Trials For Advanced Prostate Cancer Research Articles

A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk.

Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T<0.5ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360mg SC and 180mg IM with a maintenance dose of 360mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

Abstract PO3-06-13: A novel stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor targeting microtubules (60c) is effective against taxane-resistant, metastatic breast cancer

Abstract Background: Improving survival for patients diagnosed with metastatic disease and treating spontaneous chemoresistance remain major clinical challenges in treating breast cancer. Triple negative breast cancer (TNBC), characterized by a lack of therapeutically targetable receptors (ER/PR/HER2), is an aggressive subtype of breast cancer. TNBC therapy relies on a combination of systemically administered chemotherapies, including microtubule-targeting agents (MTAs) like paclitaxel (taxane class) or eribulin (vinca class); however, there are currently no FDA approved MTAs that bind to the colchicine-binding site. Approximately 70% of patients who initially respond to paclitaxel, a first-line MTA, will develop taxane resistance (TxR) within 6 months. We have previously reported that an orally bioavailable colchicine-binding site inhibitor (CBSI), sabizabulin (formerly known as Veru-111), not only inhibits TNBC tumor progression but also treats pre-established metastatic disease in a taxane-refractory PDX model, HCI-10-Luc2. Sabizabulin is currently in phase II/III trials for advanced prostate cancer. To further improve potency and metabolic stability, we created next-generation derivatives of the sabizabulin scaffold, including 60c. Results: 60c shows improved potency compared to sabizabulin against taxane-sensitive and TxR TNBC models, inhibiting proliferation and clonogenicity at low nanomolar concentrations, and inducing apoptosis in a dose-dependent manner. In vivo, 60c therapy significantly suppressed primary tumor growth and lung metastasis in an orthotopic MDA-MB-231-TxR xenograft model without gross toxicity, and with equivalent efficacy to combrestatin A4 phosphate (CA-4P), another CBSI in clinical trials. In the taxane-refractory HCI-10-Luc2 PDX model, 60c significantly suppressed both the growth of the primary tumor (by ~3.5 fold) and the expansion of pre-established axillary metastases (by ~26 fold) whereas paclitaxel had no effect. Analysis of total photon flux of organs excised at study endpoint showed that 60c had distinct anti-metastatic tropism as compared to sabizabulin. Whereas 60c completely suppressed metastases to the spleen (0/9 mice had signal), and significantly reduced metastatic burden in the leg bones (only 3/9 mice had signal) and in the kidney (only 2/9 mice had signal), 60c had no statistically significant effect on liver metastases. In contrast, we had previously reported that sabizabulin strongly repressed liver metastases in the same PDX model (0 mice with detectable liver metastases), with less potent effects on bone. Unlike 60c, sabizabulin showed no improvement relative to the vehicle control for spleen and kidney metastases. Together, our data positions 60c as a promising candidate for TNBC therapy, particularly for patients with TxR disease. Our results also suggest that different CBSI scaffolds may preferentially inhibit metastasis to specific organs, which requires further investigation. Citation Format: Damilola Oluwalana, Kelli Hartman, Raisa Krutilina, Hao Chen, Hilaire Playa, Shanshan Deng, Deanna Parke, Duane Miller, Tiffany Seagroves, Wei Li. A novel stable 6-aryl-2-benzoyl-pyridine colchicine-binding site inhibitor targeting microtubules (60c) is effective against taxane-resistant, metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-13.

Interaction of age and benefit of treatment intensification in advanced prostate cancer: An aggregate meta-analysis of 14 randomized trials.

118 Background: Treatment intensification (TI) for men with advanced prostate cancer consistently demonstrates improvements in overall survival (OS) when compared to androgen deprivation therapy (ADT) alone. However, TI increases morbidity and may contribute to worsening other-cause mortality. Herein, we aim to determine if there is an interaction of age and TI on OS in men with advanced prostate cancer. Methods: A systematic literature search in MEDLINE, Embase, and conference proceedings were searched to identify contemporary randomized phase 3 trials in advanced prostate cancer evaluating the role of TI with chemotherapy and/or androgen receptor-signaling inhibition (ARSI) between 1/1/2010-9/1/2023. Trials in metastatic hormone-sensitive prostate cancer (mHSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) were included given potential for competing risks; mCRPC trials were excluded. Meta-analyses were performed with random-effect modeling. Meta-regression was performed using Hartung-Knapp methods in mHSPC trials accounting for drug (docetaxel, abiraterone acetate/prednisone (AAP), non-AAP ARSIs (apalutamide, enzalutamide, or darolutamide)), use of RT to primary, percent high volume disease, percent synchronous metastatic disease, and median PSA. Age was dichotomized as &lt; or ≥ 70 in 8 trials, and &lt; or ≥ 65 in 6 trials. Results: Fourteen trials with 16 randomized comparisons (n=17,765 patients) were included. A total of 9,229 younger and 7,458 older men were included in age-specific analyses. Overall, TI significantly improved OS (HR 0.72, 95%CI 0.69-0.76, p&lt;0.0001), which was consistent irrespective of disease state (mHSPC HR 0.72, 95%CI 0.78-0.77; nmCRPC HR 0.74, 95%CI 0.66-0.83). There was a significant interaction between age and TI on OS (p-interaction &lt;0.001); TI in younger men significantly improved OS (HR 0.65, 95%CI 0.59-0.72, p&lt;0.0001). Older men derived less benefit from TI, but TI did improve OS (HR 0.80, 95%CI 0.74-0.87, p&lt;0001). In subgroup of older men in mHSPC trials, a significant treatment effect difference based on drug class was observed (p=0.047); AAP (HR 0.92, 95%CI 0.78-1.10, p=0.38), docetaxel (HR 0.86, 95%CI 0.70-1.05, p=0.13), and non-AAP ARSIs (HR 0.71, 95%CI 0.63-0.81, p&lt;0.001). On meta-regression of mHSPC trials, age remained an independent variable associated with TI benefit (p=0.005). Limitations include the post-hoc nature of this aggregate meta-analysis and use of dichotomized age. Conclusions: TI improves OS for men with mHSPC and nmCRPC, but a significant interaction between age and TI on OS was identified. Further work leveraging individual patient data is needed to understand drivers of this observation, including impact of treatment compliance, comorbid conditions, adrenal suppression, outcomes in different prognostic groups, and competing risks in older patients.

Toxicity-benefit analysis of advanced prostate cancer trials using weighted toxicity scoring.

110 Background: The weighted toxicity score (WTS) is a metric suitable for comparing the toxicity burden in experimental versus control arms of randomized controlled trials (RCTs). When compared against clinical endpoints, the WTS can be used to evaluate the cost versus benefit of anti-cancer agents. This study sought to apply the WTS to prostate cancer (PC) clinical trials. Methods: Select phase 3 PC RCTs with reported adverse event (AE) data were compiled. The WTS was computed for each trial arm and compared to reported hazard ratios (HRs) of primary and/or secondary endpoints (i.e., overall survival (OS) and progression-free survival (PFS)). Average WTSs for the experimental versus control arms were used to calculate the toxicity differential between treatment arms. Average HRs for OS and PFS were used to compare efficacy. Results: Sixteen RCTs were analyzed (investigational agents: androgen-receptor signaling inhibitors (ARSi) [n = 4], poly (ADP-ribose) polymerase inhibitors (PARPi) monotherapy [n = 3], ARSi + PARPi as well as ARSi + ARSi combination therapies [n = 3 each], and triple therapy [n=3]). The median number of distinct reported AEs across all studies was 18 (range, 9-61). Overall, toxicity and efficacy were greater among experimental than control arms (6.62 versus 4.00 median WTS; median HR for OS 0.71, median HR for PFS 0.61). The triple therapy studies observed the lowest increase in toxicity by adding an ARSi to control therapy (10.4%), associated with 52% lower risk of progression, and 29% lower risk of death. Comparably, the ARSi + PARPi trials noted the highest increase in toxicity (79.7%), with 32% lower risk of progression and 12% lower risk of death. The PARPi monotherapy, ARSi monotherapy, and ARSi + ARSi combination therapy studies reported increased toxicity due to experimental therapy in descending order (Table). Conclusions: The WTS enables toxicity versus benefit assessment for anti-cancer regimens. Clinical application of this metric may facilitate individualized treatment planning in advanced PC management. [Table: see text]

Meta-Analysis of Candidate Surrogate End Points in Advanced Prostate Cancer

BackgroundThe Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate end point for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate end points exist in advanced prostate cancer.MethodsWe searched for trials in advanced prostate cancer, defined as node-positive, metastatic castration-sensitive, nonmetastatic, or metastatic castration-resistant prostate cancer. Eligible randomized trials reported OS and one or more intermediate clinical end points, including biochemical failure (BF), clinical failure, biochemical failure–free survival (BFS), progression-free survival (PFS), and radiographic PFS. Candidacy for surrogacy was assessed by using the second condition of the meta-analytic approach; R2 was weighted by the inverse variance of the log intermediate clinical end point hazard ratio and defined as R2>0.70.ResultsA total of 143 randomized trials (n=75,601 patients) were included. No candidate end points met the criteria for surrogacy (R2 BF [n=28,922], 0.42 [95% confidence interval (CI), 0.18 to 0.64]; BFS [n=25,741], 0.57 [95% CI, 0.37 to 0.73]; clinical failure [n=22,616], 0.31 [95% CI, 0.075 to 0.56]; PFS [n=52,639], 0.50 [95% CI, 0.35 to 0.63]; and radiographic PFS [n=52,548], 0.50 [95% CI, 0.35 to 0.63]). Within preplanned subgroups according to castration-sensitive or castration-resistant disease or according to treatment type, neither BFS nor PFS consistently met criteria for surrogacy. Sensitivity analyses showed that candidacy for surrogacy of all end points tested did not change over time.ConclusionsOur aggregate screening method for surrogate end points in advanced prostate cancer showed that commonly used clinical end points are not clear valid surrogate end points for OS. (Funded by the Prostate Cancer Foundation and the National Cancer Institute.)

US Population Reference Values for Health-Related Quality of Life Questionnaires Based on Demographics of Patients with Prostate Cancer.

IntroductionThe patient experience with prostate cancer differs throughout the disease continuum, with health-related quality of life (HRQoL) and symptoms worsening as the disease progresses. To understand the prostate cancer experience, it is important to understand the experience of same-aged men without prostate cancer as a basis for comparison. This study provides the US population reference values for six patient-reported outcome (PRO) questionnaires.MethodsA cross-sectional online survey, including several PRO questionnaires, was administered in 2019 to a representative sample of US adults. The male sample (N = 876) was raked by age to have similar characteristics of men in key advanced prostate cancer trials (mean/median age: 67.5/70.0 years), with the majority being white and non-Hispanic.ResultsResults from six PRO questionnaires (Brief Pain Inventory; Quality of Life in Neurological Disorders 2.0 Cognitive Short Form; PRO Measurement Information System Fatigue-Short Form; Functional Assessment of Cancer Therapy-General; European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module) indicated that the US representative sample of men have good role, physical, and emotional functioning but slightly impaired social, functional, and overall well-being. In addition, they have normal cognitive function, few financial problems, minimal pain and fatigue, minimal urinary and bowel symptoms, and limited use of incontinence aids.ConclusionsThe availability of the reference values for these PRO questionnaires will enable researchers to compare the HRQoL of patients with advanced prostate cancer in the US with that of the general US population and allow for a better interpretation of those scores. Registration numbers of advanced prostate cancer trials: NCT02677896, NCT02003924, NCT01212991, NCT00974311.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02204-3.

Candidate surrogate endpoints in advanced prostate cancer: Aggregate meta-analysis of 143 randomized trials.

5039 Background: The Intermediate Clinical Endpoints (ICEs) in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate endpoint for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate endpoints for OS exist in advanced prostate cancer. Methods: In this meta-analysis, PubMed was searched for trials in advanced prostate cancer, defined as node positive (N1M0), metastatic castration-sensitive (mCSPC), non-metastatic (M0CRPC), or metastatic castration-resistant prostate cancer (mCRPC). Eligible randomized trials were required to report OS and ≥1 intermediate clinical endpoint (ICE). ICEs included biochemical-failure (BF), clinical failure (CF), BF-free survival (BFS), progression-free survival (PFS), radiographic PFS (radiographic +/- other study defined endpoints). Candidacy for surrogacy was assessed using the second condition of the meta-analytic approach, correlation of the treatment effect of the ICE and OS, using R2 weighted by the inverse variance of the log ICE hazard ratio and defined as an R2 &gt; 0.70. Results: A total of 143 randomized trials (n = 75,601 patients) were included. No candidate endpoints met criteria for surrogacy; R2 BF (n = 28,922) 0.42 (95%CI 0.18-0.64), BFS (n = 25,741) 0.57 (95%CI 0.37-0.73), CF (n = 22,616) 0.31 (95%CI 0.0075-0.56), PFS (n = 52,639) 0.50 (95%CI 0.35-0.63), and radiographic PFS (n = 52,548) 0.50 (95%CI 0.35-0.63). Within preplanned subgroups by castration sensitive or resistant disease, or by treatment type, neither BFS nor PFS met criteria for surrogacy. When assessing radiographically-defined progression (exclusive or with clinical progression), PFS for the overall group and by castration status did not meet criteria for surrogacy. Sensitivity analyses demonstrated that candidacy for surrogacy of all endpoints tested did not change over time. Conclusions: Our aggregate screening method for surrogate endpoints in advanced prostate cancer demonstrated commonly used clinical endpoints are not valid surrogate endpoints for OS, and further composite endpoint construction is necessary.

Editorial introductions

Editorial introductions

Health-related quality of life (HRQoL) patient-reported outcomes (PROs) and survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).

53 Background: HRQoL is a relevant endpoint in trials in advanced prostate cancer. An association between HRQoL and OS has been reported. The Functional Assessment of Cancer Therapy-Prostate (FACT-P) is a validated HRQoL PRO in mCRPC. Methods: We evaluated the association between FACT-P and OS in the COU-301 and COU-302 trials (abiraterone vs placebo in mCRPC pts). FACT-P scores, sub-scores (physical (PWB), emotional (EWB), functional (FWB), social (SWB) well-being, prostate cancer subscale (PCS) FACT-G and the Trial Outcome Index (TOI) were calculated. A decrease in 3 (PWB, EWB, SWB, FWB, PCS), 9 (FACT-G, TOI) or 10 (FACT-Total) points after 3 cycles was considered clinically relevant. The association between FACT-P and OS was evaluated with Kaplan-Meier, Cox-regression models and c-indices. Results: 2,177 pts (COU-301: 1,121 /COU-302: 1,056) had valid baseline (BL) FACT-P scores. Mean BL score was 106.6 (COU-301) and 122.3 (COU-302). BL total scores were associated with OS in both COU-AA-301 (p&lt;0.001) and COU-302 (p&lt;0.001), independent of treatment. All FACT-P sub-scores except SWB were associated with OS (Table). A decrease in FACTP scores was associated with decreased OS in COU-301 (19.6 vs 14.2m; HR: 1.8; p&lt;0.001) and COU-302 (34.4 vs 27.7m; HR: 1.3; p=0.009) datasets. Conclusions: BL FACTP scores (except SWB subscale) are significantly associated with outcome. Early declines in HRQoL can be observed and are associated with worse outcome. Prospective evaluation of the significance of changes in HRQoL is needed. YODA Project 2018-3745.[Table: see text]

Management of advanced prostate cancer in Hong Kong: Insights from an APCCC-Derived survey.

The 2017 Advanced Prostate Cancer Consensus Conference (APCCC) convened an international multidisciplinary panel to vote on controversial issues in the management of advanced prostate cancer (APC). We aimed to compare their conclusions with the opinions of local specialists and explore the practicability of international recommendations in the healthcare setting in Hong Kong. Urologists and clinical oncologists practicing in Hong Kong were invited to complete a survey based on the original APCCC 2017 questionnaire and recently published trials in APC. A joint committee of expert key opinion leaders was convened to discuss and analyze the voting differences between local specialists and the APCCC 2017 panel. The respondents constituted 21% (28/132) of registered urologists and 21% (31/146) of clinical oncologists in Hong Kong. Discrepancies in three key areas were identified as being the most timely for this analysis: (a) management of metastatic hormone-sensitive/naïve prostate cancer; (b) management of metastatic castration-resistant prostate cancer; and (c) treatment monitoring and initiation of androgen-deprivation therapy. Fears of toxicity and intolerance among patients and physicians (especially urologists) may be driving the relative underuse of chemotherapy in multiple APC patient groups in Hong Kong. Local patients can face long wait times and limited access to contemporary imaging modalities compared with other developed countries. Increased collaborative efforts by urologists and clinical oncologists could ensure that patients gain wider access to the latest diagnostic, treatment and monitoring modalities for APC in Hong Kong.

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Abstract B013: Combined molecular targeting Src and mTOR pathways to impair prostate cancer cell survival

Abstract Overexpression of oncoproteins Src and mTOR has been shown to be highly associated with prostate cancer progression and poor clinical outcomes; therefore, small-molecule Src or mTOR inhibitors are being extensively evaluated in clinical trials for advanced prostate cancer. However, clinical data suggest that single treatment with any of these inhibitors only yields limited effects in patients. One possibility is that redundant signaling pathways in tumor cells exist that allow tumor cell uninterrupted upon blockade of purely one pathway. We hypothesize that Src and mTOR are two compensatory pathways that may cooperate to promote prostate cancer survival. Here we studied treatment effects of combining inhibitors targeting Src (saracatinib) and mTOR (rapamycin) on functional behaviors associated with tumor growth in prostate cancer cells with high level expression of both kinases. Combination of both inhibitors was found to inhibit cell proliferation and clonogenic survival more strongly than either single agent, as assessed by MTT and colony formation assay, respectively. Western blot analysis demonstrated that co-targeting Src and mTOR kinases leads to not only inhibition on phosphorylation of these oncoproteins but also greater blockade of multiple downstream pathways such as focal adhesion kinase (FAK), Akt, ERK, S6K, and 4E-BP1. These data indicate that combined application of small-molecule inhibitors targeting two different key pathways may cause significant impairment of phenotypes associated with prostate cancer growth and survival, suggesting that this combinative intervention modality may serve as a potential anticancer strategy that could be further tested in advanced prostate cancer models in vivo. Citation Format: Yao Dai, Dietmar W. Siemann. Combined molecular targeting Src and mTOR pathways to impair prostate cancer cell survival [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B013.

Eligibility criteria requirements and adherence in advanced prostate cancer trials.

245 Background: Eligibility criteria for advanced (metastatic and locally advanced) prostate cancer trials vary between trials and are specific to the therapy evaluated, and may not represent the general population. This reduces comparability between studies, generalizability of results, and may contribute to high screen failure rates (~25%). In this study, we aimed to better understand the eligibility criteria across trials and adherence to eligibility criteria. Methods: We compared eligibility criteria between trials and collected baseline demographics to assess for adherence to criteria for 13 phase III advanced prostate cancer trials published from 1999-2016. Results: Disease characteristics, age, performance status, tumor markers, and most hepatic, renal, and hematological criteria were consistent across trials. However, discrepancies in hemoglobin, absolute neutrophil count, glomerular filtration rate (GFR) and bilirubin criteria were observed (Table). Overall, 8/13 trials included patients that did not meet criteria but were analyzed by intent-to-treat. Criteria that were not followed included: hemoglobin and albumin (lower than permitted); while testosterone, serum creatinine, pain scores, and ECOG performance status were higher (more unwell) than permitted. Conclusions: Specific eligibility criteria vary across the trials, and a number of trials accrued ineligible patients. After accounting for drug-specific criteria, greater standardization of and consideration of general population for eligibility criteria is needed to improve homogeneity of trial populations across studies, generalizability of results, and possibly reduce screen failure rates in prostate cancer trials. [Table: see text]

Abstract 1915: microRNA-320a inhibits cancer cell migration and invasion through targeting LAMP1 in castration-resistant prostate cancer

Abstract BACKGROUND: In early-stage prostate cancer (PCa), more than 90% of patients initially respond to the therapeutic use of androgen deprivation; however, many cases become refractory and progress to castration resistant prostate cancer (CRPC). CRPC is difficult to treat, and most clinical trials for advanced PCa with metastasis to bones or other sites have shown limited benefits. Therefore, understanding the molecular mechanisms of metastatic pathways of CRPC underlying current genomic approaches would help to improve therapies for this disease. Our recent studies of microRNA (miRNA) expression signatures of CRPC revealed that microRNA-320a (miR-320a) was significantly reduced in cancer tissues, suggesting miR-320a acts as a tumor-suppressor in CRPC cells. The aim of this study was to investigate the functional significance of miR-320a in CRPC cells and to identify miR-320a-mediated target genes involved in oncogenesis and metastasis of the disease. METHODS: Gain-of-function studies were performed using transfection of mature miR-320a into cancer cells (DU145 and PC3). Genome-wide gene expression analysis and in silico analysis were applied to identify molecular targets regulated by miR-320a in PCa cells. A luciferase reporter assay was carried out to determine regulation of miR-320a. Loss-of-function studies using siRNA were performed to investigate the functional role of target genes. RESULTS: The expression levels of miR-320a were significantly reduced in PCa tissues and the cell lines. Restoration of mature miR-320a in cancer cells led to significant inhibition of cell migration and invasion activities in PCa cell lines. Lysosomal-associated membrane protein 1 (LAMP1) was identified as a direct target of miR-320a in this assays. Silencing of LAMP1 significantly inhibited cell proliferation, migration and invasion in PCa cells. Moreover, overexpression of LAMP1 was observed in PCa and CRPC clinical specimens. CONCLUSIONS: To the best of our knowledge, this is the first report demonstrating that tumor-suppressive miR-320a directly regulated LAMP1 in PCa cells. The identification of novel target gene regulated by tumor-suppressive miRNAs may lead to a better understanding of molecular mechanisms of CRPC metastatic pathways. Citation Format: Atsushi Okato, Yusuke Goto, Akira Kurozumi, Mayuko Kato, Ryosuke Matsushita, Satoko Kojima, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki. microRNA-320a inhibits cancer cell migration and invasion through targeting LAMP1 in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1915.

Abstract 1910: Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 in prostate cancer

Abstract BACKGROUNDS: Most patients with prostate cancer (PCa) initially respond to androgen-deprivation therapy, but eventually becomes hormone-insensitive and progress to castration-resistant prostate cancer (CRPC). CRPC is difficult to treat, and most clinical trials for advanced PCa have shown limited benefits, with disease progression and metastasis to the skeleton or other sites. Therefore, understanding the molecular mechanisms of CRPC and the metastatic pathways underlying PCa using genomic approaches would help to prevent and improve therapies for the disease. Our previous studies showed that three tumor-suppressive microRNAs (miRNAs), miR-26a/b, miR-29a/b/c and miR-218, significantly inhibited cancer cell migration and invasion. Therefore, we hypothesized that these miRNAs-regulated target genes deeply contributed to cancer metastasis. METHODS: Genome-wide gene expression analysis and in silico analysis were applied to investigate molecular targets regulated by miR-26a/b, miR-29a/b/c and miR-218 in PCa cells. A luciferase reporter assay was carried out to determine whether 3’ UTR of target genes have actual biding sites for these miRNAs. To investigate the functional role of target genes in PCa cells, loss-of-function studies by using siRNAs of targets genes were performed. RESULTS: Our in silico analysis and luciferase reporter assays showed that lysyl oxidase-like 2 (LOXL2) was directly regulated by tumor-suppressive miR-26a/b, miR-29a/b/c and miR-218 in PCa cells. Overexpression of LOXL2 was observed in PCa clinical specimens by immunohistochemical staining. Moreover, downregulating the LOXL2 gene significantly inhibited cell migration and invasion in PCa cells. The function of the LOXL2 is covalent crosslinking of collagen and/or elastin in the ECM. Aberrant expression of LOXL2 has been reported in several diseases, including cancers. CONCLUSIONS: Our present data showed that the gene promoting metastasis, LOXL2, was epigenetically regulated by tumor-suppressive microRNAs, miR-26a/b, miR-29a/b/c and miR-218 providing important insights into the molecular mechanisms of PCa metastasis. Elucidation of tumor-suppressive miRNAs regulated molecular pathways and targets could provide new information on potential therapeutic strategies in PCa. Citation Format: Mayuko Kato, Akira Kurozumi, Yusuke Goto, Ryosuke Matsushita, Ichiro Fukumoto, Atsushi Okato, Rika Nishikawa, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki. Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1910.

Outcome measures in advanced prostate cancer trials: A systematic review of contemporary trial registrations.

e16123 Background: Selection of outcome measures is central to effective trial design. Guidelines from regulatory bodies indicate that investigators should demonstrate improvement in survival or qu...

Correlation between time to prostate cancer metastasis and overall survival after androgen-deprivation therapy initiation.

250 Background: Currently,overall survival (OS) is used to determine treatment efficacy in trials for advanced prostate cancer (PC). Reliable intermediate endpoints could hasten drug development efforts. We therefore sought to determine the association between an intermediate endpoint—time to metastasis (TTM)—and OS in PC patients receiving androgen deprivation therapy (ADT) for biochemical recurrence (BCR). Methods: The Dana-Farber PC database identified 415 patients who received ADT for non-metastatic BCR with median 6.4 years follow-up. Associations between TTM and OS were measured from (i) time of ADT initiation (n=398) and (ii) time of castration-resistance (n=247) using a non-parametric Kendall tau rank correlation for bivariate time to event outcomes. A Cox regression model was used to assess the association of development of metastasis and OS for landmark timepoints. Results: Among 398 subjects analyzed from start of ADT, 180 (45%) developed metastases with median TTM 6.25 years. A total of 152 (38%) died, with a median OS of 8.5 years. For men developing metastases within five years of ADT initiation, hazard ratio (HR) for mortality was 7.42 (p&lt;0.0001, 95% CI 4.18-13.17). Among 247 subjects assessed from time of castration resistant PC (CRPC), 172 (70%) developed metastases with a median TTM 2.6 years. In this subgroup, 140 (56%) patients died with median OS 5.25 years. For men developing metastases within three years of developing castration-resistance, HR for mortality was 5.25 (p&lt;0.0001, 95% CI 3.20-8.61). Overall, correlation between TTM and OS from ADT initiation and OS was 0.25 (P&lt;0.0001, 95% CI 0.20-0.29). Correlation between TTM and OS from CRPC was 0.32 (P&lt;0.0001, 95% CI 0.25-0.37). Conclusions: TTM was significantly correlated with OS in PC patients treated with ADT for BCR. Prospective data in a large validation cohort will help determine whether TTM is suitably predictive of OS to serve as a primary endpoint in clinical trials.

Pain questionnaire performance in advanced prostate cancer: comparative results from two international clinical trials

To compare pain assessment questionnaires commonly used in advanced prostate cancer trials and to determine the psychometric characteristics and longitudinal relationships by contrasting questionnaire data from two international phase 2 trials. Scores from the Present Pain Intensity (PPI) question of the McGill Pain Questionnaire, the pain intensity scale of the Brief Pain Inventory (BPI), and the Functional Assessment of Cancer Therapy-Prostate (FACT-P) were analyzed using Pearson correlation, intraclass correlation coefficient, and Cronbach's α, respectively. Concordance was evaluated with Cohen's kappa coefficient and McNemar test at baseline (n=224) and two subsequent observations. PPI and FACT-P scores were associated with the BPI score at baseline for Trials 1 and 2: PPI r=0.66 and 0.80, respectively (P<0.001); FACT-P (pain scale) r=-0.76 and -0.82, respectively (P<0.001). However, concordance analysis revealed that the BPI identified pain (score>0) at higher rates than the PPI: at baseline, BPI: 89% (64/72) and 77% (95/124), PPI: 68% (49/72) and 64% (79/124) [Trials 1 and 2, respectively; McNemar test (P<0.001) for both studies]. The FACT-P pain scale identified pain similarly to the BPI pain intensity scale; longitudinal analysis produced comparable findings. All pain scales met standard psychometric acceptability criteria, but the BPI and FACT-P performed better than the PPI. Data suggest the BPI pain intensity and FACT-P pain scales are better than the PPI question at capturing the pain experience among patients with advanced prostate cancer. Additional comparative research is needed in larger population samples.

Abstract 927: Combined targeting c-Src and c-Met pathways to impair prostate cancer cell growth and invasion.

Abstract Overexpression of tyrosine kinases c-Src and c-Met has been shown to be highly associated with prostate cancer progression and poor clinical outcomes, therefore small molecule Src or Met inhibitors are being extensively evaluated in clinical trials for advanced prostate cancer. However clinical data suggest that single treatment with any of these inhibitors only yield limited effects in patients. One possibility is that redundant signaling pathways in tumor cells exist that allows tumor cell uninterrupted upon blockade of purely one pathway. We hypothesize that c-Src and c-Met are two compensatory pathways that may cooperate to promote prostate cancer progression, hence here we studied treatment effects of combining inhibitors targeting c-Src (dasatinib, saracatinib) and c-Met (ASLAN002, also named BMS-777607) on multiple functional behaviors associated with tumor growth and metastasis in c-Src and c-Met expressing prostate cancer cells (PC-3, DU145). Combination of Src inhibitors and ASLAN002 was found to inhibit cell proliferation and colony formation more strongly than either single agent, as assessed by MTT and clonogenicity, respectively. In a wound-healing assay, compared to either treatment alone, the combinatorial treatment exhibited greater suppression on cell motility induced by hepatocyte growth factor, the only known ligand of c-Met. Similarly, using a Matrigel-based Transwell assay, Src inhibitors plus ASLAN002 resulted in significant reduction of cell invasion in the presence or absence of HGF. Western blot analysis demonstrated that co-targeting Met and Src kinases lead to not only inhibition on c-Met and c-Src autophosphorylation but also greater blockade of multiple downstream kinases such as focal adhesion kinase (FAK), Akt and extracellular signal-regulated kinase (ERK). These data indicate that combined application of small molecule Src and Met inhibitors cause significant impairment on various phenotypes associated with prostate cancer progression in vitro including proliferation, survival, migration and invasion, suggesting that this combination intervention modality may serve as a potential anti-metastatic strategy that could be further tested in metastatic prostate cancer models in vivo. Citation Format: Yao Dai, Kyung-Mi Bae, Dietmar W. Siemann. Combined targeting c-Src and c-Met pathways to impair prostate cancer cell growth and invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 927. doi:10.1158/1538-7445.AM2013-927

Serum Antibodies to Blood Group A Predict Survival on PROSTVAC-VF

There is evidence that therapeutic cancer vaccines can lengthen survival for some patients with cancer, but responses vary widely from one person to another. Methods to predict clinical outcomes will advance the field and provide new insights into critical determinants of in vivo efficacy. This retrospective study included 141 subjects from phase II trials of PROSTVAC-VF, a poxvirus-based cancer vaccine currently in phase III clinical trials for advanced prostate cancer. A glycan microarray was used to profile prevaccination antiglycan antibody populations in sera as potential biomarkers for PROSTVAC-VF. The screen for predictive biomarkers identified antiglycan antibodies that consistently stratified subjects into groups with different Kaplan-Meier survival estimates. Because of the potential for overfitting, a permutation test was used to estimate the false discovery rate. Prevaccination antibody levels to blood group A trisaccharide (BG-Atri) were found to have a statistically significant correlation with survival. Long-term survival was approximately doubled in subjects with abundant anti-BG-Atri immunoglobulin M (IgM) relative to subjects with little or no preexisting IgM for BG-Atri. This survival correlation was specific to vaccine treatment, as no correlation was observed in control patients immunized with wild-type poxviruses lacking the key tumor antigen, prostate-specific antigen (PSA). Moreover, anti-BG-Atri IgM levels were not correlated with general measures of disease severity, such as PSA levels, Gleason score, or Halabi predicted survival. In addition to reporting a new potentially predictive biomarker for PROSTVAC-VF, this study highlights the use of glycan microarray technology for improving our understanding of vaccine immunology. Clin Cancer Res; 19(5); 1290-9. ©2012 AACR.