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Clinical Cancer Research 14, 209, January 1, 2008. doi: 10.1158/1078-0432.CCR-07-1355
© 2008 American Association for Cancer Research
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Cancer Therapy: Clinical

A Phase II Clinical Trial of Sorafenib in Androgen-Independent Prostate Cancer

William L. Dahut2, Charity Scripture1,2, Edwin Posadas2, Lokesh Jain1,2,6, James L. Gulley2, Philip M. Arlen2, John J. Wright2,4, Yunkai Yu2, Liang Cao2, Seth M. Steinberg3, Jeanny B. Aragon-Ching2, Jürgen Venitz6, Elizabeth Jones5, Clara C. Chen5 and William D. Figg1,2,6

Authors' Affiliations: 1 Clinical Pharmacology Program, 2 Medical Oncology Branch, and 3 Biostatistics and Data Management Section, Center for Cancer Research, and the 4 Cancer Therapy and Evaluation Program, 5 National Cancer Institute, Bethesda, Maryland; and 6 Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia

Requests for reprints: William D. Figg, Medical Oncology Branch, National Cancer Institute, Building 10, Room 5A01, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-402-3623; Fax: 301-402-8606; E-mail: wdfigg{at}helix.nih.gov.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC).

Experimental Design: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles.

Results: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimenn. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC0-12) and maximum concentration (Cmax) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (tmax) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively.

Conclusions: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.

Sorafenib is a novel, oral multikinase inhibitor that has activity against Raf kinase (serine-threonine kinase) and tyrosine kinases including vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, c-kit, and c-Ret. It has been approved for the treatment of metastatic renal cell cancer (1). It inhibits tumor cell proliferation by targeting the Ras/Raf/Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling pathway at the level of Raf kinase, and exerts its antiangiogenic effect by targeting the receptor tyrosine kinases VEGF receptor 2, VEGF receptor 3, and platelet-derived growth factor receptor, and their associated signaling cascades (2). It is also found to induce apoptosis in several human cancer cell lines by down-regulating the levels of antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1; ref. 3).

Angiogenesis, the formation of new microvessels from existing vasculature, is necessary for progressive tumor growth (4). VEGF, a proangiogenic factor, and its receptor have also been shown to be important in prostate cancer. Angiogenesis is an important step in the progression of prostate cancer from early to advanced disease (5–7) and is an essential step in the metastasis of solid tumors (8, 9). Sorafenib has shown activity in preclinical tumor xenograft models of prostate cancer (Bayer data on file). Clinically, antiangiogenic agents have shown efficacy in the treatment of prostate cancer (10–13). Accumulating evidence suggests that the Ras/Raf/mitogen-activated protein kinase/ERK signaling pathway is dysregulated in the setting of androgen-independent prostate cancer (AIPC; refs. 14–16). Therefore, inhibition of angiogenesis in combination with Raf inhibition may be a viable strategy for the treatment of AIPC.

It is hypothesized that sorafenib will affect molecular signals downstream of both VEGF receptor and Raf kinase and thereby inhibits cell proliferation and angiogenesis signaling resulting in tumor regression. To evaluate the effect of sorafenib in metastatic AIPC, a single-arm, phase II, open-label clinical trial was conducted to assess the anticancer efficacy, toxicity, and pharmacokinetics in this tumor type.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Patient selection. Eligible patients had histologically proven progressive metastatic androgen-independent adenocarcinoma of the prostate with radiographic evidence of disease. Criteria for progressive disease included an expanding measurable lesion, the presence of a new lesion, and/or an increasing prostate-specific antigen (PSA) level on successive measurements. Additional eligibility criteria were exposure to no more than one previous cytotoxic chemotherapy; Eastern Cooperative Oncology Group performance status of 0 to 2; life expectancy of ≥12 weeks; a castrated level of testosterone (<50 ng/mL) achieved by bilateral orchiectomy or administration of lutenizing hormone–releasing hormone agonist; and adequate organ function as defined by the following biological criteria: leukocytes ≥3,000/µL, granulocyte count ≥1,500/µL, platelet count ≥100,000/µL, total serum bilirubin ≤1.5 x institutional upper limit of normal, transaminases (aspartate aminotransferase and alanine aminotransferase) ≤2.5 x upper limit of normal, and creatinine ≤1.5 x upper limit of normal or creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above upper limit of normal.

Patients had to have adequate antiandrogen withdrawal, off prior chemotherapy within 4 weeks, and without existing brain metastasis, bleeding diathesis, or uncontrolled intercurrent illnesses. Concurrent use of bisphosphonates was permitted for patients with known bone metastases. Patients with a history of hypertension (as defined by a systolic blood pressure >170 mm Hg or a diastolic pressure >100 mm Hg), which was well controlled on medication, were eligible for enrollment. Use of verapamil or diltiazem was not permitted while on study due to potential for drug interaction. The concomitant use of other CYP3A substrates and herbal supplements was discouraged.

Study design. This study was designed to be an open-label, single-center, phase II clinical trial using a two-stage optimal design. The study was approved by the National Cancer Institute Institutional Review Board and all patients on study signed the informed consent. Patients received 400 mg sorafenib orally twice daily for each day of a 28-day cycle. Radiographic assessments were done within 1 month of enrollment and every two cycles thereafter. Confirmatory scans were repeated 4 weeks following initial documentation of objective response. Response and progression were evaluated using the Response Evaluation Criteria in Solid Tumors (17). For bone scans, progression was defined as appearance of a new lesion, and improvement was defined as the complete resolution of at least one lesion.

The primary end point was disease progression defined as either the appearance of new lesions or unidimensional or bidimensional tumor measurements increasing >50%, or increase in PSA according to Prostate-Specific Antigen Working Group definitions (18) or symptomatic progression. Secondary end points included measurement of overall response rate and overall survival; demonstration of biological effect by sorafenib in the patient and on the tumor (when possible) via correlative studies done on serially obtained tissue biopsies, bone marrow biopsies, and WBC collections; measurement of the pharmacokinetics of sorafenib in patients with prostate cancer; and description of the PSA response rate to therapy with sorafenib.

Statistical considerations. A two-stage optimal design, as described by Simon (19), was used to rule out a 30% probability of 4-month progression-free survival while targeting a 50% probability of patients having 4-month progression-free survival. Conventional error probabilities of {alpha} = 0.10 and β = 0.10 were used. Sorafenib would be considered inactive if the proportion of patients with progression-free survival at the 4th monthly evaluation was consistent with a poor 30% rate but not consistent with a rate as high as 50%. Using these parameters, 22 patients were to be enrolled initially and evaluated for progression at 4 months. If 7 or fewer patients were found to be progression-free at the 4-month evaluation, then no further patients were to be enrolled. If 8 or more patients had not progressed by that time, then enrollment was to be allowed to continue until 46 patients were enrolled. Under the design, if the true rate of 4-month progression-free survival was 30%, the probability of early termination was 67%. Because of the results obtained during the study, the design was modified to allow accrual to the full 46 patients following a change of end point evaluation that was felt to be desirable in view of the interim findings.

Sample collection and processing. Sorafenib doses were administered twice daily at 0 and 12 h, and blood samples were collected on day 1 immediately before the first dose (baseline) and at 0.25, 0.50, 1, 2, 4, 6, 8, 12, and 24 h after the ingestion of initial doses. Blood samples were collected into heparinized tubes using an indwelling venous catheter. Immediately after collection, all blood samples were centrifuged at 1,200 x g for 15 min at 4°C; plasma was separated and stored at –80°C.

Pharmacokinetics. Sorafenib concentrations in plasma samples were determined using a validated liquid chromatography-tandem mass spectrometry method (20). Briefly, to 50 µL of plasma sample, 0.5 mL of acetonitrile containing internal standard ([2H3,15N]sorafenib) was added followed by centrifugation for 10 min at 13,063 x g. The 25-µL volume of supernatant was injected onto the column and isocratic elution was done with an acetonitrile/water 90:10 (v/v) mobile phase. The workable concentration range for the method was 5 to 2,000 ng/mL, with mean accuracy and precision for quality control samples ranging from 92.86% to 99.88% and 1.19% to 4.53%, respectively. For samples in which initial analysis determined the sorafenib concentration to be above the upper limit of quantification, a validated sample dilution was carried out.

Pharmacokinetic parameters, including area under the curve (AUC0-12), maximum concentration (Cmax), and time to maximum concentration (tmax) for sorafenib, were evaluated by noncompartmental analysis using WinNonlin professional software version 5.0 (Pharsight Corp.). Statistical analysis was done with JMP statistical software version 5.1 (SAS Institute). The accumulation after second dose was calculated as the ratio of sorafenib concentration at 24 h to that at 12 h, for each individual patient.

Dose modifications. Toxicities were reported using the Common Toxicity Criteria for Adverse Events version 3. Dose adjustments were made based on the reported toxicities that were attributed to sorafenib therapy. For grade 4 clinical toxicity (except pulmonary embolism without significant hypoxia and hemodynamic instability), patients were to be taken off the study permanently. For grade 3 clinical toxicity or grade 3 or grade 4 metabolic/hematologic toxicity, sorafenib was held and the patients were evaluated at least weekly until toxicity improved to grade ≤1 or pretreatment baseline. Treatment was discontinued in patients who experienced grade ≥3 or grade 4 toxicities that did not resolve to grade ≤1 or baseline within 3 weeks. No dose interruptions were made for grade 1 toxicities. Grade 2 nausea, vomiting, or diarrhea was managed symptomatically without reduction in the dose of sorafenib. However, if symptoms persisted despite symptomatic treatment, the dose of sorafenib was reduced to 200 mg/d. Other grade 2 toxicities did not warrant a dose reduction unless side effects became intolerable to the patient. Further dose reductions were permitted to 200 mg daily. However, reductions below this dose/schedule were not allowed. Patients with intolerable or limiting toxicities while on daily dose of 200 mg sorafenib were taken off the study.

Patients were required to have their blood pressure measured and recorded weekly during the first 4 weeks of treatment with sorafenib and as needed thereafter. Sorafenib was discontinued for grade 4 hypertension and was held for patients who developed grade 3 or symptomatic grade 2 hypertension with administration of antihypertensive agents for treatment. Patients whose hypertension was well controlled resumed sorafenib at reduced doses of 200 mg/d.

PSA expression in LNCaP cells. LNCaP (from American Type Culture Collection) cells were grown per specifications in RPMI 1640 (21). PSA expression experiments were done as described by Dixon et al. (22). Cells were treated with varying concentrations of sorafenib solubilized in DMSO (final concentration, <1%). The treatment was repeated successively at 24-h interval. In cells for which PSA was to be analyzed at the 48th hour, treatment was repeated at the 24th hour; in cells for which PSA was to be analyzed at the 72nd hour, treatment was repeated at the 24th and 48th hours. PSA measurements were taken every 24 h using a PSA ELISA kit (Alpha Diagnostics). Cell count was done using Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc.).

Analysis of phospho-ERK in bone marrow biopsies. Cell lysates were prepared from snap-frozen bone marrow biopsies using the FastPrep system in the presence of phosphatase inhibitors. Samples were normalized against protein concentrations. The phospho-ERK (pERK) assay was done with MSD multiplex mitogen-activated protein kinase reagents (Meso-Scale Discovery). The pERK levels were determined based on standard curve generated with recombinant pERK2 (R&D Systems). Quality assurance was based on all sample data, which were found to be within the range of pERK standards. Lysate from HT-29 treated with sorafenib gave >3-fold reduction of pERK levels compared with control.


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics. Twenty-two patients were enrolled between September 2004 and April 2005. The baseline clinical and biological characteristics are presented in Table 1 . The median age of patients was 63.9 years and PSA concentration at study entry was 53.3 ng/mL. Of these 22 patients, 55% had only bone metastases whereas the remaining patients had metastases in other soft tissues along with bone metastases.


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  		Table 1. Patients' baseline characteristics

 
Exposure to study medication. All patients received at least one cycle of treatment. Protocol-required dose reductions for the management of sorafenib toxicity were necessary for six patients.

Response to therapy. No complete or partial response was noted in all 22 patients who received at least one cycle of treatment. No patient had a PSA decline of >50%. Seven patients were progression-free by PSA criteria at 4 months (Fig. 1 ). Of the remaining 15 patients, one refused further treatment and the rest progressed at or before 4 months. The median progression-free survival duration was 1.8 months. Nine of the 14 patients who progressed at or before 4 months progressed only by PSA consensus criteria. Six patients with PSA progression had a decrease in PSA immediately after discontinuation of study agent (23). However, it is noteworthy that two patients showed improvement of metastatic lesions on bone scan. As a result, although the proportion of patients who were progression-free at 4 months was too low by the original design to permit accrual to a second stage, the study was amended to obtain more information about disease progression with this agent when followed by clinical and radiographical criteria alone. Remarkably, of all the patients who had bone metastasis, only four patients had worsening of bone scans on disease progression. Overall response rate and overall survival were not determined at this stage but will be calculated for the whole patient data set inclusive of both the stage I and II results.


Figure 1
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  		Fig. 1. Kaplan-Meier progression-free survival for all the patients enrolled onto the first stage of study.

 
Safety. Sorafenib was generally well tolerated and had manageable side effects. The intensity of these events was usually mild to moderate. Most side effects were of short duration and resolved without incident. The highest grade of observed toxicity per patient is summarized in Table 2 . Grade 1 and 2 toxicities that occurred in >10% of patients and all grade 3 and 4 toxicities are listed. Grade 3 toxicities included hypertension, hyponatremia, and hand-foot syndrome. Skin rash was reported in 59% patients.


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  		Table 2. Toxicities during sorafenib treatment (n = 22 patients)

 
Pharmacokinetics. Plasma concentration-time profile for patients, with mean plasma concentration (± SE) indicated on the ordinate, is shown in Fig. 2 . The estimated pharmacokinetic parameters AUC0-12, Cmax, and tmax after first dose of sorafenib showed high variability among patients. The distributions for AUC0-12 and Cmax were found to be skewed, so a log transformation was used to stabilize the variance and make the distribution more normal. The analysis was done on transformed values and the results were back-transformed to original scale for description. The geometric mean for exposure of sorafenib following first dose, as measured by AUC0-12, was 9.76 h mg/L (95% confidence interval, 6.76-14.09) and for Cmax was 1.28 mg/L (95% confidence interval, 0.88-1.87). The percent coefficients of variance (CV) for AUC0-12 and Cmax were 82.56% and 106.13%, respectively. This is consistent with the literature (24–26) where percent CVs for AUC0-12 and Cmax after 400 mg twice daily oral dosing ranged between 43% and 90.5% and between 44% and 106.7%, respectively. The time to maximum concentration ranged from 2 to 12 h, with a median value of 6 h. The accumulation ratio after second dose ranged from 0.68 to 6.43 with a median value of 1.84.


Figure 2
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  		Fig. 2. Mean plasma concentration of sorafenib after administration of initial doses of 400 mg twice daily dosing schedule (n = 22). Bars, SE.

 
In vitro assessment of PSA secretion. After repeated exposure of LNCaP cells to sorafenib, the cumulative concentrations of secreted PSA were shown to increase with increasing drug concentration, as shown in Fig. 3 . However, after treatment with 10 µmol/L sorafenib, significant cell death was observed. After re-treatment at 24 h with 10 µmol/L sorafenib, both the PSA concentrations and cell count were not quantifiable using the assay methods. Sorafenib was found to induce cell death in LNCaP cells in a dose-dependent manner.


Figure 3
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  		Fig. 3. A, cumulative PSA (normalized to cell count) over 72 h. B, cell count–normalized PSA in successive 24-h duration after treatment of LNCaP cells with DMSO only, 2.5, 5.0, and 10.0 µmol/L sorafenib. Bars, SD.

 
Biomarker evaluation. Sorafenib inhibits Raf kinases, which are upstream of pERK. Thus, pERK was explored as a potential biomarker for sorafenib activity. Figure 4 shows a dose-dependent decrease in the amount of pERK in HT-29 cells following treatment with sorafenib. In Fig. 5 , analysis of pERK in bone marrow biopsies did not show a consistent reduction in pERK. However, the quantity of pERK decreased in a patient showing improvement in bone scan lesions following sorafenib treatment (27).


Figure 4
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  		Fig. 4. Sorafenib inhibits pERK and induces cancer cell death. A, survival of HT-29 cells following 3 d of sorafenib (Bay) treatment were determined by ATPLite assay (Perkin-Elmer) where relative luminescence units (RLU) were plotted. B, immunoblot analysis of total and pERK following sorafenib treatment at indicated levels for 4 h. C, the quantitative measurement of pERK protein was determined with a pERK immunoassay (Meso-Scale Discovery).

 

Figure 5
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  		Fig. 5. Analysis of pERK in bone marrow biopsies following sorafenib treatment. A, detection of pERK by immunoassay (Meso-Scale Discovery). pERK standards were obtained from R&D Systems. Relative luminescence units were plotted. HT-29 lysates and HT-29 Bay (10 µmol/L sorafenib) lysates were used as controls. Sorafenib at 10 µmol/L results in a 3-fold reduction of pERK in HT-29. B, standard curve for pERK with a recombinant pERK (R&D System). This protein provides a control for quantification of ERK1 Thr202/Tyr204 or ERK2 Thr185/Tyr187. C, levels of pERK in bone marrow biopsies from patients treated with sorafenib as picograms of pERK per milligram of total tissue lysate.

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
This is the first phase II trial of sorafenib in patients with AIPC. Experience to date suggests that sorafenib given on a continuous dosing schedule of 400 mg twice daily is tolerated by patients with AIPC.

Pharmacokinetics results for AUC0-12, Cmax, and tmax after first oral dose indicate variability in rate and extent of sorafenib absorption. This could partly be explained by the lack of restriction on food intake before and after drug administration, given the fact that sorafenib bioavailability is altered when coadministered with food as compared with the fasted state (1). An accumulation ratio of >1 indicates drug accumulation after multiple dosing and is expected based on sorafenib mean elimination half life ranging from 25 to 48 h (1).

In vitro studies suggested that PSA is not necessarily a good marker of sorafenib activity because PSA seems to increase with sorafenib treatment in LNCaP prostate cancer cell lines while exhibiting simultaneous cell growth inhibition. In vitro results are in concordance with clinical findings in which 17 of the 22 patients showed increase in PSA concentrations from baseline after the first cycle of treatment. Notably, 13 of the 21 patients progressed only by PSA criteria, and 6 of these patients were found to have a decline in PSA after the drug was discontinued (in the absence of initiating another treatment). Remarkably, two patients who experienced a continuous increase in PSA while receiving sorafenib showed an improvement in metastatic lesions on bone scan after two and four cycles of treatment, respectively; one patient reported a significant decrease in narcotic requirements for pain management.

Similar to sorafenib, several other experimental agents have been shown to increase PSA secretion in in vitro models, including TNP-470, sodium phenylacetate, and phenylbutyrate (28). These agents also clinically increase PSA concentrations, which decline on their discontinuation. Changes in PSA secretion are thought to be, in part, due to drug-induced increase in PSA transcriptional activity. These observations suggest that PSA may not be a true marker of disease progression or tumor burden especially in patients being treated with agents that may increase PSA secretion, such as sorafenib. Therefore, in this select group of patients, the increase in PSA is not associated with disease progression.

All the patients had bone metastasis (Table 1), but only four patients had worsening of metastatic lesions on bone scans (Table 3 ) on disease progression. These results suggest that sorafenib may have a role in patients with metastatic bone lesions. This may be secondary to the inhibition of the ERK/mitogen-activated protein kinase pathway resulting in suppression of osteopontin-induced cell migration, which is thought to be one of the mechanisms causing tumor cell metastasis to bone (29).


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  		Table 3. Response to treatment

 
Overall results indicate that sorafenib might be efficacious in AIPC patients presenting primarily with metastatic bone lesions and that PSA seems to be a poor marker of disease progression in AIPC. Therefore, the protocol has been amended to reflect the clinical and radiographic measurements as the criteria of disease progression. Further accrual to stage II of this trial is currently ongoing. Evidence suggests that the modulation of the Ras/Raf/ERK/mitogen-activated protein kinase pathway may have clinical benefits in AIPC.


   Acknowledgments
 
We thank the nursing staff of National Cancer Institute and the fellows of the Medical Oncology Branch at National Cancer Institute for their care of our patients; Dr. Howard Parnes for his assistance in the conduct of this trial; Cynthia Graves for data management assistance; and Cancer Therapy and Evaluation Program for sponsoring the trial. Most importantly, we appreciate the patients with cancer who enroll in investigational trials to advance on the knowledge of this disease.


   Footnotes
 
Grant support: Intramural Research Program of the National Cancer Institute.

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.

Note: This is a U.S. Government work. There are no restrictions on its use. The views expressed within this article do not necessarily reflect those of the U.S. Government.

Received 6/ 1/07; revised 8/30/07; accepted 9/27/07.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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M. Dror Michaelson, M. M. Regan, W. K. Oh, D. S. Kaufman, K. Olivier, S. Z. Michaelson, B. Spicer, C. Gurski, P. W. Kantoff, and M. R. Smith
Phase II study of sunitinib in men with advanced prostate cancer
Ann. Onc., May 1, 2009; 20(5): 913 - 920.
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N. S. Azad, J. B. Aragon-Ching, W. L. Dahut, M. Gutierrez, W. D. Figg, L. Jain, S. M. Steinberg, M. L. Turner, E. C. Kohn, and H. H. Kong
Hand-Foot Skin Reaction Increases with Cumulative Sorafenib Dose and with Combination Anti-Vascular Endothelial Growth Factor Therapy
Clin. Cancer Res., February 15, 2009; 15(4): 1411 - 1416.
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G. Colloca, F. Checcaglini, and A. Venturino
About sorafenib in castration-resistant prostate cancer
Ann. Onc., October 1, 2008; 19(10): 1812 - 1813.
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G. Gravis, F. Bladou, N. Salem, A. Goncalves, B. Esterni, J. Walz, S. Bagattini, M. Marcy, S. Brunelle, and P. Viens
Results from a monocentric phase II trial of erlotinib in patients with metastatic prostate cancer
Ann. Onc., September 1, 2008; 19(9): 1624 - 1628.
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