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Personalizing prostate cancer therapy: the way forward Jeremy P. Cetnar and Tomasz M. Beer Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA
Advances in genomic sequencing and molecular characterization are improving our understanding of the biology of prostate cancer and challenging us to translate emerging data into meaningful clinical outcomes. Several recently approved treatments for advanced prostate cancer extend survival; however, these therapies are not personalized based on predictive biomarkers. Innovative strategies for early phase drug testing that harness our growing knowledge of important prognostic markers and emerging predictive biomarkers are needed. In this review we discuss new strategies to assess drug response in early phase clinical trial testing.
Introduction Despite recent clinical successes that extend survival with advanced disease, nearly 30,000 men still lose their lives each year as a result of complications from castrate-resistant prostate cancer (CRPC) [1]. For these men, curative treatments for metastatic disease remain elusive. Since the pivotal findings of Nobel Laureate Charles Huggins and his partner Clarence Hodges, prostate cancer has been regarded as a hormonally driven malignancy. In men with metastatic prostate cancer, androgen deprivation therapy (ADT) is the standard initial therapy owing to the dependence of prostate cancer growth on androgen receptor (AR) signaling. Although ADT is initially effective in controlling metastatic prostate cancer in most patients, subsequent growth and proliferation ensues in nearly all patients leading to a castrate-resistant disease state. The importance of understanding how prostate cancer cells survive and later proliferate in a castrate milieu cannot be overstated. This addiction of prostate cancer growth to AR signaling remains the focus of research and the target for multiple new therapies. Major recent clinical advances have validated the scientific focus on this area of prostate cancer biology [2,3].
Approximately one-third of patients with localized prostate cancer recur following definitive therapy with a rising prostate-specific antigen (PSA) being the only indication of residual cancer. For patients not cured with salvage strategies, the median time to the development of metastases is approximately eight years [4]. The long and heterogeneous natural history of prostate cancer has created challenges for those seeking regulatory approval of new agents. For cancer-directed agents, overall survival has been the standard measure of efficacy and all new agents have focused on metastatic castration-resistant disease. For research and regulatory purposes the natural history and progression of metastatic prostate cancer has been separated into different clinical phenotypes [5]. Although these categories draw clear divides through what is, in reality, a continuous disease process, they are necessary and have enabled standardization of clinical trial designs and comparisons of different treatments between similar groups. The disease states model (Fig. 1) first proposed by Scher et al. [5] has been successful in bringing a unified structured framework to clinical trial designs in prostate cancer.
Personalized medicine Treatment paradigm Stage IV prostate cancer is a heterogeneous disease. Although fiveyear survival rate for patients with localized prostate cancer is excellent (100%), for those with stage IV disease it is only 28% [1]. Corresponding author: Beer, T.M. ([email protected]), ([email protected])
The essence of personalized cancer medicine is the pairing of an individual with the very best treatment based on distinct characteristics of the tumor, individual, or both. In the case of prostate cancer, this treatment can range from immune therapy to targeted molecular therapy to cytotoxic chemotherapy. The pairing of a tumor-specific molecular defect with targeted therapy designed to
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Death from other causes
Clinically localized disease
Rising PSA non-castrate
Clinical metastases: non-castrate
Clinical metastases: castrate
Rising PSA: castrate
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Death from disease Drug Discovery Today
FIGURE 1
Prostate cancer clinical-states model: a framework for patient management and drug development. Reproduced, with permission, from [5]. Abbreviation: PSA, prostate-specific antigen.
exploit that particular defect is the prototypical example of personalized medicine. It is likely that other embodiments of this concept will emerge in the future. Progress in personalized oncology has relied on rapid genomic analyses, the subsequent discovery of driver mutations and an expanding portfolio of targeted agents. The most significant clinical gains in recent history are the result of predictive biomarkers and targeted therapy. This revolution started with the treatment of chronic myelogenous leukemia with imatinib, a tyrosine kinase inhibitor of the BCR-ABL translocation [6]. This has led to major treatment advances in other tumors, which harbor targetable mutations such as human epidermal growth factor receptor (HER)2 amplification in breast cancer, epidermal growth factor receptor (EGFR) mutations and ALK-EML4 translocations in nonsmall-cell lung cancer, KRAS mutations in colon cancer and BRAF mutations in melanoma [7–11]. This era of personalized cancer therapy has led to improved survival rates, reduced toxicity and increased efficiency in clinical trial accrual and completion through the selection of enriched populations in some cancers. Prostate cancer has yet to benefit significantly from this new paradigm. Recently approved therapies, such as abiraterone acetate (AA) and enzalutamide, target the androgen signaling axis, but their efficacy cannot be predicted based on quantifiable biomarkers with sufficient resolution to individualize therapy. Thus, to date, we are not able to individualize therapy selection and sequencing for advanced prostate cancer patients prospectively. Although prostate cancer lacks a predictive biomarker, there are many prognostic factors such as performance status, age, serum lactate dehydrogenase concentrations, tumor Gleason score, PSA kinetics and the presence of visceral metastatic disease. These clinical prognostic factors do not significantly inform therapy selection but do enable us to stratify patients by their expected survival. Among the most common genetic events in the development of prostate cancer are ERG rearrangements and phosphatase and tensin homolog (PTEN) deletions. Prostate cancer is known to harbor a unique fusion between the prostate-specific androgen-regulated TMPRSS2 gene and the ETS genes: ERG, ETV1 or ETV4, in 50% of cases [12]. The presence of these gene fusions is essentially 100% specific for prostate cancer. The therapeutic implications of this fusion are unclear. Currently, there are no therapies that directly target this gene fusion. However, there are 2
ongoing clinical trials that integrate these gene fusions and stratify based on their presence (NCT01682772, NCT01576172). In addition to TMPRSS2-ERG, there are multiple other potentially clinically relevant genomic alterations that have recently been reported in prostate cancer, such as RB1 loss, MYC amplification, PI3KCA amplification and AKT mutations [13]. These all represent current and future targets for therapy.
Matching disease phenotype with treatment Given the absence of predictive biomarkers, clinical research has sought to match a given therapy with clinical prostate cancer phenotypes. For example, patients without visceral disease who are asymptomatic or minimally symptomatic can be treated with sipuleucel-T, patients with bone-predominant disease can be treated with radium-223 or patients with CRPC and bone metastases can be treated with a bone-modifying agent such as zoledronic acid or denosumab. These approaches are rather rudimentary, however, and the next step in the development of successful therapies must include a deeper understanding of the targets that drive prostate cancer progression in individual patients and testing of drugs that target these abnormalities. Although important progress has been made in the treatment of advanced prostate cancer, conventional approaches to drug development have yielded mixed results. Targeted agents in particular, with the exception of drugs that target the AR, have fared poorly and nothing highlights this more clearly than our record in the effort to add targeted therapy to docetaxel. A frequent theme has been discordant outcomes seen in Phase I/II clinical trials compared with subsequent Phase III trials. Table 1 lists all of the targeted agents used in combination with docetaxel that have failed to show a clinical benefit in Phase III testing, despite promising results in Phase I testing or positive testing in Phase II studies. These discordant findings beg the question of why? Is it simply that these Phase II studies were not adequately powered? Or is it that Phase II prostate studies suffer from a selection bias of better performance status patients with fewer co-morbidities? Could it be that some of the Phase II studies were not as positive as we had hoped? Could some have been the result of random variation in results, a field-wide multiple comparison problem. Probably part of the answer can be attributed to each of these possibilities. Another likely contributor is the fact that our tools for determining clinical benefit, such as PSA decline and response evaluation criteria in solid tumors (RECIST) criteria (commonly used in Phase II studies), do not sufficiently represent the underlying biology of prostate cancer and might not adequately reflect the mechanism of action of a particular treatment or its full impact on overall survival. Measures of tumor response to therapy are particularly challenging in prostate cancer. PSA changes with chemotherapy only partially explain the subsequent survival differences and, for some therapies, might not be relevant at all. This is particularly so for immune therapies or cytostatic treatments inhibiting angiogenesis [14]. Furthermore, prostate cancer has a proclivity for metastasizing to bone; therefore using standard RECIST criteria that focus on soft tissue disease is not helpful. Given these challenges, the Prostate Cancer Working Group 2 (PCWG2) has published guidelines regarding the design and interpretation of early phase clinical trials [5].
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TABLE 1
Trial
Drug
Main result
Refs
ASCENT II
DN101 (calcitriol)
Poorer survival in experimental arm
[33]
VITAL II
GVAX vaccine
Poorer survival in experimental arm
[34]
N/A
Atrasentan
No difference in survival
[35]
ENTHUSE
Zibotentan
No difference in survival
[36]
MAINSAIL
Lenalidomide (RevlimidW)
No difference in survival
[37]
W
CALGB 90401
Bevacizumab (Avastin )
No difference in survival
[38]
READY
Dasatinib (SprycelW)
No difference in survival
[39]
No difference in survival
[40]
VENICE
W
Aflibercept (Zaltrap )
Abbreviation: N/A, not applicable.
Endpoints for clinical testing In prostate cancer, most Phase I/II clinical trials use a variety of endpoints and report them independently. One of the most common primary endpoints for a Phase II study is progressionfree survival (PFS) according to PCWG2. The challenge with using PFS for assessing efficacy is that it has not been validated in a prospective manner as a surrogate for overall survival. However, when retrospectively studied, PFS at 3 and 6 months does predict overall survival [15]. To date, no therapeutic agent for prostate cancer has achieved FDA approval based solely on PFS. The use of AA plus prednisone in the pre-chemotherapy setting recently demonstrated a significant improvement in PFS compared with prednisone alone, which was compelling enough for the data and safety monitoring committee to recommend unblinding and active treatment [3]. Subsequently, AA gained FDA approval in the pre-chemotherapy setting based on this statistically significant PFS benefit and with a strong trend in favor of a survival advantage, but this was an expansion of an already existing indication (postchemotherapy) based on an overall survival advantage. Secondary endpoints in Phase II trials typically include overall survival, response rate, incidence of skeletal complications, change in circulating tumor cell (CTC) count and other correlative studies such as change in bone turnover markers, phosphorylation of downstream molecular targets or expression of identified genes thought to predict a more aggressive clinical course.
Neoadjuvant treatment There are a number of innovations in clinical trial design that are being explored in prostate cancer. For early phase clinical trials involving targeted agents, key questions center on the successful engagement of the intended target, and of course the clinical impact of target engagement. One approach to answer these questions is in the context of neoadjuvant treatment, which enables tumor response assessment via surgical staging and molecular analysis of the tumor tissue that could include tissue drug levels, target expression and target function in the presence of the drug. A recent example of such an approach involved the examination of the AA by Taplin et al. [16]. They recently reported on a randomized Phase II trial in which patients with high risk localized prostate cancer received a luteinizing-hormone-releasing hormone (LHRH) agonist with or without AA or prednisone before prostatectomy with the primary endpoint of measuring
intraprostatic testosterone and dihydrotestosterone levels, which represent the pharmacodynamic targets of the drug. Other researchers have studied the neoadjuvant effects of OGX011 (custirsen), a second-generation antisense inhibitor of clusterin, on resected prostate tissue [17]. OGX-011 reduced clusterin expression in primary prostate tumors, and increased the apoptotic index of prostate cancer cells in a dose-dependent manner. Although there is no standard neoadjuvant treatment, these studies validated the feasibility of such an approach. A number of other targeted agents have entered clinical trial testing for the treatment of high-risk localized disease, including bevacizumab, sunitinib, thalidomide, gefitinib, imatinib, ipilumimab and sipuleucel-T [18]. The use of neoadjuvant treatment for localized prostate cancer has several limitations, with perhaps the most important being the lack of information on CRPC, the most lethal phenotype. Therefore, others have started the practice of obtaining tissue from malignant bone lesions in those with CRPC. Bone metastases are the most common site of spread from prostate cancer and represent a major source of morbidity. Biopsying the bone can be challenging because the samples obtained are small, contain a mixture of bone, bone marrow, stroma and tumor cells, and the decalcification process can limit analysis and degrade biologic material. As part of a Phase II clinical trial, men with progressive CRPC received everolimus, an oral inhibitor of mammalian target of rapamycin, and underwent serial bone biopsies of malignant lesions in the pelvis with CT guidance (NCT00629525). Thirty-one patients underwent a baseline bone biopsy, and again 28 days later following administration of everolimus. Of the 54 biopsies obtained, 21 (39%) yielded specimens that were adequate for RNA isolation and results of 36 (67%) biopsies were positive for cancer at histologic evaluation with hematoxylin and eosin (H&E) staining [19]. This relatively low yield illustrates the challenges of obtaining adequate metastatic osseous tissue to perform tumor profiling. In addition, the issue of inter- and intra-tumoral heterogeneity complicates the application of this approach. Recent work has focused on codifying the accumulating experience with biopsy techniques to maximize tumor yield [19]. Given the technical aspects and patient discomfort involved in percutaneous biopsies of metastatic lesions, there has been a growing interest in noninvasive methods of evaluating biomarkers. Broadly, these innovations fall into two categories: serum analysis and enhanced imaging techniques.
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Main results from all reported Phase III trials of targeted therapies in combination with docetaxel in metastatic castration-resistant prostate cancer
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Serum biomarkers
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Tumor characterization through serum analysis has developed into a powerful interrogation tool, offering a frequent and easily accessible tissue. The most commonly studied serum marker is the CTC, which is a circulating tumor cell in the blood that is thought to represent either the primary tumor or metastatic site [20]. The genetic similarity to the primary tumor and its biologic function (inactive, exfoliated cell versus biologically active cell capable of establishing a metastases) remains controversial. These rare cells have been approximated to average one CTC for every one billion peripheral blood cells, emphasizing the challenges in their isolation and analysis. There are currently multiple approaches for identification and isolation that rely on positive and negative selection techniques. The traditional positive selection strategy is based on the expression of cell-surface markers, such as epithelial cell adhesion molecule (EpCAM), and is employed by the CellSearch1 assay, the only FDA-approved CTC detection system. However, some tumors downregulate expression of EpCAM during epithelial–mesenchymal transitions and therefore other strategies are being employed to isolate CTCs [21]. Nevertheless, CTC biomarkers show utility in predicting overall survival as well as assessing treatment effects, and hold promise for many contexts of use [22]. The analysis of CTCs could have a profound impact on genomic and transcriptional profiling. Enhanced capture of CTCs could assist in development of predictive biomarkers enabling the personalized tailoring of therapy based on a patient’s tumor profile. For example, identification of AR amplification suggests that individualized biomarker-driven therapy directly against the AR might be possible [23,24]. But perhaps the most promising use of CTC count would be as a surrogate for overall survival that would greatly accelerate the drug approval process [25]. Whether or not the current or future CTC platforms can achieve a level of surrogacy, sufficient to serve as a basis of drug approval, remains to be seen.
Pharmacodynamic imaging One shortcoming of the current CTC platform is the lack of sensitivity in many men with CRPC in the pre-docetaxel setting (>50% of which do not have CTCs identified) despite progressive metastatic disease [22] and an even greater lack of sensitivity in earlier disease states. Future CTC platforms could prove more sensitive. Further, other strategies, such as pharmacodynamic imaging, might reveal treatment response more accurately than traditional serum biomarkers or conventional imaging. The use of positron emission tomography (PET) imaging with novel radiotracers has increased owing to its ability to visualize bone lesions and soft tissue metastases. The use of fluoride 18 NaF as a radiotracer for PET imaging was FDA-approved in 1972; however, its use today is mostly investigational. Sodium fluoride is a bone-seeking imaging agent that is taken up in areas of new bone formation. F-18 NaF PET/CTs demonstrate exquisite sensitivity for bone metastases [26]. Alterations in bone response to therapy might indicate that a drug is engaging its target, which has led to pharmacodynamic imaging as a response marker for targeted therapies. For example, Yu et al. demonstrated a change in vascular parameters using pre- and post-NaF PET/CT in patients receiving investigational dasatinib [27]. In addition to fluoride 18 NaF, 18F-dihydrotestosterone has been used as a radiotracer in 4
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other studies assessing AR-directed therapies [28]. Although rather time consuming, expensive and requiring expertise in interpretation, use of novel tracers in PET/CTs could aid in drug development by providing early evidence of treatment effect. One challenge is the short half-life of some of the innovative tracers, requiring the on-site availability of a cyclotron.
Challenges of immune therapy Immunologic therapy presents unique challenges in clinical trial design. Sipuleucel-T, an autologous dendritic cellular immunotherapy, is approved in minimally symptomatic or asymptomatic CRPC, based on a survival benefit and tolerable safety profile [29]. Although it improved overall survival, there was no difference in PFS compared to the control arm. Furthermore, the response rate and PSA decline were no different in the sipuleucel-T-treated patients than in placebo-treated patients. Thus, the conventional measures of drug activity, such as PSA decline, radiographic response rate and PFS, are not helpful in studies using sipuleucel-T, and possibly other immune therapies. Therefore, determining clinical benefit in early phase clinical trials remains a significant challenge. In the case of immune therapy, evaluating immune response, such as through the measurement of sera cytokine levels, or specific T cell populations, is crucial to the development of future therapies. Modified clinical endpoints, such as extended observation for progression of disease, that allow for delayed treatment effects could also be considered in trials of immunotherapy.
Adaptive clinical design Although there are no predictive biomarkers that are currently in use for prostate cancer, other methods can serve to enrich patient populations. Prognostic factors, such as performance status, age, serum lactate dehydrogenase concentrations, tumor Gleason score, patient-reported pain and the presence of visceral metastatic disease, can define risk groups most in need of novel treatments. They could also serve to decrease the clinical heterogeneity of patients enrolled in clinical trials. Stratification using biomarkers is also emerging as a tool for better understanding and defining patient populations. For example, Ryan et al. retrospectively analyzed COU-AA-301, a randomized, double-blinded study of AA plus prednisone versus prednisone alone. They determined that serum androgen levels strongly correlated with survival [30]. Another proposed model that simultaneously streamlines drug development and companion diagnostics is an adaptive trial design. Adaptive trial designs continuously integrate acquired biomarker data from current patients on a trial into treatment decisions for future patients participating in the same clinical trial. Identifying putative predictive biomarkers early on and then continuously integrating acquired biomarker data into the ongoing trials are increasingly being recognized as necessary and as the most ethical means for minimizing harm and maximizing patient benefit. Recent examples of clinical studies that have used an adaptive strategy include the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial for non-smallcell lung cancer and the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 (I-SPY 2) trial for locally advanced breast cancer [31,32]. The Trial of Olaparib in Patients with Advanced Castration-Resistant Prostate Cancer (TO-PARP) study is an adaptive trial design that rests on the
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hypothesis that poly(ADP-ribose)polymerase (PARP) inhibition will benefit a select group of patients (NCT01682772).
Concluding remarks The era of personalized medicine has arrived and is shaping therapy in several solid tumors. Recent developments in prostate cancer therapy have yielded many new therapies, but none that is deployed in molecularly defined populations. The need for treatment individualization in prostate cancer is particularly notable because the disease is biologically and clinically heterogeneous. Determining efficacy for novel targeted treatments has been challenging and, in particular in combination with docetaxel chemotherapy, has been disappointing. There are several innovative strategies that could
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improve our ability to evaluate whether or not a drug is hitting its target. The serial analysis of tumor biopsies (in either the primary tumor or site of metastasis), the development of pharmacodynamic imaging with novel radiotracers and the evaluation of CTCs have all lead to important biologic insights. We expect these advances increasingly to define clinical trials and ultimately clinical care for prostate cancer. The sharing of biologic and clinical data is another priority for the field. The robust development of prognostic and predictive biomarkers requires access to larger datasets than any one investigator, institution or sponsor can muster.
Conflict of interest The authors declare no conflicts of interest.
References 1 Siegel, R. et al. (2013) Cancer statistics. CA Cancer J. Clin. 63, 11–30 2 Scher, H.I. et al. (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 3 Ryan, C.J. et al. (2013) Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 4 Pound, C.R. et al. (1999) Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281, 1591–1597 5 Scher, H.I. et al. (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J. Clin. Oncol. 26, 1148–1159 6 Druker, B.J. et al. (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 7 Slamon, D.J. et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 8 Tsao, M.S. et al. (2005) Erlotinib in lung cancer – molecular and clinical predictors of outcome. N. Engl. J. Med. 353, 133–144 9 Shaw, A.T. et al. (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med. 368, 2385–2394 10 Roth, A.D. et al. (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993 SAKK 60-00 trial. J. Clin. Oncol. 28, 466–474 11 Chapman, P.B. et al. (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 12 Kumar-Sinha, C. et al. (2008) Recurrent gene fusions in prostate cancer. Nat. Rev. Cancer 8, 497–511 13 Roychowdhury, S. and Chinnaiyan, A.M. (2013) Advancing precision medicine for prostate cancer through genomics. J. Clin. Oncol. 31, 1866–1873 14 Armstrong, A.J. et al. (2012) Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer. Eur. Urol. 61, 549–559 15 Halabi, S. et al. (2009) Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer. J. Clin. Oncol. 27, 2766–2771 16 Taplin, M.E. et al. (2012) Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): results of a randomized phase II study. J. Clin. Oncol. 30 abstr. 4521 17 Chi, K.N. et al. (2005) A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 20 -methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J. Natl. Cancer Inst. 97, 1287–1296 18 McKay, R.R. et al. (2013) Rationale for and review of neoadjuvant therapy prior to radical prostatectomy for patients with high-risk prostate cancer. Drugs 73, 1417–1430 19 Spritzer, C.E. et al. (2013) Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer – factors affecting diagnostic success. Radiology 269, 816–823 20 Allard, W.J. et al. (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res. 10, 6897–6904 21 Issadore, D. et al. (2012) Ultrasensitive clinical enumeration of rare cells ex vivo using a micro-hall detector. Sci. Transl. Med. 4 141ra192 22 de Bono, J.S. et al. (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin. Cancer Res. 14, 6302–6309 23 Leversha, M.A. et al. (2009) Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin. Cancer Res. 15, 2091–2097
24 Shaffer, D.R. et al. (2007) Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin. Cancer Res. 13, 2023–2029 25 Scher, H.I. et al. (2011) Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castrationresistant prostate cancer (mCRPC): planned final analysis (FA) of COU-AA-301, a randomized double-blind, placebo-controlled phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J. Clin. Oncol. 29 abstr. LBA4517 26 Schirrmeister, H. et al. (2001) Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer. J. Nucl. Med. 42, 1800–1804 27 Yu, E.Y. et al. (2013) Correlation of 18F-fluoride PET response to dasatinib in castration-resistant prostate cancer bone metastases with progression-free survival: preliminary results from ACRIN 6687. J. Clin. Oncol. 31 abstr. 5003 28 Autio, K.A. et al. (2013) Evaluating 18F-16B-fluoro-5a-dihydrotestosterone (FDHT) and FDG-PET as a measure of disease progression in metastatic castration resistant prostate cancer (mCRPC). J. Clin. Oncol. 31 abstr. 5090 29 Kantoff, P.W. et al. (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 30 Ryan, C.J. et al. (2013) Serum androgens as prognostic biomarkers in castrationresistant prostate cancer: results from an analysis of a randomized phase III trial. J. Clin. Oncol. 31, 2791–2798 31 Kim, E.S. et al. (2011) The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 1, 44–53 32 Barker, A.D. et al. (2009) I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin. Pharmacol. Ther. 86, 97–100 33 Scher, H.I. et al. (2011) Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castrationresistant prostate cancer. J. Clin. Oncol. 29, 2191–2198 34 Small, E. et al. (2009) A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). GU CA Symp. abstr. 07 35 Quinn, D.I. et al. (2013) Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 14, 893–900 36 Fizazi, K.S. et al. (2013) Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 31, 1740–1747 37 Petrylak, D.P. et al. (2012) A phase 3 study to evaluate the efficacy and safety of docetaxel and prednisone (DP) with or without lenalidomide (LEN) in patients with castrateresistant prostate cancer (CRPC): the MAINSAIL trial. Ann. Oncol. 23 abstr. LBA24 38 Kelly, W.K. et al. (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J. Clin. Oncol. 30, 1534–1540 39 Araujo, J.C. et al. (2013) Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 14, 1307–1316 40 Tannock, I. et al. (2013) Aflibercept versus placebo in combination with docetaxel/ prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): results from the multinational phase III trial (VENICE). J. Clin. Oncol. 31 abstr. 13
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Drug Discovery Today Volume 00, Number 00 July 2014
Personalizing prostate cancer therapy: the way forward Jeremy P. Cetnar and Tomasz M. Beer Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA
Advances in genomic sequencing and molecular characterization are improving our understanding of the biology of prostate cancer and challenging us to translate emerging data into meaningful clinical outcomes. Several recently approved treatments for advanced prostate cancer extend survival; however, these therapies are not personalized based on predictive biomarkers. Innovative strategies for early phase drug testing that harness our growing knowledge of important prognostic markers and emerging predictive biomarkers are needed. In this review we discuss new strategies to assess drug response in early phase clinical trial testing.
Introduction Despite recent clinical successes that extend survival with advanced disease, nearly 30,000 men still lose their lives each year as a result of complications from castrate-resistant prostate cancer (CRPC) [1]. For these men, curative treatments for metastatic disease remain elusive. Since the pivotal findings of Nobel Laureate Charles Huggins and his partner Clarence Hodges, prostate cancer has been regarded as a hormonally driven malignancy. In men with metastatic prostate cancer, androgen deprivation therapy (ADT) is the standard initial therapy owing to the dependence of prostate cancer growth on androgen receptor (AR) signaling. Although ADT is initially effective in controlling metastatic prostate cancer in most patients, subsequent growth and proliferation ensues in nearly all patients leading to a castrate-resistant disease state. The importance of understanding how prostate cancer cells survive and later proliferate in a castrate milieu cannot be overstated. This addiction of prostate cancer growth to AR signaling remains the focus of research and the target for multiple new therapies. Major recent clinical advances have validated the scientific focus on this area of prostate cancer biology [2,3].
Approximately one-third of patients with localized prostate cancer recur following definitive therapy with a rising prostate-specific antigen (PSA) being the only indication of residual cancer. For patients not cured with salvage strategies, the median time to the development of metastases is approximately eight years [4]. The long and heterogeneous natural history of prostate cancer has created challenges for those seeking regulatory approval of new agents. For cancer-directed agents, overall survival has been the standard measure of efficacy and all new agents have focused on metastatic castration-resistant disease. For research and regulatory purposes the natural history and progression of metastatic prostate cancer has been separated into different clinical phenotypes [5]. Although these categories draw clear divides through what is, in reality, a continuous disease process, they are necessary and have enabled standardization of clinical trial designs and comparisons of different treatments between similar groups. The disease states model (Fig. 1) first proposed by Scher et al. [5] has been successful in bringing a unified structured framework to clinical trial designs in prostate cancer.
Personalized medicine Treatment paradigm Stage IV prostate cancer is a heterogeneous disease. Although fiveyear survival rate for patients with localized prostate cancer is excellent (100%), for those with stage IV disease it is only 28% [1]. Corresponding author: Beer, T.M. ([email protected]), ([email protected])
The essence of personalized cancer medicine is the pairing of an individual with the very best treatment based on distinct characteristics of the tumor, individual, or both. In the case of prostate cancer, this treatment can range from immune therapy to targeted molecular therapy to cytotoxic chemotherapy. The pairing of a tumor-specific molecular defect with targeted therapy designed to
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1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.07.006
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Death from other causes
Clinically localized disease
Rising PSA non-castrate
Clinical metastases: non-castrate
Clinical metastases: castrate
Rising PSA: castrate
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Death from disease Drug Discovery Today
FIGURE 1
Prostate cancer clinical-states model: a framework for patient management and drug development. Reproduced, with permission, from [5]. Abbreviation: PSA, prostate-specific antigen.
exploit that particular defect is the prototypical example of personalized medicine. It is likely that other embodiments of this concept will emerge in the future. Progress in personalized oncology has relied on rapid genomic analyses, the subsequent discovery of driver mutations and an expanding portfolio of targeted agents. The most significant clinical gains in recent history are the result of predictive biomarkers and targeted therapy. This revolution started with the treatment of chronic myelogenous leukemia with imatinib, a tyrosine kinase inhibitor of the BCR-ABL translocation [6]. This has led to major treatment advances in other tumors, which harbor targetable mutations such as human epidermal growth factor receptor (HER)2 amplification in breast cancer, epidermal growth factor receptor (EGFR) mutations and ALK-EML4 translocations in nonsmall-cell lung cancer, KRAS mutations in colon cancer and BRAF mutations in melanoma [7–11]. This era of personalized cancer therapy has led to improved survival rates, reduced toxicity and increased efficiency in clinical trial accrual and completion through the selection of enriched populations in some cancers. Prostate cancer has yet to benefit significantly from this new paradigm. Recently approved therapies, such as abiraterone acetate (AA) and enzalutamide, target the androgen signaling axis, but their efficacy cannot be predicted based on quantifiable biomarkers with sufficient resolution to individualize therapy. Thus, to date, we are not able to individualize therapy selection and sequencing for advanced prostate cancer patients prospectively. Although prostate cancer lacks a predictive biomarker, there are many prognostic factors such as performance status, age, serum lactate dehydrogenase concentrations, tumor Gleason score, PSA kinetics and the presence of visceral metastatic disease. These clinical prognostic factors do not significantly inform therapy selection but do enable us to stratify patients by their expected survival. Among the most common genetic events in the development of prostate cancer are ERG rearrangements and phosphatase and tensin homolog (PTEN) deletions. Prostate cancer is known to harbor a unique fusion between the prostate-specific androgen-regulated TMPRSS2 gene and the ETS genes: ERG, ETV1 or ETV4, in 50% of cases [12]. The presence of these gene fusions is essentially 100% specific for prostate cancer. The therapeutic implications of this fusion are unclear. Currently, there are no therapies that directly target this gene fusion. However, there are 2
ongoing clinical trials that integrate these gene fusions and stratify based on their presence (NCT01682772, NCT01576172). In addition to TMPRSS2-ERG, there are multiple other potentially clinically relevant genomic alterations that have recently been reported in prostate cancer, such as RB1 loss, MYC amplification, PI3KCA amplification and AKT mutations [13]. These all represent current and future targets for therapy.
Matching disease phenotype with treatment Given the absence of predictive biomarkers, clinical research has sought to match a given therapy with clinical prostate cancer phenotypes. For example, patients without visceral disease who are asymptomatic or minimally symptomatic can be treated with sipuleucel-T, patients with bone-predominant disease can be treated with radium-223 or patients with CRPC and bone metastases can be treated with a bone-modifying agent such as zoledronic acid or denosumab. These approaches are rather rudimentary, however, and the next step in the development of successful therapies must include a deeper understanding of the targets that drive prostate cancer progression in individual patients and testing of drugs that target these abnormalities. Although important progress has been made in the treatment of advanced prostate cancer, conventional approaches to drug development have yielded mixed results. Targeted agents in particular, with the exception of drugs that target the AR, have fared poorly and nothing highlights this more clearly than our record in the effort to add targeted therapy to docetaxel. A frequent theme has been discordant outcomes seen in Phase I/II clinical trials compared with subsequent Phase III trials. Table 1 lists all of the targeted agents used in combination with docetaxel that have failed to show a clinical benefit in Phase III testing, despite promising results in Phase I testing or positive testing in Phase II studies. These discordant findings beg the question of why? Is it simply that these Phase II studies were not adequately powered? Or is it that Phase II prostate studies suffer from a selection bias of better performance status patients with fewer co-morbidities? Could it be that some of the Phase II studies were not as positive as we had hoped? Could some have been the result of random variation in results, a field-wide multiple comparison problem. Probably part of the answer can be attributed to each of these possibilities. Another likely contributor is the fact that our tools for determining clinical benefit, such as PSA decline and response evaluation criteria in solid tumors (RECIST) criteria (commonly used in Phase II studies), do not sufficiently represent the underlying biology of prostate cancer and might not adequately reflect the mechanism of action of a particular treatment or its full impact on overall survival. Measures of tumor response to therapy are particularly challenging in prostate cancer. PSA changes with chemotherapy only partially explain the subsequent survival differences and, for some therapies, might not be relevant at all. This is particularly so for immune therapies or cytostatic treatments inhibiting angiogenesis [14]. Furthermore, prostate cancer has a proclivity for metastasizing to bone; therefore using standard RECIST criteria that focus on soft tissue disease is not helpful. Given these challenges, the Prostate Cancer Working Group 2 (PCWG2) has published guidelines regarding the design and interpretation of early phase clinical trials [5].
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TABLE 1
Trial
Drug
Main result
Refs
ASCENT II
DN101 (calcitriol)
Poorer survival in experimental arm
[33]
VITAL II
GVAX vaccine
Poorer survival in experimental arm
[34]
N/A
Atrasentan
No difference in survival
[35]
ENTHUSE
Zibotentan
No difference in survival
[36]
MAINSAIL
Lenalidomide (RevlimidW)
No difference in survival
[37]
W
CALGB 90401
Bevacizumab (Avastin )
No difference in survival
[38]
READY
Dasatinib (SprycelW)
No difference in survival
[39]
No difference in survival
[40]
VENICE
W
Aflibercept (Zaltrap )
Abbreviation: N/A, not applicable.
Endpoints for clinical testing In prostate cancer, most Phase I/II clinical trials use a variety of endpoints and report them independently. One of the most common primary endpoints for a Phase II study is progressionfree survival (PFS) according to PCWG2. The challenge with using PFS for assessing efficacy is that it has not been validated in a prospective manner as a surrogate for overall survival. However, when retrospectively studied, PFS at 3 and 6 months does predict overall survival [15]. To date, no therapeutic agent for prostate cancer has achieved FDA approval based solely on PFS. The use of AA plus prednisone in the pre-chemotherapy setting recently demonstrated a significant improvement in PFS compared with prednisone alone, which was compelling enough for the data and safety monitoring committee to recommend unblinding and active treatment [3]. Subsequently, AA gained FDA approval in the pre-chemotherapy setting based on this statistically significant PFS benefit and with a strong trend in favor of a survival advantage, but this was an expansion of an already existing indication (postchemotherapy) based on an overall survival advantage. Secondary endpoints in Phase II trials typically include overall survival, response rate, incidence of skeletal complications, change in circulating tumor cell (CTC) count and other correlative studies such as change in bone turnover markers, phosphorylation of downstream molecular targets or expression of identified genes thought to predict a more aggressive clinical course.
Neoadjuvant treatment There are a number of innovations in clinical trial design that are being explored in prostate cancer. For early phase clinical trials involving targeted agents, key questions center on the successful engagement of the intended target, and of course the clinical impact of target engagement. One approach to answer these questions is in the context of neoadjuvant treatment, which enables tumor response assessment via surgical staging and molecular analysis of the tumor tissue that could include tissue drug levels, target expression and target function in the presence of the drug. A recent example of such an approach involved the examination of the AA by Taplin et al. [16]. They recently reported on a randomized Phase II trial in which patients with high risk localized prostate cancer received a luteinizing-hormone-releasing hormone (LHRH) agonist with or without AA or prednisone before prostatectomy with the primary endpoint of measuring
intraprostatic testosterone and dihydrotestosterone levels, which represent the pharmacodynamic targets of the drug. Other researchers have studied the neoadjuvant effects of OGX011 (custirsen), a second-generation antisense inhibitor of clusterin, on resected prostate tissue [17]. OGX-011 reduced clusterin expression in primary prostate tumors, and increased the apoptotic index of prostate cancer cells in a dose-dependent manner. Although there is no standard neoadjuvant treatment, these studies validated the feasibility of such an approach. A number of other targeted agents have entered clinical trial testing for the treatment of high-risk localized disease, including bevacizumab, sunitinib, thalidomide, gefitinib, imatinib, ipilumimab and sipuleucel-T [18]. The use of neoadjuvant treatment for localized prostate cancer has several limitations, with perhaps the most important being the lack of information on CRPC, the most lethal phenotype. Therefore, others have started the practice of obtaining tissue from malignant bone lesions in those with CRPC. Bone metastases are the most common site of spread from prostate cancer and represent a major source of morbidity. Biopsying the bone can be challenging because the samples obtained are small, contain a mixture of bone, bone marrow, stroma and tumor cells, and the decalcification process can limit analysis and degrade biologic material. As part of a Phase II clinical trial, men with progressive CRPC received everolimus, an oral inhibitor of mammalian target of rapamycin, and underwent serial bone biopsies of malignant lesions in the pelvis with CT guidance (NCT00629525). Thirty-one patients underwent a baseline bone biopsy, and again 28 days later following administration of everolimus. Of the 54 biopsies obtained, 21 (39%) yielded specimens that were adequate for RNA isolation and results of 36 (67%) biopsies were positive for cancer at histologic evaluation with hematoxylin and eosin (H&E) staining [19]. This relatively low yield illustrates the challenges of obtaining adequate metastatic osseous tissue to perform tumor profiling. In addition, the issue of inter- and intra-tumoral heterogeneity complicates the application of this approach. Recent work has focused on codifying the accumulating experience with biopsy techniques to maximize tumor yield [19]. Given the technical aspects and patient discomfort involved in percutaneous biopsies of metastatic lesions, there has been a growing interest in noninvasive methods of evaluating biomarkers. Broadly, these innovations fall into two categories: serum analysis and enhanced imaging techniques.
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Main results from all reported Phase III trials of targeted therapies in combination with docetaxel in metastatic castration-resistant prostate cancer
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Serum biomarkers
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Tumor characterization through serum analysis has developed into a powerful interrogation tool, offering a frequent and easily accessible tissue. The most commonly studied serum marker is the CTC, which is a circulating tumor cell in the blood that is thought to represent either the primary tumor or metastatic site [20]. The genetic similarity to the primary tumor and its biologic function (inactive, exfoliated cell versus biologically active cell capable of establishing a metastases) remains controversial. These rare cells have been approximated to average one CTC for every one billion peripheral blood cells, emphasizing the challenges in their isolation and analysis. There are currently multiple approaches for identification and isolation that rely on positive and negative selection techniques. The traditional positive selection strategy is based on the expression of cell-surface markers, such as epithelial cell adhesion molecule (EpCAM), and is employed by the CellSearch1 assay, the only FDA-approved CTC detection system. However, some tumors downregulate expression of EpCAM during epithelial–mesenchymal transitions and therefore other strategies are being employed to isolate CTCs [21]. Nevertheless, CTC biomarkers show utility in predicting overall survival as well as assessing treatment effects, and hold promise for many contexts of use [22]. The analysis of CTCs could have a profound impact on genomic and transcriptional profiling. Enhanced capture of CTCs could assist in development of predictive biomarkers enabling the personalized tailoring of therapy based on a patient’s tumor profile. For example, identification of AR amplification suggests that individualized biomarker-driven therapy directly against the AR might be possible [23,24]. But perhaps the most promising use of CTC count would be as a surrogate for overall survival that would greatly accelerate the drug approval process [25]. Whether or not the current or future CTC platforms can achieve a level of surrogacy, sufficient to serve as a basis of drug approval, remains to be seen.
Pharmacodynamic imaging One shortcoming of the current CTC platform is the lack of sensitivity in many men with CRPC in the pre-docetaxel setting (>50% of which do not have CTCs identified) despite progressive metastatic disease [22] and an even greater lack of sensitivity in earlier disease states. Future CTC platforms could prove more sensitive. Further, other strategies, such as pharmacodynamic imaging, might reveal treatment response more accurately than traditional serum biomarkers or conventional imaging. The use of positron emission tomography (PET) imaging with novel radiotracers has increased owing to its ability to visualize bone lesions and soft tissue metastases. The use of fluoride 18 NaF as a radiotracer for PET imaging was FDA-approved in 1972; however, its use today is mostly investigational. Sodium fluoride is a bone-seeking imaging agent that is taken up in areas of new bone formation. F-18 NaF PET/CTs demonstrate exquisite sensitivity for bone metastases [26]. Alterations in bone response to therapy might indicate that a drug is engaging its target, which has led to pharmacodynamic imaging as a response marker for targeted therapies. For example, Yu et al. demonstrated a change in vascular parameters using pre- and post-NaF PET/CT in patients receiving investigational dasatinib [27]. In addition to fluoride 18 NaF, 18F-dihydrotestosterone has been used as a radiotracer in 4
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other studies assessing AR-directed therapies [28]. Although rather time consuming, expensive and requiring expertise in interpretation, use of novel tracers in PET/CTs could aid in drug development by providing early evidence of treatment effect. One challenge is the short half-life of some of the innovative tracers, requiring the on-site availability of a cyclotron.
Challenges of immune therapy Immunologic therapy presents unique challenges in clinical trial design. Sipuleucel-T, an autologous dendritic cellular immunotherapy, is approved in minimally symptomatic or asymptomatic CRPC, based on a survival benefit and tolerable safety profile [29]. Although it improved overall survival, there was no difference in PFS compared to the control arm. Furthermore, the response rate and PSA decline were no different in the sipuleucel-T-treated patients than in placebo-treated patients. Thus, the conventional measures of drug activity, such as PSA decline, radiographic response rate and PFS, are not helpful in studies using sipuleucel-T, and possibly other immune therapies. Therefore, determining clinical benefit in early phase clinical trials remains a significant challenge. In the case of immune therapy, evaluating immune response, such as through the measurement of sera cytokine levels, or specific T cell populations, is crucial to the development of future therapies. Modified clinical endpoints, such as extended observation for progression of disease, that allow for delayed treatment effects could also be considered in trials of immunotherapy.
Adaptive clinical design Although there are no predictive biomarkers that are currently in use for prostate cancer, other methods can serve to enrich patient populations. Prognostic factors, such as performance status, age, serum lactate dehydrogenase concentrations, tumor Gleason score, patient-reported pain and the presence of visceral metastatic disease, can define risk groups most in need of novel treatments. They could also serve to decrease the clinical heterogeneity of patients enrolled in clinical trials. Stratification using biomarkers is also emerging as a tool for better understanding and defining patient populations. For example, Ryan et al. retrospectively analyzed COU-AA-301, a randomized, double-blinded study of AA plus prednisone versus prednisone alone. They determined that serum androgen levels strongly correlated with survival [30]. Another proposed model that simultaneously streamlines drug development and companion diagnostics is an adaptive trial design. Adaptive trial designs continuously integrate acquired biomarker data from current patients on a trial into treatment decisions for future patients participating in the same clinical trial. Identifying putative predictive biomarkers early on and then continuously integrating acquired biomarker data into the ongoing trials are increasingly being recognized as necessary and as the most ethical means for minimizing harm and maximizing patient benefit. Recent examples of clinical studies that have used an adaptive strategy include the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial for non-smallcell lung cancer and the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 (I-SPY 2) trial for locally advanced breast cancer [31,32]. The Trial of Olaparib in Patients with Advanced Castration-Resistant Prostate Cancer (TO-PARP) study is an adaptive trial design that rests on the
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hypothesis that poly(ADP-ribose)polymerase (PARP) inhibition will benefit a select group of patients (NCT01682772).
Concluding remarks The era of personalized medicine has arrived and is shaping therapy in several solid tumors. Recent developments in prostate cancer therapy have yielded many new therapies, but none that is deployed in molecularly defined populations. The need for treatment individualization in prostate cancer is particularly notable because the disease is biologically and clinically heterogeneous. Determining efficacy for novel targeted treatments has been challenging and, in particular in combination with docetaxel chemotherapy, has been disappointing. There are several innovative strategies that could
REVIEWS
improve our ability to evaluate whether or not a drug is hitting its target. The serial analysis of tumor biopsies (in either the primary tumor or site of metastasis), the development of pharmacodynamic imaging with novel radiotracers and the evaluation of CTCs have all lead to important biologic insights. We expect these advances increasingly to define clinical trials and ultimately clinical care for prostate cancer. The sharing of biologic and clinical data is another priority for the field. The robust development of prognostic and predictive biomarkers requires access to larger datasets than any one investigator, institution or sponsor can muster.
Conflict of interest The authors declare no conflicts of interest.
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24 Shaffer, D.R. et al. (2007) Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin. Cancer Res. 13, 2023–2029 25 Scher, H.I. et al. (2011) Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castrationresistant prostate cancer (mCRPC): planned final analysis (FA) of COU-AA-301, a randomized double-blind, placebo-controlled phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J. Clin. Oncol. 29 abstr. LBA4517 26 Schirrmeister, H. et al. (2001) Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer. J. Nucl. Med. 42, 1800–1804 27 Yu, E.Y. et al. (2013) Correlation of 18F-fluoride PET response to dasatinib in castration-resistant prostate cancer bone metastases with progression-free survival: preliminary results from ACRIN 6687. J. Clin. Oncol. 31 abstr. 5003 28 Autio, K.A. et al. (2013) Evaluating 18F-16B-fluoro-5a-dihydrotestosterone (FDHT) and FDG-PET as a measure of disease progression in metastatic castration resistant prostate cancer (mCRPC). J. Clin. Oncol. 31 abstr. 5090 29 Kantoff, P.W. et al. (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 30 Ryan, C.J. et al. (2013) Serum androgens as prognostic biomarkers in castrationresistant prostate cancer: results from an analysis of a randomized phase III trial. J. Clin. Oncol. 31, 2791–2798 31 Kim, E.S. et al. (2011) The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 1, 44–53 32 Barker, A.D. et al. (2009) I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin. Pharmacol. Ther. 86, 97–100 33 Scher, H.I. et al. (2011) Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castrationresistant prostate cancer. J. Clin. Oncol. 29, 2191–2198 34 Small, E. et al. (2009) A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). GU CA Symp. abstr. 07 35 Quinn, D.I. et al. (2013) Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial. Lancet Oncol. 14, 893–900 36 Fizazi, K.S. et al. (2013) Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 31, 1740–1747 37 Petrylak, D.P. et al. (2012) A phase 3 study to evaluate the efficacy and safety of docetaxel and prednisone (DP) with or without lenalidomide (LEN) in patients with castrateresistant prostate cancer (CRPC): the MAINSAIL trial. Ann. Oncol. 23 abstr. LBA24 38 Kelly, W.K. et al. (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J. Clin. Oncol. 30, 1534–1540 39 Araujo, J.C. et al. (2013) Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 14, 1307–1316 40 Tannock, I. et al. (2013) Aflibercept versus placebo in combination with docetaxel/ prednisone for first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC): results from the multinational phase III trial (VENICE). J. Clin. Oncol. 31 abstr. 13
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