Annals of Oncology Advance Access published online on May 7, 2008
Annals of Oncology, doi:10.1093/annonc/mdn174
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Results from a monocentric phase II trial of erlotinib in patients with metastatic prostate cancer
1 Department of Medical Oncology, Institut Paoli-Calmettes
2 INSERM UMR 599
3 Université de la Méditerranée, UFR Médecine
4 Department of Urology, CHRU Marseille, Hôpital Sainte Marguerite
5 Department of Radiotherapy Oncology
6 Department of Biostatistic
7 Department of Surgery
8 Department of Anatomo-Pathology
9 Department of Radiology, Institut Paoli-Calmettes, Marseille, France
* Corresponding to: Dr G. Gravis, Institut Paoli-Calmettes, 232 Boulevard de Sainte Marguerite, 13009 Marseille, France. Tel: +33-4-91-22-37-40; Fax: +33-4-91-22-36-18; E-mail: gravisg{at}marseille.fnclcc.fr
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Abstract |
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Background: Erlotinib is an orally active small-molecule tyrosine kinase inhibitor targeted against human epidermal growth factor receptor 1/epidermal growth factor receptor (ErbB1), known to be overexpressed in a variety of cancers, including prostate cancer.
Patients and methods: This was a phase II monocentric study of 30 patients with advanced or metastatic prostate cancer, 29 had castration-resistant prostate cancer and 23 had received prior chemotherapy. Patients received erlotinib: 150 mg/day, increased to 200 mg at week 4, and continued until progression or unacceptable toxicity. Efficacy was defined as a decrease or stabilization of prostate-specific antigen (PSA) without clinical progression. Clinical benefit was evaluated by Karnofsky performance status and pain intensity, and response was an improvement in one of these parameters without worsening in the other.
Results: Median age was 69 years (range 51–77 years), and median PSA 102 ng/ml (range 3–1213 ng/ml). Dose escalation to 200 mg was possible in 16 (55%) patients. Moderate toxicity was observed. No patient had a decrease in PSA, 14% had stabilization, less than the 
20% expected. PSA-doubling time, evaluated before and after erlotinib, was increased for 10 patients (P = 0.0058). Clinical benefit was achieved in 40% of patients.
Conclusion: Erlotinib demonstrated an improvement in clinical benefit. Future directions should include evaluating its use in less advanced prostate cancer.
castration-resistant prostate cancer, clinical benefit, metastatic prostate cancer, tyrosine kinase inhibitor
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background |
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Prostate cancer is the third leading cause of cancer in men. The treatment of prostate cancer by radical prostatectomy or curative radiotherapy has a high curability rate in patients with localized prostate cancer. Advanced metastatic prostate cancer can, however, only be treated by surgical or medical castration often in combination with peripheral antiandrogen blockade. The majority of patients who initially respond to hormone manipulation eventually progress to castration-resistant prostate cancer (CRPC). The treatment option for this stage of disease is chemotherapy by docetaxel, which demonstrated improvement in survival [1].
The human epidermal growth factor receptor 1/epidermal growth factor receptor (HER1/EGFR) and its ligand epidermal growth factor (EGF) and transforming growth factor-
(TGF-) are important in cell proliferation, as well as for cell motility, cell adhesion, cancer invasion, cell survival, and angiogenesis [2, 3]. During the progression of localized disease to advanced or metastatic disease, an up-regulated expression of numerous growth factors and their receptors has been described. In particular, the overexpression of EGFR and its ligand has been associated with an increased rate of relapse after therapy [4–6]. Moreover, the percentage of prostate cancers expressing EGFR increases during prostate cancer progression with the highest percentage found in metastatic CRPC [7]. EGFR expression was evaluated by immunohistochemistry in 29 patients treated with radical prostatectomy, in 29 patients treated with luteinizing hormone-releasing hormone agonists and antiandrogen therapy followed by radical prostatectomy, and in 16 patients with CRPC metastatic disease. In these three groups of patients, EGFR expression was found in, respectively, 41.4%, 75.9%, and 100% [7]. In particular, a change from paracrine to autocrine EGFR regulation has been shown in CRPC [8]. EGFR targeted therapies by using monoclonal antibodies or tyrosine kinase inhibitors (TKIs) have shown inhibition of tumor growth in androgen-dependent prostate cancer and CRPC [4].
Erlotinib is an orally active small-molecule TKI targeted against HER1/EGFR (ErbB1)-associated tyrosine kinase. Erlotinib has been demonstrated to significantly improve survival when given as a single agent to patients with relapsed non-small-cell lung cancer. This phase II monocentric study was conducted in order to evaluate the efficacy and safety of erlotinib monotherapy in advanced or metastatic prostate cancer.
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patients and methods |
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patients
The protocol was approved by the local ethics committee and all patients provided written informed consent before enrollment. Inclusion criteria for the study were histologically proven prostate cancer; elevated prostate-specific antigen (PSA)
5 ng/ml; advanced prostate cancer with progression after local treatment with metastatic or nonmetastatic disease, where progression was defined as PSA progression confirmed by three consecutive increases in PSA levels; Karnofsky performance status (KPS) 50%; adequate hematology; liver function; and biochemistry tests. Exclusion criteria were chemotherapy, radiotherapy, or estramustine therapy within the 4 weeks before study inclusion; any changes in hormonal treatment in the previous 60 days; unstable angina; New York Heart Association Class III–IV; myocardial infarction in the previous 6 months; pulmonary disease; and significant ophthalmologic abnormalities. Hormone sensitivity was not an exclusion criterion.
study design
The study was designed as a phase II, monocentric study. Patients were enrolled to receive erlotinib at a starting dose of 150 mg/day for 3 weeks. If no moderate to severe toxic effects had been reported in the first 3 weeks, the dose was increased to 200 mg/day at week 4 and maintained until disease progression. Disease progression was evaluated every 8 weeks and defined as >25% increase in PSA or new bone lesions or progressive measurable disease. In the event of moderate to severe toxicity, which was evaluated weekly for 4 weeks then monthly, treatment was stopped for up to 14 days for grade 3 toxicity until resolution to grade 
1. Erlotinib was then resumed at a reduced dose as follows: 200–150 mg then to 100 mg, or 150–100 mg then to 50 mg. Treatment was discontinued in the event of grade 4 toxicity. Toxicity was assessed according to the World Health Organisation criteria. Patients were monitored weekly during the first month of treatment, then monthly thereafter, and 30 days after the end of treatment.
The primary end point of the study was an absence of PSA progression without clinical progression defined by a PSA response of 50% reduction from baseline PSA levels, confirmed by a repeat determination at least 2 weeks later or PSA stabilization with no new bone lesions and no measurable disease progression.
Baseline PSA was measured at study entry, at day 1 of therapy cycle 1, and then monthly.
Secondary end points were evaluation of progression-free survival (PFS), overall survival, measurement of clinical benefit in symptomatic metastatic patients, quality of life (QoL), and safety profile. Tumor assessment was evaluated by physical examination, bone scan, and abdominal computed tomography (CT) scan within 28 days before study entry and then every 2 months. Responses were confirmed after a minimum period of 4 weeks. Time to PSA progression was defined as the time between study entry and determination of a PSA increase for >25% (and 5 ng/ml) over baseline or blood cell count nadir. Prostate-specific antigen-doubling time (PSADT) was calculated from natural logarithm of 2 (0.693) divided by the slope of the relationship between the log of PSA and time of PSA measurement for each patient [9]. Time to clinical disease progression was defined as the time between study entry and determination of clinical study progression (determined by bone scan, CT scan, magnetic resonance imaging, or pain), without PSA increase. Time to death was calculated from the date of study entry to death or last contact.
Clinical benefit, evaluated in metastatic symptomatic patients, was based on the KPS and pain was evaluated with the visual analog scale (VAS) [10] and morphine consumption. Clinical benefit was assessed at study entry, then monthly during therapy, and 4 weeks after the end of treatment [11]. Clinical benefit response was defined as an improvement in one of these parameters that sustained for >4 weeks, without the worsening of any other parameter.
For patients with a baseline pain intensity score 2, a positive pain intensity response was defined as an improvement of 50% from baseline sustained for 4 weeks. Patients’ self-evaluation was assessed monthly. Analgesic consumption was measured in morphine-equivalent milligram per day. A positive response was defined as a decrease of 50% from baseline sustained for 4 weeks (assuming a minimum analgesic consumption 10 mg/day at baseline). Improvement in the KPS was defined as a 20% increase from baseline sustained for 4 weeks (for patients with a KPS of 50–60–70).
Clinical benefit response was defined as an improvement sustained for 4 weeks of one of these parameters, without the worsening of any other.
Patient QoL [European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire for cancer patient (QLQ-C30)] was assessed before treatment, every 2 months during treatment, and at the end of the treatment [12, 13]. QoL was assessed by the EORTC QLQ-C30 scoring procedure. This 30-item questionnaire is cancer specific and has been validated for prostate carcinoma [14]. Authorization for its use was obtained from the EORTC Quality of Life Study Group (Brussels, Belgium).
statistical analysis
This phase II trial was planned using a Fleming two-stage design [15]. The two-stage design called for a maximum of 30 patients, 15 each in stage 1 and stage 2, and had type 1 error of 0.031 and power of 0.84. Two to four responders (or stabilized patients) among the first 15 patients were needed to justify beginning stage 2.
Survival curves were derived from Kaplan–Meier estimates. Statistical analysis was done using R.2.3.0 statistical software (R Development Core Team, http://www.r-project.org/).
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From April 2004 to February 2006, 30 patients were enrolled. Baseline patient characteristics and prior treatments for all patients are listed in Table 2. Median age was 69 years (range 51–77 years). In all, 28 patients had metastatic CRPC (93%) and 26 had bone metastases (93%). Median PSA was 102 ng/ml (range 3–1213 ng/ml), median PSADT was 1.9 months, and median velocity was 15.8 ng/ml/month. About 23 patients (77%) had previously received chemotherapy with a median of two lines (1–7), 21 of them having received taxane-based regimens.
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Based on toxicity, dose escalation was possible after 3 weeks in 16 (55%) patients. The median duration of treatment was 60 days (range 14–199 days). Dose reduction was required for 13% of patients due to toxicity. The most common toxicity grades were 1 and 2. Drug-related adverse events grade 1, 2 that occurred in >10% of patients were diarrhea (50%), cutaneous toxicity (23%), nausea (17%), and constipation (13%). Few grade III, IV toxic effects were observed (see Table 3).
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No complete or partial PSA response was observed in this study. Of the 29 efficacy-assessable patients, four (14%) had biologically stable disease (>50% reduction and >25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) that lasted for a median of 90.5 days (range 28–168 days). After the first 15 patients had been accrued, two patients had PSA stabilization so 15 more patients were included. At the final analysis only four had stabilization, which was less than the 20% PSA response or stabilization expected to conclude the efficacy of erlotinib. Ten patients were treated for
3 months, and the PSADT significantly increased from an average of 1.95 ng/ml/month before treatment to 3.91 ng/ml/month after 3 months of treatment (P = 0.006). As shown in Figure 1, the PSADT increased significantly in most of these patients. Median PSA PFS for all patients was 29 days [95% confidence interval (CI) 28 to 33]. The median clinical PFS was 70 days (95% CI 59 to infinity). Median survival was 17.4 months (95% CI 9.46 to infinity). All patients stopped therapy because of progressive disease.
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Twenty patients with metastatic symptomatic prostate cancer, were assessable for clinical benefit with one of these parameters at the time of study entry: KPS <80%, and/or VAS
2, and/or morphine consumption >10 mg. Clinical benefit evaluations, based on KPS and pain, were assessed monthly during therapy. Clinical benefit was achieved in 8 of 20 assessable patients (40%). Significant VAS decrease was observed for five patients (37.5%) without the worsening of any other parameter, two patients had increased KPS, and for one patient both KPS and VAS improved. QoL questionnaires were completed by 96.7% of the patients at baseline and the response rate was 79.3%, 85.7%, and 100%, respectively, for 2, 4, and 6 months and was 73.3% at the end of treatment. Functional patient scores decreased during treatment, and symptoms were worse than baseline scores. Physical and working capacities and social activity continued decreasing progressively after 2 months of treatment until the end of the treatment. Diarrhea and anorexia were the most frequent adverse events at 2 months, and pain, dyspnea, and fatigue were significantly higher than those at baseline. Stable global QoL was observed during treatment.
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discussion |
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Clinically advanced prostate cancer has been treated with hormonal therapy and, more recently, with chemotherapy. Targeted therapies have shown promising results in many solid tumors and the growing number of targeted agents is creating numerous opportunities for clinical research in advanced prostate cancer.
The choice of EGFR as a therapeutic target in this study was based on the known role of the EGF- and TGF--activated signaling in carcinogenesis and tumor progression in prostate cancer. Erlotinib has shown significant antitumor activity in a number of other epithelial cancers, including non-small-cell lung cancer and pancreatic carcinoma [16, 17]. Overexpression of EGFR in prostate cancer cells has led to the development of novel therapeutic approaches targeting EGF and its signal transduction cascade.
Although our study did not demonstrate any response with conventional response criteria, it demonstrated a PSA stabilization in four patients and the PSADT was significantly modified in 10 patients. Clinical benefit quantified by KPS, VAS, and morphine consumption was observed for 40% of patients. It is noteworthy that patients had variable stages of disease: two patients had only PSA progression after local treatment and one of them had not received any hormonal therapy. For men who develop an elevated PSA after radical prostatectomy and/or radiotherapy, the delay before initiating hormonal therapy has not been determined. It was possible, in this situation, to evaluate erlotinib efficacy because patients were evaluated monthly by PSA assay and erlotinib was discontinued in case of biological progression for androgen blockade. About 93% were metastatic with CRPC disease and most of them had previously received first- or second-line treatment of metastatic or advanced prostate cancer. A previous study using a small-molecule TKI targeted to EGFR (gefitinib) reported no activity in CRPC, as was observed with other inhibitors of the HER kinase family (trastuzumab and pertuzumab) [18–20].
Was PSA decrease or stabilization a good end point for assessing a possible response to this molecule? It appears that the results obtained with radiographic PFS and/or PSA PFS for men with CRPC are not strongly concordant with survival times [21]. PSA levels present great variability among patients, which may be explained by different PSA expression in prostate cancer cells as well as tumor cell heterogeneity. Several experimental agents have been shown to increase PSA expression in in vitro models. Recently, a phase II study of sorafenib has shown an improvement in metastatic lesions with an increase in PSA and in vitro studies have indicated that PSA increases with sorafenib [22]. A short PSADT before onset of chemotherapy in CRPC was, however, associated with increased risk of death [23]. Understanding which biomarker predicts response to erlotinib is probably important for its application in the metastatic setting.
In this study, the most common adverse events were diarrhea and cutaneous toxicity. These events resolved in most patients and no therapy withdrawal for toxicity was observed. The toxicity profile of erlotinib in this study confirmed the safety of the starting dose of 150 mg/day. A higher dose of 200 mg was possible only in 55.17% of patients without cutaneous or digestive toxicity.
Median duration of treatment was 60 days (range 14–199 days). Generally, treatment was stopped because of disease progression. Twenty-eight patients had a median PSA increase delay of 29 days (95% CI: 28–33). It could be argued that the disease evaluation in our study was too early and that the conclusion of treatment inefficacy was based solely on PSA progression. Recently, at the meeting of the American Society of Clinical Oncology held in 2007, the Prostate Cancer Clinical Trials Working Group consensus criteria for phase II trials of CRPC recommended to treat for a minimum of 12 weeks before assessing disease status. Changes in bone scan should be reported as new lesions or no new lesions. Progression should be confirmed with a second scan [24]. Based on the above criteria, it could be postulated that a different study design would give different results. The median survival observed in this study (17.4 months) was rather longer than that observed in other phase II trials in taxane pretreated metastatic CRPC (13 months) [25]. Without a phase III trial, however, it is impossible to determine the real survival impact of erlotinib in this situation.
Previous reports indicate that mutations in the EGFR gene are associated with sensitivity to gefitinib and erlotinib in lung cancer [26–28]. EGFR expression levels and mutations have not been evaluated on the tumor in this study.
A phase II study using another EGFR kinase inhibitor, gefitinib, in metastatic CRPC demonstrated neither PSA response nor objective responses according to response evaluation criteria in solid tumors criteria [29]. Exons 18–21 of the EGFR tyrosine kinase (TK) domain were sequenced from the genomic DNA of eight patients. No mutations in the EGFR TK domain were detected.
The inclusion of erlotinib in combination with other targeted agents should be investigated in preclinical and in clinical settings, in order to define the best combination with respect to efficacy and tolerability. A phase I study of gefitinib combined with docetaxel and estramustine in CRPC demonstrated acceptable and predictable tolerability [30]. A phase II trial of docetaxel and erlotinib as first-line treatment for CRPC has shown comparable anticancer activity with increased toxicity [31]. It was unclear whether an orally active EGFR inhibitor provides additional clinical benefit over each drug alone.
The low or no activity observed with HER kinase inhibitors may indicate that this target does not have a primary pathogenic role in this disease.
The major difficulty is the correct evaluation of such an activity. An important in short-term goal is to identify a molecular signature for detecting patients who could benefit from such therapy.
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Roche.
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Received for publication December 12, 2007. Revision received March 14, 2008. Revision received March 20, 2008. Accepted for publication March 26, 2008.
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