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Efficacy and Safety of Single-Agent Pertuzumab (rhuMAb 2C4), a Human Epidermal Growth Factor Receptor Dimerization Inhibitor, in Castration-Resistant Prostate Cancer After Progression From Taxane-Based Therapy

David B. Agus, Christopher J. Sweeney, Michael J. Morris, David S. Mendelson, Douglas G. McNeel, Frederick R. Ahmann, Jin Wang, Mika K. Derynck, Kimmie Ng, Benjamin Lyons, David E. Allison, Michael W. Kattan, Howard I. Scher

From the Cedars-Sinai Prostate Cancer Center, Los Angeles; Genentech Inc, South San Francisco, CA; Indiana University Medical Center, Indianapolis, IN; Memorial Sloan-Kettering Cancer Center, New York, NY; Premiere Oncology of Arizona, Scottsdale; Arizona Cancer Center, Tucson, AZ; University of Wisconsin, Madison, WI; and the Cleveland Clinic Foundation, Cleveland, OH

Address reprint requests to David B. Agus, MD, Cedars-Sinai Prostate Cancer Center, 8631 West Third St, Suite 215E, Los Angeles, CA 90048; e-mail: David.Agus{at}cshs.org

	ABSTRACT

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PURPOSE: Pertuzumab represents a new class of targeted anticancer agents, human epidermal growth factor receptor (HER) dimerization inhibitors. The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent pertuzumab in castration-resistant prostate cancer (CRPC) patients who had experienced progression after prior chemotherapy.

PATIENTS AND METHODS: Patients received pertuzumab every 3 weeks. All castration-resistant patients had experienced progression after at least one taxane-based regimen. Patients received a loading dose of 840 mg pertuzumab (cycle 1) followed by 420 mg for subsequent cycles. The primary end point was overall response and safety. A separate retrospective analysis of actual survival time versus predicted survival time for a patient population with comparable prognostic features was performed.

RESULTS: Patients were enrolled (N = 42) and treated (n = 41). No patients had complete or partial response (as defined by Response Evaluation Criteria in Solid Tumors Group or 50% decline in prostate-specific antigen). Of 30 efficacy-assessable patients, five had stable disease (SD) for at least 23 weeks; one of five had SD for 36 weeks. Pertuzumab was well tolerated; diarrhea was the most common adverse effect (61.0%, grades 1 to 3). Retrospective analysis of survival using a validated nomogram suggested that survival was prolonged with pertuzumab treatment, compared with historic controls with similar baseline prognostic features.

CONCLUSION: Pertuzumab was well tolerated and resulted in no objective responses, but several patients had SD more than 23 weeks from a heavily pretreated population. Retrospective analysis suggested prolonged median survival time with pertuzumab compared with historical controls. Thus, inhibition of HER dimerization may have clinical utility in CRPC patients.

	INTRODUCTION

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A milestone in prostate cancer management was the demonstration, for the first time, that systemic taxane-based chemotherapy prolonged the lives of men with progressive castration-resistant prostate cancer (CRPC).^1,2 These clinical trials led to approval of docetaxel, and established a new treatment standard for patients with CRPC. Not all of these patients respond to taxane-based therapy, and they eventually experience progression with a median survival of only 12 months.³ With an established first-line standard chemotherapy treatment of docetaxel, drug development efforts are now focusing on docetaxel combinations designed to improve outcomes as first-line therapy, and separately, to identify therapeutic approaches for those who have experienced treatment failure after this therapy.

The human epidermal growth factor receptor (HER) family of receptors (HER1/epidermal growth factor receptor [EGFR], HER2, HER3, HER4) dimerize and activate intracellular signaling pathways (mitogen-activated protein kinase and phosphatidylinositol 3-kinase), leading to cellular growth, proliferation, and survival.^4,5 HER and associated ligands play a key role in normal prostate function, whereas upregulation of HER signaling leads to activation of androgen receptor–mediated signaling pathways that promote tumor growth and progression to castration resistance.^6-9 HER2, the preferred partner for dimer formation with ligand-activated HER receptors,^6,10-13 has been associated with progression to castration resistance.^14,15 Several proposed mechanisms include increased expression of HER2, ligand activation of HER dimerization partners (especially EGFR), constitutive activation of HER2 heterodimers, and ligand-independent activation of the androgen receptor. Autocrine hypersecretion of EGFR ligands (eg, transforming growth factor alpha), may also contribute to tumor progression¹⁶ and has been associated with androgen independence in prostate cancer cell lines.¹⁷ Expression-profiling studies of prostate cancers that have progressed after castration show a high frequency of HER expression relative to untreated hormone-naïve primary tumors.^14,18 In addition, preferential dimerization of EGFR with HER2 has been shown to contribute to tumor growth, particularly at castrate hormonal levels.¹⁹ Recently, androgen-mediated signaling has been linked to the HER-kinase axis.²⁰ Indeed, HER2/HER3 heterodimers have been shown to associate with androgen receptor transactivation and contribute to the proliferation signal.²¹ Inhibition of HER dimerization, therefore, is a rational target in CRPC.

Pertuzumab (Omnitarg; rhuMAb 2C4; Genentech Inc, South San Francisco, CA), a humanized monoclonal antibody based on an immunoglobulin G1() framework directed at an epitope in the HER2 dimerization domain²² is the first of a new class of HER dimerization inhibitors. When bound, pertuzumab inhibits the ability of HER2 to dimerize or pair with other HER receptors, preventing the activation of HER tyrosine kinase signaling¹⁷ and blocking pathways that mediate tumor growth.²³ Inhibition of ligand-dependent heterodimerization with pertuzumab effectively inhibits tumor growth and diminishes mitogen-activated protein kinase and phosphatidylinositol 3-kinase activity in both androgen-dependent and androgen-independent prostate cancer xenograft models.¹⁷ Antitumor activity of pertuzumab was demonstrated in a phase I clinical trial in 21 patients with advanced cancers including CRPC (n = 5),²⁴ including tumor regression in one patient and stable disease (SD) of 2.5 months in three patients.

Previous trials using targeted biologic agents as monotherapy in patients with advanced prostate cancer have proved unsuccessful,²⁵ and to date few trials with agents of this type have been conducted in this patient group. Based on the promising preclinical and early clinical observations, this phase II clinical trial was initiated to assess the safety and efficacy of pertuzumab in patients who had experienced progression after taxane-based chemotherapy. Retrospectively, the survival of treated patients was related to the predicted survival using a validated clinical outcome nomogram.²⁶

	PATIENTS AND METHODS

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Patient Population
The study population consisted of patients with CRPC who had experienced progression after one to two regimens of chemotherapy, of which one included a microtubule inhibitor. All patients provided written informed consent and the protocol was approved by institutional review boards at participating institutions. All patients had an Eastern Cooperative Group performance status of 0 or 1 and a life expectancy of more than 12 weeks. Adenocarcinoma of the prostate was confirmed histologically and disease progression was determined by three consecutive increasing prostate-specific antigen (PSA) levels, measurable disease (evaluated using Response Evaluation Criteria in Solid Tumors Group [RECIST]), or one or more new bone lesions.²⁷ Castrate levels of testosterone were maintained by a luteinizing hormone-releasing hormone agonist (< 50 ng/mL) for nonorchiectomy patients with antiandrogen treatment ceasing at least 4 weeks before study day 1 (6 weeks for nilutamide and bicalutamide). Adequate hematology, liver function, and biochemistry tests were required. Key exclusion criteria included evidence of CNS metastases; prior treatment with HER-targeted agents; left ventricular ejection fraction (LVEF) less than 50%; significant anthracycline exposure (doxorubicin > 360 mg/m², mitoxantrone > 120 mg/m², or idarubicin > 90 mg/m²); and prior chemotherapy, radiotherapy, therapeutic radionucleotide, or immunotherapy within 4 weeks of trial day 1. Ongoing corticosteroid treatment was excluded except for stable (< 20 mg) daily doses of prednisone for reasons other than prostate cancer.

Treatment Schedule
This was a single-arm, open-label, multicenter trial. Patients only received pertuzumab (a loading dose [840 mg] for the first cycle of treatment followed by 420 mg for cycle 2 and beyond). Each cycle lasted 3 weeks. Pertuzumab was provided by Genentech Inc as a single-use formulation containing 25 mg/mL (175 mg per 10 mL vial) pertuzumab (rhuMAb 2C4) in 10 mmol/L histidine (pH 6.0), 240 mmol/L sucros, and 0.02% Tween-20. Pertuzumab was added to 250 mL 0.9% NaCl USP for intravenous infusion during 90 (cycle 1) or 30 minutes (subsequent cycles).

Response Rates and Disease Progression
Primary efficacy outcome measures were investigator-assessed best overall response at any time during the study, and progression of disease at 3 months (determined by RECIST^27,28 in efficacy-assessable patients who received at least one dose of pertuzumab and one postbaseline assessment, or died before assessment). Secondary end points included duration of response, time to progression, and progression at 6, 9, and 12 months on study. Tumor assessments were evaluated by physical examination and image-based evaluation within 28 days before study day 1 and then every four cycles (12 weeks). Assessments included a bone scan and computed tomography scan or magnetic resonance imaging of the chest, abdomen, and pelvis. The same radiographic procedure used at baseline was used throughout the study. Measurable responses were confirmed after a minimum period of 4 weeks. Time to disease progression was defined as the time from study start to determination of disease progression. Duration of response was defined as the time from the initial response to the time of disease progression.

Baseline PSA was measured within 2 weeks of study day 1, cycle 1. Thereafter, PSA measurements were taken on day 1 of every cycle before pertuzumab infusion. PSA response was defined as a confirmed decline of 50%. PSA response date was defined as the date of the first 50% decline. Progressive disease was defined as a more than 50% (and 5 ng/mL) PSA increase over baseline or nadir, whichever was lower.

Safety and Tolerability
Incidence, nature, severity, and relatedness of adverse events were graded according to National Cancer Institute Common Toxicity Criteria (version 2.0). Clinical evaluations were performed on day 1 of each cycle. Special attention was paid to cardiac function, infusion-related symptoms, and allergic reactions. Laboratory assessments (serum chemistries, blood counts, PSA) were performed locally at each cycle.

Cardiac Toxicity
Cardiac function was monitored because of potential cardiotoxicity associated with HER2 inhibition.²⁹ Cardiac toxicity evaluations included changes in LVEF and serum levels of troponin T. LVEF was measured locally by two-dimensional echocardiographic scan (ECHO) or multiple gated acquisition (MUGA) at baseline and every 4 cycles. Where possible, LVEF was confirmed at a central laboratory (Gentiae, San Bruno, CA). Serum samples for measurement of cardiac troponin T were collected at every treatment cycle.

Statistical Analysis
Study design and sample size were based on response rate in accordance with a Simon two-stage design.³⁰ If at least two responses were observed (by RECIST criteria), an additional 20 patients would be enrolled for a maximum of 45 patients. Primary efficacy analysis included all efficacy-assessable patients. The 95% Blyth-Still-Casella exact CI was calculated for the rate of best overall response and the rate of progression. Six responders (13%) or more would merit additional study of pertuzumab as a single agent.

Survival Analysis
Under separate protocols approved by the institutional review boards, baseline prognostic factors were analyzed retrospectively using a validated nomogram for survival. This nomogram uses pretreatment age, Karnofsky performance scale (generated by converting Eastern Cooperative Group performance status), hemoglobin, PSA, lactate dehydrogenase, alkaline phosphatase, and albumin to predict duration of survival in patients with metastatic CRPC. Predicted survival probabilities were calculated using the corrected group-prognosis method.³¹ This approach uses the regression model underlying a nomogram for survival developed by Smaletz et al²⁶ to predict survival probabilities for each patient at each unique observed failure time. Using the corrected group-prognosis method, probabilities at each failure time were averaged, and the predicted survival curve for all patients was plotted as mean survival versus time. Nonparametric bootstrapping with 1,000 resamples was used, and empirical percentiles were calculated to illustrate 95% CIs. The predicted survival data were then compared with actual survival data obtained under separate protocols.

	RESULTS

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Patient Population
Forty-two men enrolled and 41 patients were treated. One patient withdrew before treatment because of a rapid decline in medical condition. Baseline patient characteristics, prognostic factors, and prior treatments for all treated patients are listed in Tables 1 and 2. All patients had prior taxane-based chemotherapy. Most had more than one prior hormonal therapy, with a median number of two prior treatments (range, one to seven). Mean time from discontinuation of the first antiandrogen treatment was 30.5 months; 53.7% of these patients responded to their primary hormonal treatment for 1 year.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Survival curves for the 40 assessable patients from the study. Actual survival curves and those determined based on historic controls with similar prognostic factors using a validated nomogram are shown.

View this table: [in this window] [in a new window]   Table 4. Incidence of Adverse Events Regardless of Causality by Highest NCI-CTC Grade Occurring in 10% of Treated Patients

	DISCUSSION

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Pertuzumab administered as a single agent was well tolerated, but no objective tumor regressions were observed. The trial was designed as a two-stage study with overall response as the primary efficacy end point. However, tumor regressions were not seen in preclinical studies, and because it was well tolerated and a number of patients showed prolonged stabilization of disease, enrollment was continued. Five (16.7%) of the 30 patients treated did not progress for a minimum of 23 weeks (5+ months), which is comparable to the duration of response seen with docetaxel alone in the registration trial for the drug (Tax 327). This raises the question, long debated in the prostate cancer literature, whether SD (lack of clinical progression) is an appropriate end point for studies in this patient group, particularly because this was the anticipated outcome based on the preclinical data. The results raise the question whether signaling inhibitors and agents that are not directly cytotoxic can be developed using the currently mandated clinical trial standards based on the outcomes with cytotoxic agents in other diseases, which, notably, did not include prostate cancer patients.²⁸ Eligibility criteria for trials as defined by RECIST and end points based solely on tumor regression recently were determined to be not applicable to the majority of clinical manifestations of prostate cancers.³² These results suggest that focusing on clinically meaningful measures of disease progression may be more important than focusing on a response rate that may not identify an effective therapy. In retrospect, we recognize that this was not a useful end point to make decisions on activity, and is in part why the trial had continued to the second stage without meeting its prespecified response criteria.

The absence of PSA declines was also consistent with the preclinical studies and a trial of pertuzumab in chemotherapy-naïve patients.³³ However, the dissociation of PSA changes and effects on prostate cancer growth are well documented preclinically,³⁴ raising additional questions on the role of PSA changes as an outcome measure.

Overall, pertuzumab was well tolerated and not associated with cardiac toxicity. In this study, only two patients had LVEF decreases 10% confirmed by central laboratory; both decreases remained within the normal range ( 50%) and were asymptomatic. Both patients had reversal of LVEF decreases on subsequent local ECHO evaluations. One patient experienced an asymptomatic troponin T increase but this patient had a history of anemia, coronary artery disease, and diabetes. The most common toxicity was diarrhea in 61%, with approximately 5% grade 3 and no grade 4. Only 17% of patients had rash and none were grade 3 or higher.

The central question is whether the outcomes detailed in this study are an indication that the agent is active. Is it biologically plausible? In this regard, there is increasing evidence to implicate the HER2 pathway in prostate cancer progression to castration-resistant disease.^14,35,36 Immunohistochemical studies of prostate cancers representing untreated localized disease, and separately, castration-resistant phenotypes, have shown significant HER2 overexpression in resistant tumors relative to the primary lesions; within the same patient, the primary tumor may be negative and the resistant lesion may be positive. Amplification is rare, in contrast to results in breast cancer tumors. Given these hurdles, identification of biologic markers of responsive tumors is difficult, especially because metastatic CRPC tissue is rarely accessible. Recent preclinical data demonstrated a clear interplay between the androgen receptor and the HER2 pathway,^15,19 whereby forced overexpression of HER2 shortened the interval to tumor development in prostate cancer xenograft model systems and ligand-independent activation of the androgen receptor by HER-kinase axis activator. Other studies have shown that although a signaling cascade from the HER2/HER3 dimer to the androgen receptor exists (although it is not demonstrated to effect PSA transcription), neither the EGFR nor the downstream Akt are involved in mediating this signaling mechanism. This suggests the involvement of an alternative pathway.²⁰ The complex pathophysiology in these patients, and likelihood that alternate signaling pathways are also dysregulated, may explain the absence of PSA declines despite inhibition of the HER2 pathway with pertuzumab.

The survival analysis based on a nomogram for survival developed using clinical factors from patients treated on sequential protocols at a Comprehensive Cancer Center must be considered cautiously. Limitations are that the analysis was retrospective, it was developed for a chemotherapy-naïve group, and the overall number of patients included from the current study cohort was small. The nomogram was developed from patient data obtained before approval of docetaxel for prostate cancer, and we use it here to look for signals of patient benefit only. The results are intriguing: patients in the current group had experienced progression during at least one chemotherapy regimen, with an anticipated survival that was significantly lower than actually observed. There are few data on response rates and prognosis of patients treated in the second-line setting after taxane-based therapy. Trials with mitoxantrone and prednisone, and newer agents such as ixabepilone and satraplatin after taxane therapy, are ongoing, and phase II data will be available shortly. In this study the median survival was 16.4 months, which is above the range for second-line chemotherapies such as mitoxantrone and docetaxel.^3,37 Retrospective analysis of mitoxantrone after taxane or the reverse sequence suggests that the taxanes are efficacious as first-line or second-line treatment; however progression-free survival is short (2 to 3 months).^37,38

The current treatment option for patients with CRPC who have experienced treatment failure after chemotherapy is best supportive care or a clinical trial. This study shows that pertuzumab is well tolerated, and although no responses were observed, it may have an impact on survival in a retrospective analysis. Perhaps the most critical message is that randomized trials with an appropriate control group based on time to progression or survival as the primary end points of efficacy may be required to identify agents in which tumor regression is not anticipated. Only in this way can decisions be made objectively about whether or not to continue clinical development.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Jin Wang, Genentech; Mika K. Derynck, Genentech; Benjamin Lyons, Genentech; David E. Allison, Genentech Leadership: Michael W. Kattan, Oncovide Technologies Consultant: Michael W. Kattan, Genentech Stock: Jin Wang, Genentech; Mika K. Derynck, Genentech; Kimmie Ng, Genentech; Benjamin Lyons, Genentech; David E. Allison, Genentech Honoraria: Michael J. Morris, Genentech Research Funds: David B. Agus, Genentech; Christopher J. Sweeney, Genentech; Michael J. Morris, Genentech; David S. Mendelson, Genentech; Douglas G. McNeel, Genentech; Frederick R. Ahmann, Genentech; Howard I. Scher, Genentech Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: David B. Agus, Christopher J. Sweeney, Douglas G. McNeel, Mika K. Derynck, Howard I. Scher

Provision of study materials or patients: David B. Agus, Christopher J. Sweeney, Michael J. Morris, David S. Mendelson, Douglas G. McNeel, Frederick R. Ahmann, Howard I. Scher

Collection and assembly of data: David B. Agus, Frederick R. Ahmann, Mika K. Derynck, Kimmie Ng, Benjamin Lyons, Howard I. Scher

Data analysis and interpretation: David B. Agus, Christopher J. Sweeney, Michael J. Morris, David S. Mendelson, Jin Wang, Mika K. Derynck, Kimmie Ng, Benjamin Lyons, David E. Allison, Michael W. Kattan, Howard I. Scher

Manuscript writing: David B. Agus, Christopher J. Sweeney, Mika K. Derynck, Kimmie Ng, David E. Allison, Michael W. Kattan, Howard I. Scher

Final approval of manuscript: David B. Agus, Christopher J. Sweeney, Michael J. Morris, David S. Mendelson, Douglas G. McNeel, Frederick R. Ahmann, Mika K. Derynck, Kimmie Ng, Benjamin Lyons, David E. Allison, Michael W. Kattan, Howard I. Scher

	NOTES

 
Supported by Genentech Inc, South San Francisco, CA.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted April 17, 2006; accepted November 30, 2006.

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				C. Festuccia, G. L. Gravina, P. Muzi, R. Pomante, L. Ventura, R. L Vessella, C. Vicentini, and M. Bologna Bicalutamide increases phospho-Akt levels through Her2 in patients with prostate cancer Endocr. Relat. Cancer, September 1, 2007; 14(3): 601 - 611. [Abstract] [Full Text] [PDF]

				G. Attard and J. S. De Bono In Reply J. Clin. Oncol., June 10, 2007; 25(17): 2499 - 2499. [Full Text] [PDF]

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