone With or Without Maintenance GM-CSF
Clinical Genitourinary Cancer
Immunotherapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), an agent that previously demonstrated antitumor activity, was evaluated within an intermittent chemotherapy framework of docetaxel with prednisone (D+P) in metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods
mCRPC patients with ≥ 50% prostate-specific antigen (PSA) decline after 6 cycles of D+P were randomized to either GM-CSF or observation (Obs). At disease progression (PD), D+P was reinitiated for 6 cycles followed by the same “off chemotherapy” regimen in patients eligible for chemotherapy interruption. The sequence was repeated until PD during chemotherapy, lack of PSA response to chemotherapy, or unacceptable toxicity. The primary end point was time to chemotherapy resistance (TTCR).
Of 125 patients enrolled, 52 (42%) experienced ≥ 50% PSA decline on induction D+P and were randomized to GM-CSF (n = 27) or Obs (n = 25). The median time to PD was 3.3 months (95% confidence interval [CI], 2.4-3.5) and 1.5 months (95% CI, 1.5-2.4) during the initial course of GM-CSF and Obs, respectively. Twelve of 26 (46%) patients responded to a second course of D+P. Eleven randomized patients (21%) experienced PD during chemotherapy, precluding accurate assessment of TTCR. The remaining 41 randomized patients discontinued study for lack of PSA response to chemotherapy (n = 8), patient choice to not restart chemotherapy with PSA PD (n = 13), toxicity (n = 7), or study withdrawal (n = 13).
Conducting a prospective study in mCRPC with maintenance immunotherapy within the framework of intermittent chemotherapy was feasible. The use of PSA instead of radiographic end points limited the number of evaluable patients. This study provides important insight into designing contemporary intermittent chemotherapy trials with maintenance immunotherapy in patients with advanced prostate cancer.
Keywords: Granulocyte macrophage colony stimulating factor, Immunotherapy, Maintenance therapy, Prostatic neoplasm, Taxane-based chemotherapy.
Metastatic castration-resistant prostate cancer (mCRPC) is the second leading cause of cancer death in men in the United States, with nearly 30,000 deaths per year. 1 Treatment with every 3-week docetaxel with prednisone prolongs overall survival and is the current standard first-line chemotherapy option in mCRPC. 2 However, this regimen might be associated with cumulative toxicities that can significantly impair quality of life (QOL). Applying chemotherapy on an intermittent basis has the potential clinical advantage of achieving disease control that is comparable with continuous chemotherapy but with less toxicity and improved QOL by minimizing cumulative drug exposure.
Prospective studies in advanced breast and colon cancer have demonstrated similar long-term survival and potentially improved tolerability with intermittent versus continuous chemotherapy.3, 4, 5, and 6However, heterogeneity with respect to study end points chosen and criteria for stopping and starting chemotherapy has limited the ability to form a standardized framework for this approach. Even less is known about applying intermittent chemotherapy in mCRPC. The results of several small prospective studies in which patients were treated with intermittent docetaxel-based chemotherapy have been reported, but no standardized approach exists.7, 8, and 9For example, in a phase III clinical trial in mCRPC of weekly docetaxel with or without high-dose calcitriol, patients who wished to, could suspend therapy if prostate-specific antigen (PSA) declined by > 50% from baseline and was < 4 ng/mL. In this analysis, of the 45 patients who met parameters for and suspended therapy, 45% had a PSA decline of > 50% with reinitiation of docetaxel with a median chemotherapy-free interval of 18 weeks. 7
To date, no agent combined with front-line docetaxel therapy has been shown to prolong survival in mCRPC patients.10, 11, 12, 13, 14, 15, 16, and 17This might be because of a number of reasons, including limited efficacy of the novel agents tested, difficulty of demonstrating additive benefit while receiving concurrent docetaxel-based therapy, and potentially a high disease burden at the time of treatment initiation. Establishing a framework of intermittent chemotherapy provides the potential to test novel agents as maintenance therapy after induction chemotherapy. This approach is predicated on the hypothesis that the efficacy of noncytotoxic agents in mCRPC might be optimized in settings of minimal or reduced disease burden after effective cytoreductive chemotherapy. Under these circumstances a clinically relevant outcome measure could be a prolongation of the time with no chemotherapy and/or a delayed time to chemotherapy resistance.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) was an attractive agent to test in this trial design because of previous evidence of antitumor efficacy and also a favorable safety profile.18 and 19In a previous single-agent study in patients with mCRPC, PSA decline > 50% was observed in nearly a quarter of patients and treatment was well tolerated. 18 GM-CSF has also been shown to stimulate an immune response within localized prostate cancers. 20
On the basis of these previous clinical studies, a multicenter noncomparative randomized phase II trial of intermittent docetaxel with prednisone with or without maintenance GM-CSF was undertaken within the Department of Defense Prostate Cancer Clinical Trials Consortium. 21
Patients and Methods
Patients had progressive prostate adenocarcinoma despite castrate levels of testosterone (< 50 ng/dL) with evidence of 1 or more metastases. An Eastern Cooperative Oncology Group performance status of ≤ 2 was required, as was adequate renal, hepatic, and bone marrow function. Patients could have received up to 3 previous cycles of every 3 weeks docetaxel treatment at standard doses immediately before enrolling in the study without other intervening therapy. Patients without a previous history of bilateral orchiectomy were required to continue taking a luteinizing hormone releasing hormone analogue. Key exclusion criteria included Grade ≥ 2 peripheral neuropathy at study entry, and use of previous immunotherapy including systemic GM-CSF or vaccines using GM-CSF (previous use of granulocyte colony stimulating factor for prophylaxis was allowed).
The protocol was approved by the local institutional review board of all participating centers, and written informed consent was obtained from all patients.
Treatment and Study Assessment
At the time of study design, there were no standard criteria for definitions of response or progression based on radiographic criteria. As such, PSA response and progression according to PSA Working Group (PCWG)-1 criteria were used to define eligibility for stopping and starting chemotherapy. 22 Induction chemotherapy consisted of docetaxel 60 to 75 mg/m2(per investigator discretion) on day 1 in combination with prednisone 5 mg orally twice daily every 3 weeks for 6 cycles.
After 6 cycles of induction chemotherapy, for patients with a confirmed PSA response according to PCWG1 criteria (PSA decline ≥ 50% from baseline), prednisone was tapered over 14 days and patients were randomized to either observation (Obs) or treatment with GM-CSF, dosed at 250 mg/m2subcutaneously (maximum dose, 500 mg) daily on days 15 to 28 of an every 28 day cycle as previously described. 18 Obs or GM-CSF treatment was continued until PSA or radiographic progression, at which point docetaxel treatment was resumed. Patients with a second confirmed PSA response (≥ 50% PSA decline from baseline at start of series 2 docetaxel treatment) after 6 cycles were eligible to reinitiate either Obs or GM-CSF according to previous treatment arm assignment (there was no second randomization and crossover was not allowed). Protocol therapy was continued until the first occurrence of disease progression during chemotherapy treatment, lack of PSA response to a 6-cycle course of docetaxel, patient withdrawal, initiation of nonprotocol therapy, removal at the treating physician's discretion, or unacceptable toxicity ( Figure 1 ). Serum PSA was measured every cycle, and restaging scans (bone scan and computed tomography scan of the abdomen/pelvis) were obtained every 2 cycles during GM-CSF/Obs treatment period, and at the completion of every 6 cycles of docetaxel with prednisone.
Study Design and Data Analysis
This was a multicenter randomized noncomparative phase II trial of intermittent chemotherapy with and without maintenance GM-CSF in mCRPC patients. The primary end point was the time to chemotherapy resistance in each randomized cohort, measured according to the time interval between start of first “off-chemotherapy” interval and subsequent disease progression while receiving chemotherapy, consistent with previous studies of intermittent chemotherapy in advanced solid tumor populations. 5 The target sample size was 150 patients. Based on previous studies, 2 it was estimated that 60% of patients (n = 90) would have a PSA response to induction chemotherapy and be randomized on a 1:1 basis to 1 of the 2 treatment arms (GM-CSF or Obs; n = 45 per study arm). For each treatment arm, the null hypothesis was a median time to chemotherapy resistance of < 3 months, based on the time to progression on continuous every 3 week docetaxel. 2 According to the alternative hypothesis, the median time to chemotherapy resistance from date of randomization was ≥ 5 months, corresponding to an increase in remaining progression-free from 50% to 66% at 3 months from the start of the first “off-chemotherapy” interval. This projected sample size for each treatment arm had 80% power to reject the null hypothesis for each treatment arm using a 1-sided significance level of 0.10.
Secondary outcome measures for the randomized study cohort included PSA response to successive series of chemotherapy, duration of chemotherapy-free intervals, and cumulative percentage of time spent with no chemotherapy treatment, time to progression during the first series of GM-CSF/Obs, overall survival from start of the first series of GM-CSF/Obs, and toxicity. Disease progression was defined as the first occurrence of PSA progression according to PCWG1 criteria, radiographic progression according to Response Evaluation Criteria in Solid Tumors 1.0 criteria in patients with measurable disease, 23 or the appearance of new bone lesions on radionuclide bone scan. The median time to progression and overall survival for each treatment arm from the start of GM-CSF or Obs and overall survival for the full study cohort from start of docetaxel treatment were estimated using the Kaplan–Meier product limit method.
Baseline Characteristics and Patient Disposition
One hundred twenty-five patients were enrolled. The study was closed before accruing the planned 150 patients after it was determined there would be insufficient events to determine the primary end point of time to chemotherapy resistance. Baseline characteristics are shown in Table 1 .
|Characteristic||Total Enrolled (n = 125)||Subset of Patients Randomized to|
|GM-CSF (n = 27)||Observation (n = 25)|
|Median Age (Range)||70 (47-95)||65 (47-95)||73 (61-86)|
|Median Baseline PSA (Range), ng/mL||79.9 (5.4-3962)||73.5 (5.8-1286)||76.8 (6.8-2923)|
|Median Alkaline Phosphatase (Range), U/L||136 (33-1999)||93 (33-1267)||98 (41-543)|
|Median Lactate Dehydrogenase, U/L (range)||231 (45-1059)||239 (146-803)||222 (45-1059)|
|Median Hemoglobin, g/dL (range)||11.9 (8.7-14.2)||12.0 (9.3-13.5)||10.9 (8.9-14.2)|
|Previous Treatment for CRPC, %|
|Site of Disease, %|
|Any visceral metastasis||24%||19%||27%|
Abbreviations: CRPC = castration-resistant prostate cancer; ECOG PS = Eastern Cooperative Oncology Group performance status; GM-CSF = granulocyte-macrophage colony-stimulating factor; PSA = prostate-specific antigen.
Most patients had Gleason Grade ≥ 8 prostate cancer at diagnosis, the median baseline PSA and lactate dehydrogenase were 80 ng/mL and 231 U/L respectively, and 30 patients (24%) of patients had visceral metastases (including 11 patients (9%) of patients with liver metastases), reflective of a cohort of patients with adverse prognostic features. Of the 125 patients enrolled, 49 (39%) had received no previous docetaxel, and 76 (61%) had received up to 3 cycles of every 3 weeks docetaxel treatment immediately before study entry. Baseline characteristics were generally similar between the GM-CSF and Obs arms with the exception of Gleason Grade ≥ 8 at diagnosis (58% vs. 33% in the GM-CSF and Obs arms, respectively;P = .06; Table 1 ).
Patient disposition is shown in Figure 2 . Of the 125 patients enrolled, 31 (25%) patients did not complete the 6 cycles of induction chemotherapy (progression of disease, n = 17; adverse events, n = 11, and patient withdrawal, n = 3), and 42 (34%) patients completed induction chemotherapy but were not randomized (progression of disease, n = 19; no PSA response to chemotherapy, n = 22; and adverse events, n = 1). Thus, 52 patients (42% of the total enrolled patients) had a confirmed PSA response after the first 6 cycles of docetaxel and were randomized to either GM-CSF treatment or Obs (n = 27 with GM-CSF treatment and n = 25 Obs). Of the 52 randomized patients, only 11 (21%) experienced disease progression while receiving docetaxel with prednisone, precluding accurate assessment of time to chemotherapy resistance for each study arm. The remaining 41 randomized patients discontinued the study for lack of PSA response to chemotherapy (n = 8), patient refusal to restart chemotherapy with PSA progression during the “off-chemotherapy” intervals (n = 13), study withdrawal for other reasons (n = 9), nonprotocol therapy (n = 4), or toxicity (n = 7).
Prostate-Specific Antigen Response Proportions to Docetaxel Therapy and Chemotherapy-Free Intervals
Prostate-specific antigen response to successive courses of docetaxel and the duration of chemotherapy-free intervals are shown in Table 2 . Recapturing PSA response to chemotherapy after a treatment break was observed in 12 of 26 (46%; 95% confidence interval [CI], 27%-67%) of patients who received a second course of docetaxel, including 8 of 13 patients (62%) in the GM-CSF arm and 4 of 13 (31%) patients in the Obs study arm. The median duration of the chemotherapy-free interval between the first and second courses of docetaxel was 2.6 months (range, < 0.1-7.9) and 2.3 months (range, < 0.1-6.1) in the GM-CSF and Obs arms, respectively. Of the 5 patients subsequently treated with a third course of docetaxel with prednisone, 1 patient (20%) had a third PSA response.
|GM-CSF Arm (n = 27)||Observation Arm (n = 25)|
|Median Duration of Participation in Study (Range)||7.6 Months (1.9-19.2)||8.3 Months (3.9-22.8)|
|Median Duration of Chemotherapy-Free Interval #1 (Range), Months a||2.6 (<0.1-7.9)||2.3 (<0.1-6.1)|
|Median Cumulative Percentage of Time of No Chemotherapy (Range) b||30.9% (1.7-77.1)||24.7% (0.8-50.8)|
|PSA Response to Course #2 Chemotherapy (95% CI) c||8/13 (62%) (32%-86%)||4/13 (31%) (9%-61%)|
|PSA Response to Course #3 Chemotherapy c||0/3||1/2|
a Chemotherapy-free interval measured from 21 days after the date of cycle 6 day 1 of chemotherapy with docetaxel to date of the first dose of docetaxel in the next series of chemotherapy.
b Measured from date of the first cycle of induction chemotherapy to date removed from study. The start date of each chemotherapy-free interval was defined as 21 days after the date of the last dose of docetaxel in the previous series of chemotherapy.
c Prostate-specific antigen response defined according to PSA Working Group 1 criteria (≥ 50% decline from baseline, confirmed with repeat PSA measurement at least 4 weeks later).
Abbreviation: PSA = prostate-specific antigen.
The median duration of participation in the study was 7.6 months (range, 1.9-19.2) for the GM-CSF arm and 8.3 months (range, 3.9-22.8 months) for the Obs study arm. The median cumulative percentage of time spent with no chemotherapy during the study was 28.4% (range, 0.8%-77.1%) for the entire randomized patient cohort, including 30.9% (range, 1.7%-77.1%) and 24.7% (range, 0.8%-50.8%) for the GM-CSF and Obs study arms, respectively.
Effect of GM-CSF on Time to Progression of Disease and Overall Survival
The median time to progression of disease from the start of the first course of GM-CSF was 3.3 months (95% CI, 2.4-3.5) and from the start of Obs was 1.5 months (95% CI, 1.5-2.4; Figure 3A ). Although the study was not designed to compare outcomes between treatment arms, in a post hoc analysis, the difference in time to progression was statistically significant (log rank test:P = .002).
Among the 125 enrolled patients, 109 deaths had occurred at the time of final analysis. The median overall survival from the start of the first course of docetaxel was 15.6 months (95% CI, 13.1-18.8) for the overall study cohort. The median overall survival from the start of the first “off-chemotherapy” interval was 28.4 months (95% CI, 19.2-34.1) in the GM-CSF arm and 14.0 months (95% CI, 10.5-27.6) in the Obs arm ( Figure 3B ; log-rank test,P = .08).
Overall, 15% of patients discontinued participation in the study for adverse events, including 12 of 125 patients (10%) during the induction chemotherapy and 7 of 27 patients (26%) during treatment with GM-CSF. Overall, 8 (6%) of 125 patients experienced febrile neutropenia. The most common Grade ≥ 3 treatment-related adverse events included neutropenia (n = 12), febrile neutropenia (n = 8), hyperglycemia (n = 5), sepsis and/or infection without concomitant neutropenia (n = 5), anemia (n = 3), venous thromboembolism (n = 3), and hypersensitivity reaction to docetaxel (n = 2). There were no treatment-associated deaths. Among the 26 patients who started a second course of docetaxel, the incidence of neutropenia was similar between patients who were randomized to the GM-CSF versus the Obs study arm.
Improving patient outcomes by combining novel therapies with first-line docetaxel in mCRPC has not improved on the median overall survival achieved with docetaxel and prednisone alone.10, 11, 12, 13, 14, 15, 16, and 17This might be related to either the limited efficacy of the agents evaluated or potentially the high disease burden and rapid tumor growth frequently observed at the start of chemotherapy. Evaluating novel therapeutic agents including immunotherapies as maintenance therapy after cytoreductive chemotherapy is an alternative strategy to prolong the time to chemotherapy resistance and overall survival for patients with mCRPC. Although this study was not designed for a direct comparison between treatment arms, in a post hoc analysis, there was a statistically significant longer time to progression in the GM-CSF arm than in the Obs arm, and a trend toward longer overall survival. These preliminary results support the further study of GM-CSF or other emerging immunotherapies and biologic agents as potential maintenance therapy within the framework of an intermittent chemotherapy strategy in the advanced prostate cancer setting.
Since the time of study design, there have been a number of systemic therapies approved for use in the mCRPC setting, and chemotherapy is being used later in the mCRPC disease course. Furthermore, a finite course of docetaxel (6 cycles) has recently been shown to significantly prolong survival in patients with extensive metastatic disease in the hormone-sensitive setting. 24 Therefore, a prospective evaluation of novel therapies within an intermittent chemotherapy framework might be best applied in the hormone-sensitive, rather than in the mCRPC setting. This warrants further evaluation in prospective studies.
The current study used a novel, prospectively applied framework of intermittent chemotherapy. The results demonstrate that this approach is feasible and can be successfully carried out in a multicenter, randomized clinical trial. The randomized patient cohort spent more than a quarter of time with chemotherapy during the study. Recapturing PSA response after chemotherapy-free intervals was achieved in nearly half of the patients re-treated with docetaxel during the study, although PSA response rates did appear to diminish in successive chemotherapy series. The current results are consistent with previous studies, in which the observed PSA response proportions on reinitiation of docetaxel chemotherapy in mCRPC have ranged from 25% to 60%, with declining proportions in successive series.7, 8, and 9Studies that reported higher response rates to reintroduction of chemotherapy selected patients with more robust responses to first line docetaxel. 7 The median overall survival from the start of the first course of docetaxel for the overall study cohort (15.6 months) was numerically shorter than with that observed in the phase 3 pivotal studies of docetaxel in mCRPC. 2 This might be reflective of a disease group with more adverse baseline prognostic features including a larger percentage of patients with Gleason ≥ 8 Grade at diagnosis. 2
This study provides important insight into the design of contemporary clinical trials evaluating emerging immunotherapies and other novel biologic agents within a framework of intermittent chemotherapy. At the time the study was designed, there were no standardized radiographic end points in mCRPC, and criteria for stopping and starting chemotherapy were chosen based on the then-widely used PCWG1-defined PSA criteria. 22 Reliance on PSA response criteria limited the number of patients eligible for randomization. Furthermore, mandating resumption of chemotherapy at the time of PSA progression limited the duration of chemotherapy-free intervals and led to substantial patient attrition, leading to insufficient events to accurately determine the time to chemotherapy resistance. These results underscore the need to incorporate the now-standardized PCWG2 recommendations emphasizing clinical and radiographic variables for future studies using a framework of intermittent therapy. 25 In such a study, stopping chemotherapy should be based on radiographic stable disease or objective response after a fixed number of cycles, and resuming chemotherapy should be based on radiographic or clinical progression rather than PSA progression. Such a study design would more closely mirror contemporary clinical practice and minimize patient attrition.
Similarly, time to radiographic progression during the first course of maintenance therapy, as opposed to time to chemotherapy resistance or time to PSA progression, might be the preferable primary outcome measure for future studies using an intermittent chemotherapy framework. Such an approach would capture activity of a novel agent with respect to disease stabilization, would be valid for therapies that do not directly target the androgen signaling axis and therefore might not affect PSA levels, and would not depend on patients restarting chemotherapy at the time of progression. Demonstrating prolonged time to radiographic progression during the maintenance phase(s) of a phase II study would support confirmatory phase III studies that would assess the effect on long-term survival using an intermittent chemotherapy platform.
An intermittent chemotherapy platform was explored to prospectively evaluate immunotherapy maintenance treatment in men with mCRPC. Recapturing PSA response after chemotherapy breaks was demonstrated to be feasible. Further studies are required to test a strategy of maintenance GM-CSF or other immunotherapies after induction chemotherapy in mCRPC. This study provided important insight into the design of contemporary intermittent chemotherapy trials, and a viable framework to test novel agents in the metastatic setting, emphasizing clinical and radiographic over PSA-based end points consistent with PCWG2 recommendations.
Clinical Practice Points
- Retrospective studies suggest that recapturing response after a chemotherapy treatment break in mCRPC is possible. However, the optimal duration of chemotherapy is not known and prospective studies of an intermittent chemotherapy approach in mCRPC are lacking. It is further unknown whether applying maintenance immunotherapy during chemotherapy breaks provides benefit in delaying time to chemotherapy resistance and allowing patients a greater percentage of time in which no chemotherapy is used.
- The current study is one of the first prospectively designed studies to demonstrate the feasibility of an intermittent chemotherapy approach in mCRPC. Recapturing PSA responses after a chemotherapy holiday was achievable and led to a greater percentage of time without chemotherapy. The study results also suggest a potential benefit for maintenance immunotherapy with GM-CSF to prolong time to progression, but follow-up studies will be required to definitively address the role of maintenance immunotherapy.
- This study provides important insight into contemporary clinical practice, in which clinical and radiographic end points should be emphasized over treatment decisions made on the basis of PSA testing alone. Applying chemotherapy on an intermittent basis in mCRPC is feasible and should be considered especially for patients with cumulative toxicities from treatment. There might be a role for maintenance immunotherapy to extend chemotherapy-free treatment intervals. Further studies to validate this approach are warranted.
Tomasz M. Beer has received research funding from Sanofi. The remaining authors have no conflicts of interest to disclose.
Funding provided by Sanofi, Department of Defense/Prostate Cancer Clinical Trials Consortium, the Prostate Cancer Foundation, and Genzyme.
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1 Department of Medicine, University of California San Francisco, San Francisco, CA
2 Department of Medicine, Oregon Health Sciences University, Knight Cancer Institute, Portland, OR
3 Department of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA
4 Department of Medicine, Dana-Farber Cancer Institute, Boston, MA
5 Urology Cancer Center and GU Research Network, Omaha, NE
∗ Address for correspondence: Rahul R. Aggarwal, MD, 1600 Divisadero St, Box 1711, San Francisco, CA 94143. Fax: 415-353-7779
© 2014 Elsevier Inc., All rights reserved.