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Breast and prostate cancers are generally considered immunologically ‘cold’ tumors due to multiple mechanisms rendering them unresponsive to immune checkpoint blockade therapies. With little success in garnering positive outcomes in modern immunotherapeutic clinical trials, it is prudent to re-examine the role of immunogenic neoantigens in these cold tumors. Gene fusions are driver mutations in hormone-driven cancers that can result in alternative mutation-specific neoantigens to promote immunotherapy sensitivity. This review focuses on 1) gene fusion formation mechanisms in neoantigen generation; 2) gene fusion neoantigens in cancer immunotherapeutic strategies and associated clinical trials; and 3) challenges and opportunities in computational and liquid biopsy technologies. This review is anticipated to initiate further research into gene fusion neoantigens of cold tumors for further experimental validation.

Purpose: To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer. Patients and Methods: An exploratory exposure–response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration–time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia. Results: A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure. Conclusions: The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure–safety analysis supports dose reductions in patients experiencing adverse events.

Current biotechnological developments are driving a significant shift towards integrating proteomic analysis with landmark genomic, methylomic, and transcriptomic data to elucidate functional effects. For the majority of proteins, structure and function are closely intertwined. Post-translational protein modifications (e.g., phosphorylation) leading to aberrantly active structures can originate a wide variety of pathological conditions, including cancer. Analysis of protein structure variants is thus integral to the identification of clinically actionable targets and the design of novel disease diagnosis and therapy approaches. However, it is still challenging to interrogate subtle structural changes of proteins in a rapid and cost-effective manner with current tools. This review primarily compiles the latest biosensing techniques for protein structural analysis.

Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.

Many biological events such as mutations or aberrant post-translational modifications can alter the conformation and/or folding stability of proteins and their subsequent biological function, which may trigger the onset of diseases like cancer. Evaluating protein folding is hence crucial for the diagnosis of these diseases. Yet, it is still challenging to detect changes in protein folding, especially if they are subtle, in a simple and highly sensitive manner with the current assays. Herein, we report a new colloidal-based interfacial biosensing approach for qualitative and quantitative profiling of various types of changes in protein folding; from denaturation to variant conformations in native proteins, such as protein activation via mutations or phosphorylation. The approach is based on the direct interfacial interaction of proteins freely available in solution with added tannic-acid-capped gold nanoparticles, to interrogate their folding status in their solubilized form. We found that under the optimized conditions, proteins can modulate colloids solvation according to their folding or conformational status, which can be visualized in a single step, by the naked eye, with minimal protein input requirements (limit of detection of 1 ng/μL). Protein folding detection was achieved regardless of protein topology and size without using conformation-specific antibodies and mutational analysis, which are the most common assays for sensing malfunctioning proteins. The approach showed excellent sensitivity, superior to circular dichroism, for the detection of the very subtle conformational changes induced by activating mutations and phosphorylation in epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) proteins. This enabled their detection even in complex samples derived from lung cancer cells, which contained up to 95% excess of their wild-type forms. A broader clinical translation was shown via monitoring the action of conformation-restoring drugs, such as tyrosine kinase inhibitors, on EGFR conformation and its downstream protein network, using the ERK protein as a surrogate.

Neoadjuvant therapy for breast cancer enables improved conservative operative approaches for breast cancer with similar survival. In addition, it may be used to define clinical as well as molecular systemic therapy sensitivity, aid molecular subtyping analysis of residual disease as well as incorporating potential mechanisms of resistance. Breast cancer in women in the Middle East is characterized by younger median age, more advanced stage at presentation and a higher proportion of patients with triple-negative disease. Recently, Symmans et al. published the results of neoadjuvant anthracycline+/-taxane-based chemotherapy demonstrating a strong association between residual cancer burden (RCB) and overall survival. In this and other cohorts e.g. TCGA, ICGC molecular data of pts from the Middle-East is under-represented. Aim: The aim of this project was to define the above parameters in a cohort of women treated with systemic therapy from June 2016 to October 2017 in a Middle Eastern breast cancer referral centre treated in the neo/adjuvant setting. In the neoadjuvant setting we are examining the association between primary biopsy and pathological response tissue (RCB criteria) integrating molecular pathology using massive parallel sequencing (MPS) analyses. Methodology: We designed a custom 1000 gene panel using Illumina IDT capture-based assay design and sequenced tumour samples to greater than 500X coverage. Sequencing analysis and variant calling were performed using Broad GAKT best practice; BWA, Mutect2, Oncotator pipeline. Results: We present a cohort of 57 pts with median age of 45(26-66), presenting with clinical stage I 2(4%), stageII 30(53%), stage III 25(44%) breast cancer for neoadjuvant (20) or adjuvant (37) anthracycline +/- taxane-based chemotherapy. Standard immunohistochemical (IHC) analysis revealed ER-pos PR-pos HER2-neg 38(67%) ER-pos PR-neg HER2-neg 2(4%) ER-neg PR-neg HER2-pos 3(5%), ER-pos PR-pos HER2-pos 5(9%), TNBC 9(16%). In the neoadjuvant cohort (20) pts, 7 were clinical stage II and 12 stage 3 at presentation. Anthracycline+/-taxane-based chemotherapy achieved pCR/RCB 0 7(35%), RCB I 3(15%), RBC II 4(20%), RCB III 6(30%). All Her2 positive patients received concurrent taxane-trastuzumab. Implications: Predictive molecular expression algorithms for response to systemic chemotherapy in the neoadjuvant setting have been published (Hatzis JAMA 2011; Masuda Clin Ca Res 2013).Molecular characterisation of RCB after neoadjuvant chemotherapy has looked at DNA mutations (Jiang PLOS Med 2016) and RNA expression (Lehmann J PLOS One 2016; Echavarria Clin Ca Res 2018). Integration of both provides insight into mechanisms of sensitivity and relapse using pathway analysis. We present genomic data on 20 of the neoadjuvant samples with sufficient quality DNA analysed using a custom designed 1000 gene panel using Illumina IDT capture-based assay design to greater than 500X coverage. The most commonly aberrant genes TP53, PIK3CA, GATA3, KMT2Dwere observed, with notable differences in PAX3, BRCA2, CHD2, FGFR4. Using integrated comprehensive tumour molecular comparisons pre- and post-treatment in the neoadjuvant patients and circulating tumour DNA analyses of the whole cohort will be presented. Citation Format: Dawood S, Korbie D, Pheasant M, Kazim H, Al Hamadi A, Lloyd C, Dent R, Mainwaring PN. The molecular characterisation of early and advanced breast cancer in a Middle-Eastern breast cancer cohort treated with neo/adjuvant anthracycline+/-taxane-based chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-21.

Background: Although preclinical data suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance, results from randomized clinical trials have failed to identify a subgroup of patients that derive a substantial benefit. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib can increase the anti-tumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Methods: In this randomized, open-label, phase 2 study, 167 postmenopausal women with newly diagnosed, operable, ER-positive, HER2-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to two-weeks of preoperative treatment with anastrozole 1 mg once daily or the combination of anastrozole 1mg with pictilisib 260 mg once daily. The primary endpoint was inhibition of tumor cell proliferation, as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. Secondary endpoints include induction of apoptosis (Caspase3) and safety. Comprehensive biomarkers analyses included targeted NGS of a comprehensive cancer panel of >400 genes (Ampliseq Comprehensive Cancer panel), copy number variation analyses, and pre- and post-treatment reverse-phase protein arrays (RPPA) and RNA profiling (NanoString nCounter platform). Results:There was significantly greater geometric mean Ki67 suppression of 82.5% (90% CI, 78.3%-85.8%) for the combination vs 70.7% (61.0%-78.0%) for anastrozole [geometric mean ratio (combination/ anastrozole) 0.60 (0.58-0.85);p=0.01]. Higher baseline Ki67, Luminal B status and/or negative PR status were associated with increased benefit from adding pictilisib. A significant interaction was observed between PIK3CA mutation subtypes [helical domain mutations (HD), kinase domain mutations (KD), wildtype (WT)] and mean Ki67 suppression; the combination/anastrozole geometric mean ratio of Ki67 suppression was 0.48 (0.27-0.84; p=0.02) for patients with HD mutations and 0.63 (0.39–1.0; p=0.05) for patients with PIK3Ca WT, compared to 1.17 (0.57–2.41; p=0.64) for patients with KD mutations. This was largely due to patients with HD mutations showing a particularly poor response to anastrozole alone [mean Ki67 suppression 53.9% (9.5%-76.5%)], that was reversed by the addition of pictilisib [mean Ki-67 suppression 78.1% (71.0%-83.4%)]. On the other hand, patients with KD mutations responded well to anastrozole alone [mean Ki-67 suppression 77.7% (57.0%-88.4%)] and showed no benefit from the addition of pictilisib [mean Ki-67 suppression 73.9% (59.8%-83.0%)]. There was no significant difference in induction of apoptosis between treatment groups. Comprehensive pre- and post-treatment biomarkers analyses will be presented. Conclusions: Adding pictilisib to anastrozole significantly increases the anti-proliferative response to preoperative treatment with anastrozole. A significant interaction was observed between PIK3CA mutation subtypes, with patients with helical domain mutations showing a particularly poor response to anastrozole alone that was reversed by the addition of pictilisib. Citation Format: Schmid P, Pinder S, Wheatley D, Zummit C, Macaskill EJ, Hu J, Price R, Bundred N, Hadad S, Shia A, Sarker S-J, Lim L, Mousa K, O'Brien C, Wilson TR, Lackner MR, Gendreau S, Gazinska P, Korbie D, Trau M, Mainwaring P, Thompson A, Purushotham A. Interaction of PIK3CA mutation subclasses with response to preoperative treatment with the PI3K inhibitor pictilisib in patients with estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-02.

The introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients., There is a clinical need to monitor immune-related toxicities of immune checkpoint blockade therapy. Here, the authors develop a digital SERS platform for multiplexed single cytokine counting to track immune-toxicities and demonstrate the ability to use pre-screening to identify patients at higher risk.

Background The phase 3 SPARTAN study evaluated apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and prostate-specific antigen doubling time of ≤10 mo. At primary analysis, apalutamide improved median metastasis-free survival (MFS) by 2 yr and overall survival (OS) data were immature. Objective We report the prespecified event-driven final analysis for OS. Design, setting, and participants A total of 1207 patients with nmCRPC (diagnosed by conventional imaging) were randomised 2:1 to apalutamide (240 mg/d) or placebo, plus on-going androgen deprivation therapy. After MFS was met and the study was unblinded, 76 (19%) patients still receiving placebo crossed over to apalutamide. Outcome measurements and statistical analysis OS and time to cytotoxic chemotherapy (TTChemo) were analysed by group-sequential testing with O’Brien-Fleming-type alpha spending function. Results and limitations At median 52-mo follow-up, 428 deaths had occurred. The median treatment duration was 32.9 mo for apalutamide group and 11.5 mo for placebo group. Median OS was markedly longer with apalutamide versus placebo, reaching prespecified statistical significance (73.9 vs 59.9 mo, hazard ratio [HR]: 0.78 [95% confidence interval {CI}, 0.64–0.96]; p = 0.016). Apalutamide also lengthened TTChemo versus placebo (HR: 0.63 [95% CI, 0.49–0.81]; p = 0.0002). Discontinuation rates in apalutamide and placebo groups due to progressive disease were 43% and 74%, and due to adverse events 15% and 8.4%, respectively. Subsequent life-prolonging therapy was received by 371 (46%) patients in the apalutamide arm and by 338 (84%) patients in the placebo arm including 59 patients who received apalutamide after crossover. Safety was consistent with previous reports; when adverse events were adjusted for treatment exposure, rash had the greatest difference of incidence between the apalutamide and placebo groups. Conclusions Extension of OS with apalutamide compared with placebo conferred impactful benefit in patients with nmCRPC. There was a 22% reduction in the hazard of death in the apalutamide group despite 19% crossover (placebo to apalutamide) and higher rates of subsequent therapy in the placebo group. Patient summary With data presented herein, all primary and secondary study end points of SPARTAN were met; findings demonstrate the value of apalutamide as a treatment option for nonmetastatic castration-resistant prostate cancer.

Background: Using progression-free survival (PFS)2, time from randomization to 2nd disease progression or death, is proposed as a surrogate for overall survival (OS) in oncology clinical trials. We used published data from solid tumor trials to assess whether PFS2 and OS are correlated. Methods: A literature search identified studies that reported PFS, PFS2, and OS. Two reviewers screened for eligibility, and documented PFS2, PFS or time from 1st to 2nd disease progression or death and OS. Correlation between PFS2 and OS was assessed using: (1) Kendall's Tau + Pearson's correlation coefficient in randomized controlled trials (RCTs); (2) Meta-analysis with the random effects model to compute the pooled correlation of PFS2 and OS. Results: Overall, 133 studies met search criteria, 15 (28 arms) had complete PFS2 and OS data in ovarian, gastric, colorectal, prostate, lung, renal and breast cancers. A positive correlation for PFS2 and OS was found for all 15 studies (Kendall's Tau = 0.7 [95% CIs 0.54, 0.78]); 10 RCTs (Pearson's correlation coefficient = 0.86); and meta-analysis from 7 trials (pooled Spearman's correlation coefficient = 0.84 [p = 0.0001; 95% CIs 0.71, 0.96]). Conclusions: In this retrospective analysis PFS2 strongly correlates with OS supporting the use of PFS2 to measure long-term clinical benefit when OS cannot be assessed.

5516 Background: SPARTAN evaluated APA vs PBO in pts with nmCRPC and a prostate-specific antigen doubling time of ≤ 10 mo receiving androgen deprivation therapy (ADT). At primary end point analysis of metastasis-free survival (MFS), APA significantly improved median MFS by 2 yrs, as well as time to metastasis, progression-free survival, and time to symptomatic progression vs PBO (Smith, et al. NEJM 2018); overall survival (OS) results were immature. SPARTAN was unblinded upon meeting the primary end point; pts still on PBO were allowed to cross over to APA. Final survival results are reported herein. Methods: 1207 nmCRPC pts were randomized 2:1 to APA (240 mg QD) or PBO plus ongoing ADT. At progression, pts could receive open-label sponsor-provided abiraterone acetate + prednisone. After the primary efficacy end point (MFS) was met, 76 PBO pts (19%) crossed over to APA. OS and time to cytotoxic chemotherapy (TTCx) were tested by group sequential testing procedure with O’Brien-Fleming (OBF)-type alpha spending function. Time-to-event end points were analyzed by Kaplan-Meier method and Cox model. A sensitivity analysis for OS, accounting for crossover using a naïve censoring approach, was conducted. Results: With follow-up of 52.0 mo, 428 (of 427 required) OS events had occurred. Median treatment duration: APA, 32.9 mo; PBO, 11.5 mo. Median OS was significantly longer with APA + ADT vs PBO + ADT (73.9 vs 59.9 mo), (hazard ratio [HR], 0.784, Table). APA significantly lengthened TTCx (HR, 0.629). Discontinuation rates (APA vs PBO) due to progressive disease were 42.7% vs 73.9%, and due to adverse events (AE) 15.2% vs 8.4%. Safety was consistent with previous reports; grade 3/4 treatment-emergent (TE) AEs of special interest were rash 5.2%, fractures 4.9%, falls 2.7%, ischemic heart disease 2.6%, hypothyroidism 0%, and seizures 0%. 1 TEAE leading to death (myocardial infarction) was considered potentially APA related. Conclusions: In pts with nmCRPC, APA + ADT significantly improved OS compared with PBO + ADT, with median OS > 6 yr in the APA + ADT group and 14 mo improvement over PBO + ADT. Benefit from APA was observed despite a 19% crossover from PBO. The safety profile of APA was consistent with prior interim analyses. Clinical trial information: NCT01946204 . [Table: see text]

The use of emerging nanotechnologies, such as plasmonic nanoparticles in diagnostic applications, potentially offers opportunities to revolutionize disease management and patient healthcare. Despite worldwide research efforts in this area, there is still a dearth of nanodiagnostics which have been successfully translated for real-world patient usage due to the predominant sole focus on assay analytical performance and lack of detailed investigations into clinical performance in human samples. In a bid to address this pressing need, we herein describe a comprehensive clinical verification of a prospective label-free surface-enhanced Raman scattering (SERS) nanodiagnostic assay for prostate cancer (PCa) risk stratification. This contribution depicts a roadmap of (1) designing a SERS assay for robust and accurate detection of clinically validated PCa RNA targets; (2) employing a relevant and proven PCa clinical biomarker model to test our nanodiagnostic assay; and (3) investigating the clinical performance on independent training ( n = 80) and validation ( n = 40) cohorts of PCa human patient samples. By relating the detection outcomes to gold-standard patient biopsy findings, we established a PCa risk scoring system which exhibited a clinical sensitivity and specificity of 0.87 and 0.90, respectively [area-under-curve of 0.84 (95% confidence interval: 0.81-0.87) for differentiating high- and low-risk PCa] in the validation cohort. We envision that our SERS nanodiagnostic design and clinical verification approach may aid in the individualized prediction of PCa presence and risk stratification and may overall serve as an archetypical strategy to encourage comprehensive clinical evaluation of nanodiagnostic innovations.

AIM The phase III MPACT trial (N = 861) demonstrated superior overall survival (OS) with first-line nab-paclitaxel plus gemcitabine versus gemcitabine alone (median, 8.7 months vs 6.6 months; hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62-0.83; P

It is a well-known phenomenon that cancer cells release key biological information such as DNA, RNA or proteins into body fluids (e.g., blood, urine or saliva). The analysis of these molecules-often encapsulated within nanovesicules called exosomes-is highly attractive, because it could replace current surgical biopsies, which are painful, costly and potentially risky for patients. For example, current strategies in lung cancer diagnosis involve genetic analyses from tumour tissues to detect the presence of underlying DNA mutations, known to alter the phosphorylation status and function of proteins. This information is used to direct therapy, as aberrantly phosphorylated proteins are the main targets of current drugs such as Tyrosine Kinase Inhibitors (TKIs). An alternative and less invasive strategy would be the remote analysis of these phospho-proteins by isolating them from cancer-derived exosomes. This would allow evaluating not only their phosphorylation status at diagnosis, but also the timely restoration of protein phosphorylation levels during therapy with TKIs. Yet, this proteomic approach remains vastly unexplored. Herein, we demonstrate that key lung cancer phosphoproteins, such as EGFR and ERK, are expressed in lung cancer exosomes and we outline a new exosomal proteomic-based approach for their fast and convenient detection. This approach, which could complement current genetic analysis for lung cancer detection, easily detects the phosphorylation status of lung cancer exosomal proteins within minutes after their extraction, bringing hope of circumventing the need for tissue biopsy and costly and cumbersome DNA sequencing techniques. It exploits the fact that phosphorylation induces protein conformational changes, which in turn alter protein's ability to effectively interact with bare gold surfaces. This leads to phosphorylated and non-phosphorylated protein isoforms displaying different gold-adsorption profiles. Using single-use and inexpensive, gold (Au) screen-printed electrodes (SPEs), we demonstrate the successful detection of aberrantly phosphorylated EGFR and ERK protein isoforms derived from lung cancer cell exosomes with a sensitivity down to 15 ng μL-1 in samples with up to 90% excess of their non-phosphorylated (wild-type) forms. We further show the applicability of this strategy for monitoring the action of Tyrosine Kinase Inhibitors over time. We believe that this non-invasive technique will open up new avenues for facilitating cancer diagnosis and time-point monitoring of therapeutic responses.

Protein phosphorylation is one of the most prominent post-translational mechanisms for protein regulation, which is frequently impaired in cancer. Through the covalent addition of phosphate groups to certain amino-acids, the interactions of former residues with nearby amino-acids are drastically altered, resulting in major changes of protein conformation that impacts its biological function. Herein, we report that these conformational changes can also disturb the protein's ability to interact with and adsorb onto bare gold surfaces. We exploited this feature to develop a simple electrochemical method for detecting the aberrant phosphorylation of EGFR protein in several lung cancer cell lines. This method, which required as low as 10 ng/µL (i.e., 50 ng) of purified EGFR protein, also enabled monitoring cell sensitivity to tyrosine kinase inhibitors (TKI) ― a common drug used for restoring the function of aberrantly phosphorylated proteins in lung cancer. The reported strategy based on direct gold-protein affinity interactions avoids the conventional paradigm of requiring a phospho-specific antibody for detection and could be a potential alternative of widely used mass spectrometry.

Background In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). Methods One thousand two hundred and seven patients with nmCRPC were randomized 2-:-1 to apalutamide (240-mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien–Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. Results Median follow-up was 41-months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59–0.96; P-=-0.0197), although the P-value did not cross the pre-specified O'Brien–Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45–0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. Conclusion In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

The accurate identification and stratified treatment of clinically significant early-stage prostate cancer have been ongoing concerns since the outcomes of large international prostate cancer screening trials were reported. The controversy surrounding clinical and cost benefits of prostate cancer screening has highlighted the lack of strategies for discriminating high-risk disease (that requires early treatment) from low-risk disease (that could be managed using watchful waiting or active surveillance). Advances in molecular subtyping and multiomics nanotechnology-based prostate cancer risk delineation can enable refinement of prostate cancer molecular taxonomy into clinically meaningful and treatable subtypes. Furthermore, the presence of intertumoural and intratumoural heterogeneity in prostate cancer warrants the development of novel nanodiagnostic technologies to identify clinically significant prostate cancer in a rapid, cost-effective and accurate manner. Circulating and urinary next-generation prostate cancer biomarkers for disease molecular subtyping and the newest complementary nanodiagnostic platforms for enhanced biomarker detection are promising tools for precision prostate cancer management. However, challenges in merging both aspects and clinical translation still need to be overcome.

INTRODUCTION AND OBJECTIVES:The DECIPHER prostate test (GenomeDx Biosciences, Inc., San Diego, CA) is a clinical-grade mRNA-based test with a genomic classifier (GC) score that has been independent...

INTRODUCTION AND OBJECTIVES:SPARTAN, a randomized phase 3 placebo (PBO)-controlled study in pts with high-risk nmCRPC, demonstrated that APA added to androgen deprivation therapy (ADT) prolonged me...

INTRODUCTION AND OBJECTIVES:APA, a next-generation androgen receptor inhibitor, added to androgen deprivation therapy (ADT) improved MFS by > 2 years (median 40.5 vs 16.2 mo; p < 0.0001) in high-ri...

42 Background: The SPARTAN trial recently demonstrated that addition of APA to androgen deprivation therapy (ADT) improved metastasis-free survival (MFS) and second progression-free survival (PFS2) in nmCRPC pts. We performed transcriptome-wide profiling of available primary tumor samples from pts in SPARTAN to evaluate potential biomarkers of response or resistance to APA+ADT. Methods: Pts included in SPARTAN were at high risk of developing metastasis.We used a commercially available genomic assay (DECIPHER prostate test, GenomeDx Biosciences, Inc., San Diego, CA) to assess gene expression in 233 archived primary tumors from SPARTAN pts. Using a Cox proportional hazard model, we assessed the association between scores and subtypes from previously derived prognostic and predictive gene signatures, such as DECIPHER and basal (BA) vs luminal (LU) subtyping. Results: Pts with high DECIPHER scores had greater treatment effect with APA+ADT than those with low scores. Pts with LU, a subtype known to be sensitive to ADT, greatly benefited from APA+ADT. Pts with BA, typically resistant to ADT, also benefited from APA+ADT. Conclusions: DECIPHER score and BA or LU subtype may be biomarkers of response to APA+ADT. DECIPHER may be useful for identifying pts for early treatment intensification with APA or other agents, and molecular subtyping may be an effective approach for pt selection in trials combining novel therapies with APA. Clinical trial information: NCT01946204. [Table: see text]

144 Background: In the phase 3 SPARTAN study, compared with placebo (PBO), APA, a next-generation androgen receptor inhibitor, decreased the risk of distant metastasis or death by 72% (hazard ratio [HR], 0.28; p < 0.0001) in men with high-risk nmCRPC. After 1 year of additional follow-up, PFS2 and safety were reevaluated to ensure maintenance of benefit against potential harm. Methods: Pts with nmCRPC and prostate-specific antigen doubling time of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) + androgen deprivation therapy (ADT) or PBO + ADT. All pts who developed distant metastasis, determined by blinded independent central review, were eligible to receive subsequent therapy including open-label treatment with abiraterone acetate + prednisone, provided by the sponsor. The exploratory PFS2 end point (time from randomization to disease progression on subsequent anticancer therapy or death) was evaluated, as was incidence of treatment-emergent adverse events (TEAEs). Results: Median treatment duration with APA was 25.7 mos; with PBO, 11.5 mos (original analysis, mos: APA, 19.2; PBO, 11.2). Pts randomized to APA continued to show significant benefit in PFS2 (HR, 0.5; 95% CI, 0.39-0.63; p < 0.0001) vs PBO (APA median time to PFS2 not reached vs PBO 39.3 mos). At a median follow-up of 32 mos, 51.3% of pts receiving APA, 8% of the 75 pts who crossed over from PBO to APA, and 99.7% of remaining PBO pts had discontinued study treatment. Rates of discontinuations due to progressive disease and AEs were 27.3% and 12.7%, respectively, in the APA group and 73.4% and 8.4% in the PBO group. There was no substantial change in the incidence of TEAEs in the APA group at the 1-year update. With regard to drug specific TEAEs, there were no grade 4 or 5 events; grade 3 TEAEs consisted of rash, 5.2%; falls, 2.4%; fractures, 3.1%; hypothyroidism, 0%; and seizures, 0%. Conclusions: APA was previously shown to result in an improvement in metastasis-free survival and symptomatic progression. With a median APA treatment duration of 25.7 mos, APA continues to show significant benefit in PFS2, and its safety profile remains unchanged. Clinical trial information: NCT01946204.

5024 Background: SPARTAN, a randomized phase 3 placebo (PBO)-controlled study in pts with high-risk nmCRPC and PSA doubling time ≤ 10 mo, showed that, compared with PBO, addition of APA to ongoing ADT treatment (tx) prolonged metastasis-free survival (MFS) by > 2 y, reduced the risk of symptomatic progression by 55%, and increased second progression-free survival (PFS2), which is the time from randomization to disease progression on first subsequent anticancer tx, or death. The impact of APA in terms of benefit and safety profile was evaluated in pts aged < 65, 65-74, and ≥ 75 y. Methods: Pts with nmCRPC were randomized 2:1 to APA (240 mg QD) or PBO; ADT was continuous. APA effect was analyzed by Cox models and Kaplan-Meier methods across age subgroups. Results: Baseline characteristics among age groups were similar, although ECOG PS 1 vs 0 increased with age. MFS benefit with APA was highly significant for all age subgroups (Table). In pts ≥ 75 y, MFS risk with APA vs PBO was reduced by 59%; MFS risk was reduced by 86% and 76% for pts < 65 and 65-74 y, respectively. Risk of PFS2 with APA vs PBO was reduced across all age subgroups. PFS2 in pts < 65, 65-74, and ≥ 75 y: HR, 0.09 (p < 0.0001); HR, 0.56 (p = 0.0343); HR, 0.59 (p = 0.0092), respectively. Risk of symptomatic progression was lessened with APA vs PBO for all age subgroups (Table). There was a similar increase in incidence of tx-emergent adverse events (TEAE) with age in both tx arms that remained higher with APA. Incidence of grade 3/4 TEAE (≥ 75 vs < 65 y): APA, 50% vs 37%; PBO, 37% vs 28%. Conclusions: Pts in all age subgroups with high-risk nmCRPC had significant improvement in MFS with APA + ongoing ADT. The safety profile of APA was similar across age subgroups. Clinical trial information: NCT01946204. [Table: see text]

Purpose: Marizomib (NPI-0052) is an irreversible proteasome inhibitor, derived from a marine actinomycete, with activity and specificity that is distinct from other proteasome inhibitors. Experimental Design: Phase I study (NPI-0052-102) evaluated the MTD, pharmacokinetics, and pharmacodynamics of marizomib intravenously on two dosing schedules. Results: Forty-two patients with advanced malignancies received Schedule A (0.1–0.9 mg/m2 over 1–10 minutes on days 1, 8, 15 in 4-week cycles); 44 patients with relapsed and/or refractory multiple myeloma (RRMM) and other hematologic malignancies received Schedule B (0.075–0.6 mg/m2 over 1 minute to 2 hours on days 1, 4, 8, 11, in 3-week cycles). The Schedule A recommended phase II dose was 0.7 mg/m2 over 10 minutes; Schedule B was 0.5 mg/m2 over 2 hours. The most common (>25% of patients) related adverse events were fatigue, nausea, diarrhea, and infusion site pain (Schedule A); and fatigue (Schedule B). Overall response rate of 11% was seen in 27 efficacy-evaluable RRMM Schedule B patients (1 very good partial response, 3 partial responses, 4 minimal responses, and 12 stable disease). One Schedule A patient with transformed marginal zone lymphoma had complete response. Marizomib has a short half-life ( Conclusions: Marizomib does not exhibit the severe peripheral neuropathy or hematologic toxicity observed with other proteasome inhibitors. Marizomib was generally well tolerated with low-dose dexamethasone, demonstrated activity in heavily pretreated RRMM patients, and warrants further evaluation. Clin Cancer Res; 22(18); 4559–66. ©2016 AACR.

Purpose Preclinical data support a key role for the PI3K pathway in estrogen receptor–positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Patients and Methods In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. Results There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, ≥ 79.0%) for the combination and 66.0% (95% CI, ≤ 75.4%) for anastrozole (geometric mean ratio [combination:anastrozole], 0.48; 95% CI, ≤ 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, ≤ 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. Conclusion Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer.

Prostate cancer is the main cause of cancer-related mortality among men. And although surgery and radiation have been successful treatments, between 30% and 40% of prostate cancer patients progress to advanced forms of the disease.1 Almost all patients with metastatic prostate cancer go on to develop castration-resistant prostate cancer (CRPC).2 From2004 to 2010, docetaxel-based chemotherapywas the only approved agent for the treatment of metastatic CRPC.3,4 Nevertheless, significant advances in the understanding of the androgen pathway role over the last decade have led to the development of alternative novel hormonal agents such as abiraterone and enzalutamide to treat advanced castration-resistant prostate cancer. Both agents target the androgen axis but with distinct mechanisms of action. Abiraterone inhibits the synthesis of androgen by blocking cytochrome P450 17, while enzalutamide inhibits the androgen

Background: Results from SPARTAN, a phase III placebo (PBO)-controlled study in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC), show that apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) significantly improves metastasis-free survival (MFS) compared with PBO + ADT. This analysis investigated the effects of APA in biologically distinct molecular subclasses of prostate cancer defined by gene expression profiles. Methods: Gene expression profiles (DECIPHER® prostate test, San Diego, CA) were generated from 233 archival primary prostate tumors; data were summarized based on 160 predefined gene signatures indicative of clinical prognosis and prostate cancer-related biology. Unsupervised consensus clustering identified sets of co-regulated expression signatures, and associations between signature expression, treatment, and signature-treatment interaction with MFS were evaluated using Kaplan-Meier analysis and Cox proportional hazards models. Results: Four co-regulated expression signature classes, each with distinct biological pathway functions, were identified. Class C1 included prognosis-related (risk) signatures; C2 included steroid homeostasis-related signatures; C3 included hormonal therapy nonresponsive basal and neuroendocrine-like signatures; C4 included immune and stromal signatures. Increased C1 expression was associated with shorter MFS in the PBO group (HR [95% CI], 2.18 [1.11-4.28], p = 0.02), while it was associated with longer MFS in the APA group (interaction HR [95% CI], APA vs PBO, 0.36 [0.14-0.95], p = 0.04). Similarly, increased C2 expression was associated with shorter MFS in the PBO group (HR [95% CI], 1.42 [1.02-1.98], p = 0.04), while it was associated with longer MFS in the APA group (interaction HR [95% CI], APA vs PBO, 0.57 [0.35-0.93], p = 0.02). Although there is no significant interaction effect between signature and treatment in C3, pts with low expression of C3 (adeno-like) showed longer MFS on APA vs PBO (HR [95% CI], 0.23 [0.13-0.40], p < 0.0001) compared with high-C3-expressing neuroendocrine-like tumors. Increased C4 expression was associated with decreased risk of metastasis in the APA group (HR [95% CI], 0.55 [0.35-0.86], p = 0.008) compared with PBO (interaction HR [95% CI], APA vs PBO, 0.53 [0.28-0.98], p = 0.04). Conclusion: Expression signatures were clustered into 4 correlated unique biological subclasses. Clinical benefit of APA + ADT was observed in pts with expression profiles with high risk (C1), C2, C3, or C4 compared with PBO + ADT. Citation Format: Clemente Aguilar, Michael Gormley, Shibu Thomas, Paul N. Mainwaring, David Olmos, Fred Saad, Simon Chowdhury, Elai Davicioni, Yang Liu, Deborah S. Ricci, Angela Lopez-Gitlitz, Margaret K. Yu, Matthew R. Smith, Eric J. Small, Felix Feng. Novel molecular subtypes identified in prostate cancer: Results from the SPARTAN study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5425.

5521 Background: In SPARTAN, APA + androgen deprivation therapy (ADT) prolonged metastasis-free survival (MFS) and improved PSA kinetics over placebo (PBO) + ADT in high-risk nmCRPC. All molecular subtypes derived benefit in MFS from APA (Feng FY, et al. ASCO GU 2019; abstract 42). We evaluated the association of PSA decline and efficacy outcomes in SPARTAN pts with different molecular subtypes. Methods: Gene expression from archival primary tumors (biomarker population) was assessed with the DECIPHER platform (Decipher Biosciences, Inc.) and stratified into genomic classifier (GC) high- and low-to-average risk using GC score > 0.6 and ≤ 0.6, respectively, and ADT-resistant or -sensitive basal or luminal A/B (PAM50 classifier) subtypes. PSA nadir and confirmed PSA decline (Table) were assessed in APA pts overall and at 3, 6, and 12 mo. Associations between molecular subtypes and outcomes were assessed. Results: Of 233 available samples, 154 were from APA pts; 49% of APA pts had high GC score and 66% had basal subtype. PSA levels at baseline were similar across all subtypes. Regardless of GC score or basal/luminal subtype, > 50% of patients achieved ≥ 90% reduction in PSA with APA. PSA declined faster and PSA reduction was deeper at 6 mo (Table) in GC low to average vs GC high risk and luminal vs basal subtypes. Overall, only luminal vs basal subtypes had a significantly higher % of pts with ≥ 90% PSA decline (Chi square p = 0.037). In luminal pts, deeper PSA decline with APA was consistent with improved MFS vs basal pts. In GC high pts, MFS benefit with APA was similar to that in GC low to average pts despite lower PSA decline. Although GC low to average and luminal pts had more rapid and deeper PSA responses than GC high or basal pts, respectively, all pts derived MFS benefit. Association of long-term outcomes with PSA decline in these molecular subtypes will be presented. Conclusions: In SPARTAN, all molecular subtypes of pts with nmCRPC treated with APA + ADT had MFS benefit and rapid and sustained PSA decline. PSA responses were deepest and most rapid in GC low to average and luminal subtypes. Clinical trial information: NCT01946204 . [Table: see text]

Summary Background In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL). Methods SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1–6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204. Findings Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8–26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group. Interpretation In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL. Funding Janssen Research & Development.

Purpose In the phase III METEOR trial ( ClinicalTrials.gov identifier: NCT01865747), 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive cabozantinib or everolimus. The cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients and Methods Patients completed the 19-item Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI-19) and the five-level EuroQol (EQ-5D-5L) questionnaires at baseline and throughout the study. The nine-item FKSI–Disease-Related Symptoms (FKSI-DRS), a subset of FKSI-19, was also investigated. Data were summarized descriptively and by repeated-measures analysis (for which a clinically relevant difference was an effect size ≥ 0.3). Time to deterioration (TTD) was defined as the earlier of date of death, radiographic progressive disease, or ≥ 4-point decrease from baseline in FKSI-DRS. Results The QoL questionnaire completion rates remained ≥ 75% through week 48 in each arm. There was no difference over time for FKSI-19 Total, FKSI-DRS, or EQ-5D data between the cabozantinib and everolimus arms. Among the individual FKSI-19 items, cabozantinib was associated with worse diarrhea and nausea; everolimus was associated with worse shortness of breath. These differences are consistent with the adverse event profile of each drug. Cabozantinib improved TTD overall, with a marked improvement in patients with bone metastases at baseline. Conclusion In patients with advanced renal cell carcinoma, relative to everolimus, cabozantinib generally maintained QoL to a similar extent. Compared with everolimus, cabozantinib extended TTD overall and markedly improved TTD in patients with bone metastases.

e17010Background: Approved treatments for patients with mCRPC are associated with meaningful improvements in progression-free and overall survival. The burden of mCRPC remains high, however, as it ...

Background Overall survival (OS) has become the definitive endpoint in oncology clinical trials, but may be difficult to assess due to need for lengthy follow-up, factors related to trial design or impacted by study crossover. Progression free survival (PFS) is a common primary endpoint, but, differential response to subsequent therapy may affect the correlation of PFS and OS. The European Medicines Agency encourages the use of PFS2, defined as time from initial study randomization to 2nd disease progression or death from any cause. The surrogacy of PFS2 for OS has not been confirmed. This analysis used published data from solid tumor clinical studies to assess whether PFS2 and OS are correlated. Methods A systematic literature search identified solid tumor oncology studies that included data for PFS, PFS2, and OS. Two independent reviewers screened titles, abstracts and main-text of study reports for eligibility, and collected data on median time to PFS2, PFS or time from 1st progression to 2nd disease progression or death, and median time to OS. The correlation between PFS2 and OS was assessed and verified in two steps: (1) Kendall’s Tau (Kendall rank correlation coefficient) statistics and Pearson’s correlation coefficient in randomized controlled trials (RCTs); (2) Meta-analysis with the random effects model to compute the pooled correlation of PFS2 and OS. Results In total, 133 studies met the search criteria and 15 trials had complete PFS2 and OS data (28 individual treatment and control arms) in ovarian, gastric, colorectal, prostate, lung, renal and breast tumors. A positive correlation was observed between PFS2 and OS (Kendall’s Tau = 0.7 (95% CIs 0.54, 0.78) using all 15 studies. Data from the 10 RCTs showed a Pearson’s correlation coefficient = 0.86. An additional meta-analysis of 3 tumors (breast, colorectal, and lung cancer), where more than 1 study per indication was available (7 studies; 17 individual arms), identified a Spearman’s correlation coefficient = 0.84 (p = 0.0001; 95% CIs 0.71, 0.96). Conclusions In this retrospective analysis in solid tumors, PFS2 was positively correlated with OS. The strong correlation provides confidence in using PFS2 as a surrogate for OS before OS data are mature or when OS cannot be assessed. Editorial acknowledgement Editorial assistance was provided by Ann C Sherwood, PhD with funding from Janssen Pharmaceuticals. Legal entity responsible for the study Janssen Pharmaceuticals. Funding Janssen Pharmaceuticals. Disclosure P.N. Mainwaring: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties: XING Technologies P/L; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer. L. Zhang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. S.D. Mundle: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. K. Liu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen. E. Pollozi: Shareholder / Stockholder / Stock options, Full / Part-time employment: IDEA Pharma; Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer; Advisory / Consultancy: Janssen. A. Gray: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: IDEA Pharma; Advisory / Consultancy: Janssen. M. Wildgust: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen.

Preclinical studies have suggested that purified populations of CD1c (BDCA-1) blood-derived dendritic cells (BDC) loaded with tumor-specific peptides may be a feasible option for prostate cancer immunotherapy. We performed an open-label dose-finding Phase I study to evaluate the safe use of CD1c BDC in patients with advanced metastatic hormone refractory prostate cancer. HLA-A*0201-positive patients with advanced metastatic prostate cancer were recruited and consented. The vaccine was manufactured by pulsing autologous CD1c BDC, prepared by magnetic bead immunoselection from apheresed peripheral blood mononuclear cells, with a cocktail of HLA-A*0201-restricted peptides (prostate-specific antigen, prostate acid phosphatase, prostate specific membrane antigen, and control influenza peptide) and keyhole limpet hemocyanin. The vaccine was administered intradermally or intravenously and peripheral blood was taken at predetermined intervals for clinical and immunologic monitoring. The vaccine was manufactured with a median purity of 82% CD1c BDC and administered successfully to 12 patients. Each patient received between 1 and 5 × 10 fresh CD1c BDC on day 0, followed by cryopreserved product in the same dose on days 28 and 56. The vaccine was well tolerated in all patients, with the most frequent adverse events being grade 1-2 fever, pain, or injection-site reactions. Vaccination with CD1c BDC is therefore feasible, safe, and well tolerated in patients with advanced-stage metastatic prostate cancer.

Purpose In patients with metastatic castration-resistant prostate cancer (mCRPC), overall survival (OS) is significantly improved with cabazitaxel versus mitoxantrone after prior docetaxel treatment. FIRSTANA ( ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel 20 mg/m2 (C20) or 25 mg/m2 (C25) is superior to docetaxel 75 mg/m2 (D75) in terms of OS in patients with chemotherapy-naïve mCRPC. Patients and Methods Patients with mCRPC and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomly assigned 1:1:1 to receive C20, C25, or D75 intravenously every 3 weeks plus daily prednisone. The primary end point was OS. Secondary end points included safety; progression-free survival (PFS); tumor, prostate-specific antigen, and pain response; pharmacokinetics; and health-related quality of life. Results Between May 2011 and April 2013, 1,168 patients were randomly assigned. Baseline characteristics were similar across cohorts. Median OS was 24.5 months with C20, 25.2 months with C25, and 24.3 months with D75. Hazard ratio for C20 versus D75 was 1.01 (95% CI, 0.85 to 1.20; P = .997), and hazard ratio for C25 versus D75 was 0.97 (95% CI, 0.82 to 1.16; P = .757). Median PFS was 4.4 months with C20, 5.1 months with C25, and 5.3 months with D75, with no significant differences between treatment arms. Radiographic tumor responses were numerically higher for C25 (41.6%) versus D75 (30.9%; nominal P = .037, without multiplicity test adjustment). Rates of grade 3 or 4 treatment-emergent adverse events were 41.2%, 60.1%, and 46.0% for C20, C25, and D75, respectively. Febrile neutropenia, diarrhea, and hematuria were more frequent with C25; peripheral neuropathy, peripheral edema, alopecia, and nail disorders were more frequent with D75. Conclusion C20 and C25 did not demonstrate superiority for OS versus D75 in patients with chemotherapy-naïve mCRPC. Tumor response was numerically higher with C25 versus D75; pain PFS was numerically improved with D75 versus C25. Cabazitaxel and docetaxel demonstrated different toxicity profiles, with overall less toxicity with C20.

Abiraterone improves survival, relieves pain, improves quality of life and extends time to prostate-specific antigen (PSA) progression in patients with metastatic castration-resistant prostate cancer (mCRPC). A consensus-based guide for using abiraterone in patients with mCRPC has been developed by Australian clinicians with expertise in prostate cancer, based on their experience and supported by published data. Recommendations were developed for eight key topics: abiraterone administration; steroid administration and duration of use; concomitant medications and drug interactions; timing of testing and monitoring response; safety in different populations; potential toxicities; precautions and contraindications; and referral and multidisciplinary care. Abiraterone is taken orally in a fasting state. Symptoms associated with mineralocorticoid excess are managed by coadministration of low-dose prednisone or prednisolone. Potassium levels, blood pressure and liver function need to be tested frequently during the early treatment phase. Response to treatment is monitored based on symptoms, radiological imaging and PSA levels. Potential adverse consequences of long-term steroid therapy on bone and metabolic health need to be screened for and managed. Advanced prostate cancer is best managed by a multidisciplinary team and early referral should be considered. Questions about the potential use of abiraterone in early disease and in combination with other therapies are being addressed in ongoing clinical trials.

Aim We aimed to systematically review and summarize data from the available clinical trials that examined the treatment of HER2-positive metastatic breast cancer. Methods We reviewed phase 2 and 3 studies in which an anti-HER2 agent was used in one or both arms of the study. While formal meta-analysis was not possible for such a heterogeneous group of trials, resulting forest plots outline some generalizable findings. Results There is strong evidence that the addition of an anti-HER2 agent to standard chemo- or endocrine therapy improves clinically relevant measurable outcomes. There is also consistent evidence that initial treatment with trastuzumab alone (and subsequent use of a cytotoxic) is inferior to the initial combination of trastuzumab plus chemotherapy, and that either T-DM1 or dual anti-HER2 agents are superior to single anti-HER2 agent regimens. There is no strong evidence that the use of more than one cytotoxic agent together with an anti-HER2 agent confers any benefit over a single cytotoxic, anti-HER2 combination. Conclusion This review provides a strong evidence base for current clinical practice with a discussion of treatment in the Australian setting.

Aims We evaluated and compared the safety and efficacy of sunitinib in Asian and non-Asian patients with metastatic renal cell carcinoma enrolled in a previously reported global expanded access program. Methods Previously treated and treatment-naive patients received open-label sunitinib at a starting dose of 50 mg/day for 4 weeks, followed by 2 weeks off treatment, in repeated 6-week cycles. Safety was assessed regularly, tumor measurements were performed per local practice, and survival data collected where possible. Results Data were available for 212 Asian patients from Asian sites (Asian-A), 113 Asian patients from non-Asian sites (Asian-O) and 4046 non-Asian patients. The most common grade 3/4 treatment-related adverse events were neutropenia, thrombocytopenia, hand–foot syndrome, diarrhea, asthenia and fatigue. The incidence of many adverse events was greater in Asian-A than in Asian-O or non-Asian patients. Sunitinib efficacy was comparable between Asian and non-Asian patients, with an objective response rate of 18% versus 14%; median progression-free survival of 8.7 versus 10.9 months; and overall survival of 18.9 versus 18.4 months, respectively. Conclusions Sunitinib demonstrated tolerable safety and similar efficacy in Asian and non-Asian patients. Geographic differences in the reported frequency of specific adverse events were noted across Asian patients.

Background In the phase 3 placebo (PBO)-controlled SPARTAN study, APA with ongoing androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) (HR, 0.28; 95% CI, 0.23-0.35; p Methods Pts with nmCRPC and prostate-specific antigen doubling time of ≤ 10 months were randomized 2:1 to APA (240 mg QD) or PBO, with ongoing ADT. The OS effect of APA vs PBO was assessed using a group sequential testing procedure with O’Brien-Fleming-type alpha spending function. The required p value for statistical significance at IA2 was 0.0121. OS was analyzed by Kaplan-Meier method and Cox model. Results At 41 months’ median follow-up and 285 OS events, APA was associated with improved OS compared with PBO (HR, 0.75; 95% CI, 0.59-0.96; p = 0.0197). The 4-yr OS rates for APA and PBO were 72.1% and 64.7%, respectively. After unblinding the study and prior to IA2, 76 nonprogressing PBO pts (19%) crossed over to open-label APA. At IA2, the proportion of pts who received subsequent life-prolonging therapy was 68% in the PBO group and 38% in the APA group. Rates of discontinuation due to progressive disease and adverse events (AE) were 34% and 14%, for the APA group, and 74% and 8% for the PBO group. The rates of treatment-emergent AEs for APA at IA2 were similar to the rates previously reported at IA1. Conclusions At IA2, APA was associated with a 25% reduction in risk of death compared with PBO. This OS benefit for APA was observed despite crossover of PBO pts to APA and higher rates of subsequent life-prolonging therapy for PBO pts. APA safety profile remained unchanged. These results further support APA as a standard of care option for pts with high-risk nmCRPC. Clinical trial identification NCT01946204. Editorial acknowledgement William Turner, PAREXEL. Legal entity responsible for the study Janssen Research & Development. Funding Janssen Research & Development. Disclosure M.R. Smith: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Janssen Oncology; Advisory / Consultancy: Amgen; Advisory / Consultancy: Pfizer; Research grant / Funding (self): Gilead Sciences. F. Saad: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Janssen Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: AstraZeneca/Medimmune; Honoraria (self): AbbVie; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Oncogenex. S. Chowdhury: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Johnson & Johnson; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Clovis. S. Oudard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai. B.A. Hadaschik: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy: Lightpoint Medical; Research grant / Funding (self): Profound Medical; Research grant / Funding (self): German Cancer Aid; Research grant / Funding (self): German Research Foundation; Travel / Accommodation / Expenses: AstraZeneca. J.N. Graff: Honoraria (self), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy: Exelixis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Travel / Accommodation / Expenses: Clovis Oncology; Licensing / Royalties: Oncoresponse: Exceptional responders; Honoraria (self): Astellas Medivation; Honoraria (self), Research grant / Funding (institution): Janssen Oncology; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Bristol-Myers Squibb. D. Olmos: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Clovis Oncology; Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Sanofi; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Astellas Medivation; Research grant / Funding (institution): Tokai Pharmaceuticals. P.N. Mainwaring: Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Pfizer; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen Oncology; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Medivation/Astellas; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Licensing / Royalties: 4 patents on nanotechnology; Shareholder / Stockholder / Stock options: Xing Technologies; Research grant / Funding (self): Merck KGaA. H. Uemura: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Sanofi; Honoraria (self): Daiichi-Sankyo; Honoraria (self): Merck Sharp Dohme. P. De Porre: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. A. Smith: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. K. Zhang: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. A. Lopez-Gitlitz: Full / Part-time employment: Janssen Research & Development; Shareholder / Stockholder / Stock options: Johnson & Johnson. E.J. Small: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Fortis; Advisory / Consultancy: Janssen Oncology; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Shareholder / Stockholder / Stock options: Harpoon Therapeutics. All other authors have declared no conflicts of interest.

Background: The SPARTAN study recently demonstrated that the addition of APA to androgen deprivation therapy (ADT) improved metastasis-free survival (MFS) and second progression-free survival (PFS2) in pts with nmCRPC defined by conventional imaging. We performed transcriptome-wide profiling of available primary tumor samples from pts in SPARTAN to evaluate predictors of response or resistance to APA + ADT. Methods: We used a commercially available genomic assay (DECIPHER® prostate test, GenomeDx, San Diego, CA) to assess gene expression in archived primary tumors from SPARTAN pts. DECIPHER GC, a 22-marker mRNA-based genomic classifier (GC), was validated for predicting metastatic prostate cancer (Karnes RJ, et al. J Urol. 2013), and basal/luminal (BA/LU) subtyping was validated in prostate cancer (Zhao SG, et al. JAMA Oncol. 2017; Zhang D, et al. Nat Commun. 2016). Pts were stratified into high and low risk for developing metastases based on DECIPHER GC score high (GC > 0.6) and low to average (GC ≤ 0.6), respectively, and into BA and LU subtypes. Gene signatures representing key biological pathways associated with the BA subtype were also assessed. We analyzed the association between GC scores and subtypes and outcomes using a Cox proportional hazards model. Results: A total of 233 pts were assessed; 117 pts had high GC score. Pts with both high and low to average GC score had improved outcomes with APA + ADT vs ADT alone. Pts with poor-prognosis high GC score had improved MFS (HR = 0.21, p < 0.0001) and PFS2 (HR = 0.26, p = 0.0084) with APA + ADT vs ADT, suggesting APA overcomes the negative prognosis in these pts. Approximately 65% of pts (n = 151) had the BA subtype associated with poor prognosis, indicating the high-risk nature of nmCRPC with short PSA doubling time. Key biological pathways associated with the BA subtype in nmCRPC were neuroendocrine differentiation, epithelial-mesenchymal transition, angiogenesis, and inflammation. Pts with the LU subtype, known to be sensitive to ADT, and with the BA subtype, typically resistant to ADT, benefited from APA + ADT vs ADT alone: HR for MFS = 0.22 and 0.34, p = 0.0017 and 0.0001, for LU and BA, respectively. Similar benefit was observed for PFS2. Both LU and BA pts had similar MFS benefit with ADT. LU pts had greater benefit from APA + ADT than BA pts: HR for MFS in LU vs BA subtypes was 0.40, p = 0.0295. Conclusions: Molecular signatures derived from primary tumors, such as DECIPHER GC and BA/LU subtypes, stratify pts with nmCRPC who would benefit from APA + ADT despite the high risk for progression. DECIPHER GC may be useful for identifying pts for early treatment intensification with APA or other agents, and BA/LU subtyping may be an effective approach for pt selection in trials combining novel therapies with APA. Citation Format: Felix Feng, Shibu Thomas, Michael Gormley, Angela Lopez-Gitlitz, Margaret K. Yu, Shinta Cheng, Deborah S. Ricci, Brendan Rooney, Paul N. Mainwaring, David Olmos, Fred Saad, Simon Chowdhury, Boris Hadaschik, Nick Fishbane, Elai Davicioni, Yang Liu, Eric J. Small, Matthew R. Smith. Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT129.

5023 Background: The addition of APA to ongoing ADT in pts with nmCRPC significantly prolonged metastasis-free survival (MFS), time to symptomatic progression (SymProg), and second progression-free survival (PFS2) in SPARTAN. We assessed the impact of APA on these end points in pts with or without BL CM. Methods: Using Cox proportional hazards models, treatment effect of APA was evaluated in SPARTAN pts with CM at BL, stratifying by the presence of BL diabetes/hyperglycemia (D/H), cardiovascular disease (CVD), hypertension (HTN), and renal insufficiency (RI). Results: Of 1207 SPARTAN pts, 1062 (88%) had ≥ 1 BL CM, including 703/806 (87%) APA pts and 359/401 (90%) PBO pts. A total of 226 (19%), 398 (33%), 798 (66%), and 774 (64%) pts had D/H, CVD, HTN, and RI, respectively; 323 (27%), 412 (34%), 259 (21%), and 68 (6%) pts had 1, 2, 3, and 4 CM, respectively. Incidence of CM was balanced between arms. Pts with CM were older than pts with no CM (median age, 75 vs 69 yrs, APA; 74 vs 69 yrs, PBO). MFS, SymProg, and PFS2 benefit with APA was significant in all CM subgroups, except PFS2 for pts with D/H (Table) and regardless of the number of CM. The incidence of any treatment-emergent AE was balanced between pts with and without CM. AEs with APA were not affected by any CM. Clinical trial information: NCT01946204. Conclusions: The benefit of APA + ongoing ADT in pts with nmCRPC was maintained in pts with D/H, CVD, HTN, and RI. The safety profile of APA was not affected by any CM.[Table: see text]

5025 Background: SPARTAN, a phase 3 study of APA vs placebo (PBO) added to ongoing ADT in pts with nmCRPC, demonstrated that APA significantly prolongs metastasis-free survival, time to symptomatic progression, and second progression free survival (Smith et al. NEJM 2018), with no decline in health-related quality of life (Saad et al. Lancet Oncol 2018). SPARTAN pts who received APA, vs PBO, with ongoing ADT had higher rates of falls (15.6% vs 9.0%) and fractures (11.7% vs 6.5%). An analysis was performed to identify clinical characteristics associated with falls and fractures in APA-treated SPARTAN pts. Methods: Of 1207 pts enrolled, 806 were randomized to APA. Univariate Cox proportional hazards model (UVA) assessed the association of 47 baseline clinical characteristics (demographics, comorbidities, and medication use, including bone-sparing agents) with time to fall or time to fracture. Characteristics with p values < 0.10 were included in a multivariate Cox proportional hazards model (MVA) to determine independent factors associated with these outcomes (p < 0.05). Results: Factors associated with time to both fall and fracture on UVA (p < 0.10) included older age, low serum albumin, and poor ECOG performance status (PS). Additional factors associated with time to fall were cerebrovascular accidents/transient ischemic attacks, neuropathy, depression, α-blocker use, and antidepressant use. On MVA, older age, poor ECOG PS, history of neuropathy, and α-blocker use were independently associated with falls; older age and low serum albumin were independently associated with fractures (Table). Conclusions: At initiation of APA added to ongoing ADT, nmCRPC pts with higher risk of falls and fractures can be identified and are candidates for intervention to reduce the risk for these events. Clinical trial information: NCT01946204. [Table: see text]

Fatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument. The Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes. A total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155). In patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.

The TMPRSS2:ERG gene fusion is one of a series of highly promising prostate cancer (PCa) biomarker alternatives to the controversial serum PSA. Current methods for detecting TMPRSS2:ERG are limited in terms of long processing time, high cost and the need for specialized equipment. Thus, there is an unmet need for less complex, faster and cheaper methods to enable gene fusion detection in the clinic. We describe herein a simple, rapid and inexpensive assay which combines robust isothermal amplification technique with a novel visualization method for evaluating urinary TMPRSS2:ERG status at less than USD 5 and with minimal equipment. The assay is sensitive and rapidly detects as low as 105 copies of TMPRSS2:ERG transcripts while maintaining high levels of specificity.

Cancer is a heterogeneous disease which manifests as different molecular subtypes due to the complex nature of tumor initiation, progression, and metastasis. The concept of precision medicine aims to exploit this cancer heterogeneity by incorporating diagnostic technology to characterize each cancer patient's molecular subtype for tailored treatments. To characterize cancer molecular subtypes accurately, a suite of multiplexed bioassays have currently been developed to detect multiple oncogenic biomarkers. Despite the reliability of current multiplexed detection techniques, novel strategies are still needed to resolve limitations such as long assay time, complex protocols, and difficulty in interpreting broad overlapping spectral peaks of conventional fluorescence readouts. Herein a rapid (80 min) multiplexed platform strategy for subtyping prostate cancer tumor and urine samples based on their RNA biomarker profiles is presented. This is achieved by combining rapid multiplexed isothermal reverse transcription-recombinase polymerase amplification (RT-RPA) of target RNA biomarkers with surface-enhanced Raman spectroscopy (SERS) nanotags for “one-pot” readout. This is the first translational application of a RT-RPA/SERS-based platform for multiplexed cancer biomarker detection to address a clinical need. With excellent sensitivity of 200 zmol (100 copies) and specificity, we believed that this platform methodology could be a useful tool for rapid multiplexed subtyping of cancers.

Purpose Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. Patients and Methods Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. Results A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post–random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). Conclusion Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.

The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤ 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ≥ 1 dose of motesanib. The incidence of DLTs was33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.