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A Randomised Phase 2 Study Combining LY2181308 Sodium (Survivin Antisense Oligonucleotide) with First-line Docetaxel/Prednisone in Patients with Castration-resistant Prostate Cancer
European Urology, 3, 65, pages 516 - 520
Castration-resistant prostate cancer (CRPC) is partially characterised by overexpression of antiapoptotic proteins, such as survivin. In this phase 2 study, patients with metastatic CRPC (n = 154) were randomly assigned (1:2 ratio) to receive standard first-line docetaxel/prednisone (control arm) or the combination of LY2181308 with docetaxel/prednisone (experimental arm). The primary objective was to estimate progression-free survival (PFS) for LY2181308 plus docetaxel. Secondary efficacy measures included overall survival (OS), several predefined prostate-specific antigen (PSA)–derived end points, and Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy–Prostate (FACT-P) scores. The median PFS of treated patients for the experimental arm (n = 98) was 8.64 mo (90% confidence interval [CI], 7.39–10.45) versus 9.00 mo (90% CI, 7.00–10.09) in the control arm (n = 51;p = 0.755). The median OS for the experimental arm was 27.04 mo (90% CI, 19.94–33.41) compared with 29.04 mo (90% CI, 20.11–39.26;p = 0.838). The PSA responses (≥50% PSA reduction), BPI, and FACT-P scores were similar in both arms. In the experimental arm, patients had a numerically higher incidence of grades 3–4 neutropenia, anaemia, thrombocytopenia, and sensory neuropathy. In conclusion, this study failed to detect a difference in efficacy between the two treatment groups.
Keywords: Antisense oligonucleotide, Castration-resistant prostate cancer, Docetaxel, Survivin, LY2181308.
Prostate cancer (PCa) is the second leading cause of new cancer cases and the sixth leading cause of cancer death among men  . First-line combination chemotherapy with docetaxel is commonly used in castration-resistant PCa (CRPC), , and , but this treatment eventually fails to control PCa because of several potential mechanisms. One such mechanism is chemoresistance of CRPC, which is potentially associated with the overexpression of antiapoptotic proteins, such as survivin  . LY2181308 sodium, a second-generation antisense oligonucleotide, is a survivin inhibitor that has additive antitumour activity in several tumour models, including in the PC3 cell line  . Based on this biologic observation, the objective of this phase 2 study was to evaluate the antitumour activity of LY2181308 in combination with standard-of-care treatment consisting of docetaxel and prednisone. This was the first exploratory phase 2 study to evaluate LY2181308 after completion of the first-in-human dose study  and the first study in PCa patients.
Consistent with previous first-line chemotherapy trials and , patients were eligible for this trial if they were chemonaive and had histologically confirmed metastatic prostate adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, adequate organ function, and progressive disease defined by two consecutive increases in prostate-specific antigen (PSA) levels with castration levels of testosterone ≤50 ng/dl; in addition, patients’ disease must have met the definition of CRPC (see Supplement).
From April 2008 to October 2010, 194 patients entered the study; 52 were randomly assigned to the control (docetaxel/prednisone) arm and 102 to the experimental (LY2181308/docetaxel combination therapy) arm (study design and patient disposition are depicted in Fig. 1 ). Both treatment arms were balanced regarding baseline race, age, and ECOG PS (Supplemental Table 1).
Possibly drug-related maximum grade 3 or grade 4 Common Terminology Criteria for Adverse Events (≥5% incidence in either arm) for all treated patients are listed in Supplemental Table 2. In the experimental arm, patients had a numerically higher incidence of grades 3–4 neutropenia, anaemia, thrombocytopenia, and sensory neuropathy. The most common adverse event was thrombocytopenia (n = 10; 10.2%).
In contrast to the expected median progression-free survival (PFS) time of 6 mo for the control arm  , the median PFS for the control arm was 9.00 mo (90% confidence interval [CI], 7.00–10.09). The median PFS for the experimental arm was 8.64 mo (90% CI, 7.39–10.45), indicating no difference between treatment arms ( Fig. 2 A; log-rankp = 0.755). Patients with initial stage I and II diagnoses had a median PFS of 7.39 mo (90% CI, 6.70–8.05), whereas patients with initial stage III and IV diagnoses had a median PFS of 10.09 mo (90% CI, 8.64–11.47; Fig. 2 B). Patients with high PSA values at baseline had a median PFS of 7.39 mo (90% CI, 6.44–8.11), whereas patients with low PSA values at baseline had a median PFS of 10.74 mo (90% CI, 9.00–11.99; Fig. 2 C). Although the circulating tumour cell (CTC) profiles were similar in both arms, the CTC baseline levels were predictive of PFS ( Fig. 2 D). Patients with high CTC values at baseline had a median PFS of 6.97 mo (90% CI, 5.95–8.51), whereas patients with low CTC values at baseline had a median PFS of 11.40 mo (90% CI, 9.00–12.45). No substantial change in treatment effect on PFS was observed between the two arms, even after adjusting for the baseline factors of CTC levels, disease stage group, and PSA levels (hazard ratio: 1.0; 90% CI, 0.7–1.5).
In the experimental arm, the median overall survival was 27.04 mo (90% CI, 19.94–33.41) compared with 29.04 mo (90% CI, 20.11–39.26) in the control arm (log-rankp = 0.838; Supplemental Fig. 1). The 12-mo survival rate was 79% (90% CI, 71–85) in the experimental arm and 82% (90% CI, 70–89) in the control arm. The PSA responses of ≥50% reduction were similar for both arms: 56.1% in the experimental arm and 56.9% in the control arm (p = 0.856).
Pain intensity and interference of pain with function as measured by the Brief Pain Inventory  , the Functional Assessment of Cancer Therapy–Prostate score, and its related scores were generally similar between arms at baseline and throughout the treatment period (Supplemental Fig. 2 and 5).
In conclusion, the primary outcome (ie, efficacy improvement) was not met. There are several potential reasons why this study failed to detect a difference between treatment arms. First, the inhibition of survivin by LY2181308 may not have been sufficient. In PCa, survivin expression is associated with progressive disease  , and the differential expression of nuclear or cytoplasmic expression can predict survival  . We were unable to measure survivin expression in this trial; therefore, we cannot assess the extent of survivin expression and how it relates to clinical outcome for individual patients. The pharmacokinetic profile of LY2181308 (Supplemental Fig. 6) was consistent with that observed in a previous report  , in which the reduction in survivin protein expression was at least 30% compared with baseline  . Docetaxel concentration was similar to historical data and in both arms of the study (Supplemental Fig. 6d). Hence, the overall drug exposure was considered adequate to deliver the expected antitumour activity of the combination therapy of docetaxel and LY2181308. Perhaps, to achieve a greater effect, survivin inhibition has to exceed the presumed 30% inhibition from baseline  . Finally, targeting only one of the several antiapoptosis molecules may not be sufficient to cause the appropriate change in the tumour that would render it more responsive to a taxane treatment. Perhaps other survivin- or apoptosis-modifying agents require a more biomarker-driven approach to ensure that target inhibition is achieved in all patients and to provide greater synergy with chemotherapy agents such as docetaxel.
Author contributions:Paweł Wiechno had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design:Wiechno, Somer, Mellado, Chłosta, Cervera Grau, Castellano, Reuter, Stöckle, Kamradt, Pikiel, Durán, Wedel, Callies, André, Hurt, Brown, Lahn, Heinrich.
Acquisition of data:Wiechno, Somer, Mellado, Chłosta, Cervera Grau, Castellano, Reuter, Stöckle, Kamradt, Pikiel, Durán, Wedel, Callies, André, Hurt, Brown, Lahn, Heinrich.
Analysis and interpretation of data:Wiechno, Somer, Mellado, Chłosta, Cervera Grau, Castellano, Reuter, Stöckle, Kamradt, Pikiel, Durán, Wedel, Callies, André, Hurt, Brown, Lahn, Heinrich.
Drafting of the manuscript:Wiechno, Somer, Mellado, Chłosta, Cervera Grau, Castellano, Reuter, Stöckle, Kamradt, Pikiel, Durán, Wedel, Callies, André, Hurt, Brown, Lahn, Heinrich.
Critical revision of the manuscript for important intellectual content:Wiechno, Somer, Mellado, Chłosta, Cervera Grau, Castellano, Reuter, Stöckle, Kamradt, Pikiel, Durán, Wedel, Callies, André, Hurt, Brown, Lahn, Heinrich.
Administrative, technical, or material support:Wiechno, Somer, Mellado, Chłosta, Cervera Grau, Castellano, Reuter, Stöckle, Kamradt, Pikiel, Durán, Wedel, Callies, André, Hurt, Brown, Lahn, Heinrich.
Supervision: Wiechno, Somer, Mellado, Chłosta, Cervera Grau, Castellano, Reuter, Stöckle, Kamradt, Pikiel, Durán, Wedel, Callies, André, Hurt, Brown, Lahn, Heinrich.
Financial disclosures:Paweł Wiechno certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Sophie Callies, Valérie André, Karla Hurt, Jacqueline Brown, and Michael Lahn are full-time employees of Eli Lilly and Company and hold stock in the company.
Funding/Support and role of the sponsor:Eli Lilly and Company was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
Acknowledgment statement:The authors would like to acknowledge Michelle Mynderse of inVentiv Health Clinical for writing support, Michael Man of Eli Lilly and Company for the pharmacogenetics analyses, Angela Remster of InVentiv Health Clinical (Indianapolis, IN, USA) for data management support, Tiffany Wang of InVentiv Health Clinical for statistical support, and Kay Chow and Kriss Harris of Eli Lilly and Company for supporting the pharmacokinetic and statistical analyses. We would also like to thank ICON Clinical Research and Quintiles US Field Monitoring Group for monitoring services and the participating patients and study sites.
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a Uro-Oncology Department, Cancer Center, Warsaw, Poland
b West Clinic and ACORN, Memphis, TN, USA
c Medical Oncology Department, Hospital Clínic, University of Barcelona, Barcelona, Spain
d Department of Urology, Jagiellonian University in Krakow, Krakow, Poland
e Benidorm Clinic Hospital, Benidorm, Spain
f Medical Oncology Service, 12 de Octubre University Hospital, Madrid, Spain
g Department of Haematology, Haemostaseology, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
h Clinic for Urology and Paediatric Urology, University of Saarland, Saarland, Germany
i Wojewódzkie Cancer Centre, Gdansk, Poland
j Centro Integral Oncológico Clara Campal, Madrid, Spain
k Department of Urology, Goethe-University, Frankfurt am Main, Germany
l Global Pharmacokinetics/Pharmacodynamics Department, Eli Lilly and Company, Erl Wood, UK
m Global Statistical Sciences, Eli Lilly and Company, Erl Wood, UK
n Division of Early Phase Oncology Clinical Investigation, Eli Lilly and Company, Indianapolis, IN, USA
o Global Health Outcomes, Eli Lilly and Company, Erl Wood, UK
p Haematological-Oncological Practice Brudler/Heinrich/Bangerter, Augsburg, Germany
© 2013 European Association of Urology, Published by Elsevier B.V.