bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of local treatment in patients with prostate cancer with clinically pelvic lymph node-positive disease at initial diagnosis.
Authors: Abdollah Firas , Seisen Thomas , Vetterlein Malte , Karabon Patrick , Jindal Tarun , Sood Akshay , Nocera Luigi , Nguyen Paul L. , Choueiri Toni K. , Trinh Quoc-Dien , Menon Mani
Published: March 2017

164

Background: There is limited evidence supporting the use of local treatment (LT) for prostate cancer (PCa) patients with clinically pelvic lymph node-positive (cN1) disease. Against this backdrop, we sought to examine the efficacy of any form of LT+/-androgen deprivation therapy (ADT) in treating these individuals. Methods: Within the National Cancer Data Base (2004-2012), we identified 2,967 individuals who received LT+/-ADT vs. ADT alone for cN1 PCa. Only radical prostatectomy (RP) and radiation therapy (RT) were considered as definitive LT. Instrumental variable analyses (IVA) were performed using a two-stage residual inclusion approach to compare overall mortality-free survival between patients who were treated with LT+/-ADT vs. ADT alone. The same methodology was used to further compare overall mortality-free survival between patients who were treated with RP+/-ADT vs. RT+/-ADT. Results: Overall, 1,987 (67.0%) and 980 (33.0%) patients received LT+/-ADT and ADT alone, respectively. In the LT+/-ADT group, 751 (37.8%) and 1,236 (62.2%) patients received RP+/-ADT and RT+/-ADT, respectively. In IVA, LT+/-ADT was associated with a significant overall mortality-free survival benefit (HR = 0.31; 95% CI = [0.13-0.74]; P= 0.007), when compared to ADT alone. At 5-year, overall mortality-free survival was 78.8% (95% CI: 74.1%-83.9%) vs. 49.2% (95% CI: 33.9%-71.4%) in the LT+/-ADT vs. ADT alone groups. When comparing RP+/-ADT vs. RT+/-ADT, IVA showed no significant difference in survival between the two treatment modalities (HR = 0.54; 95% CI = [0.19-1.52]; P= 0.24). Conclusions: Our study shows a significant overall mortality-free survival benefit for cN1 PCa patients who were treated with LT+/-ADT as compared to their counterparts treated with ADT alone. Conversely, no significant survival difference was observed between patients treated with RP+/-ADT vs. RT+/-ADT.
Cabozantinib plus androgen deprivation therapy in patients with androgen-dependent metastatic prostate cancer.
Authors: Corn Paul Gettys , Zurita Amado J. , Subudhi Sumit Kumar , Tu Shi-Ming , Aparicio Ana , Araujo John C. , Kim Jeri , Wang Jennifer , Efstathiou Eleni , Pagliaro Lance C. , Logothetis Christopher
Published: March 2017

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Background: Cabozantinib (Cabo), a tyrosine kinase inhibitor of c-Met and VEGFR2, modulates the tumor microenvironment in a therapeutically favorable manner. We combined Cabo with androgen deprivation therapy (ADT) in patients (pts) with androgen-dependent metastatic prostate cancer (PCa) (NCT01630590). Methods: Pts received Cabo (starting dose 60 mg PO daily) and ADT with a GnRH analogue. Pts could receive up to 3 months of ADT prior to initiating Cabo. Bone scan (BS) and CT scans were performed every 12 weeks (wks). Efficacy endpoints included response in markers, BS and RECIST, and time to castrate-resistant progression defined by radiographic progression, clinical progression, or receipt of additional anti-cancer therapy. Results: From 01/27/2014 to 01/12/2016, 62 pts were enrolled: 94% (58/62) with bone metastasis, 56% (35/62) with measurable disease, 15% (9/62) with visceral involvement and 26% (16/62) with prior treatment of their primary tumor. 79% (49/62) of pts have high volume disease defined by > 4 bone lesions and/or involvement of viscera. Median time from start of ADT to start of Cabo was 3.4 wks. Improvements in BS were observed in 81% (44/54) of evaluable pts including complete responses (CR) in 15% (8/54). In evaluable pts with measurable disease, best response was stable disease in 9% (3/33), PR in 61% (20/33) and CR in 30% (10/33). Reductions in PSA > 90%, bone specific alkaline phosphatase > 50% and urine N-telopeptides > 50% occurred in 83% (50/60), 87% (34/39), 86% (19/22) of evaluable pts, respectively. With a median follow up of 21.4 months (mo), median PFS is 15.6 mo. Median duration of Cabo treatment is 13 mo. Most common toxicities are Grade 3 hypertension (16%), pulmonary embolus (6%), diarrhea (4%), fatigue (3%), nausea (3%), and deep venous thrombosis (3%) with no Grade 4 events. Cabo dose reductions to 40 and 20 mg occurred in 68% and 18% of pts, respectively, with discontinuations due to toxicity in 10% of pts. Conclusions: Cabo plus ADT has potent clinical activity in pts with high volume androgen-dependent PCa including improvements BS and reduction in markers of bone stromal function. Studies are underway to identify biomarkers predictive of best response. Clinical trial information: NCT01630590.
A prospective international randomized phase II study evaluating the food effect on the pharmacokinetics (PK) and pharmacodynamics (PD) of abiraterone acetate (AA) in men with castration-resistant prostate cancer (CRPC).
Authors: Szmulewitz Russell Zelig , Ibraheem Abiola Falilat , Peer Cody J. , Figg William Douglas , Carthon Bradley Curtis , Kozloff Mark , Harvey Donald , Fishkin Paul A. S. , Yong Wei Peng , Chiong Edmund , Nabhan Chadi , O'Donnell Peter H. , Stadler Walter Michael , Ratain Mark J.
Published: March 2017

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Background: AA is a standard of care for the treatment of metastatic CRPC, with an approximate retail cost of $8000/month. Despite a large food effect (~17-fold increase in CMax with a high-fat meal), AA was administered under fasting conditions in its pivotal trials. There are no randomized continuous dosing studies examining prandial state dosing on AA PK/PD. We sought to test the hypothesis that LOW (250mg w/food) would have similar PK/PD and safety to standard (STD, 1000mg fasting) in patients with progressive CRPC. Methods: Patients (n = 72) with progressive CRPC from seven institutions in the US and Singapore were randomized to treatment with STD or LOW (with low-fat breakfast). Both arms received prednisone 5mg twice daily. PSA was assessed monthly, and testosterone, DHEA/DHEAS were assessed every 12 weeks along with standard disease burden assessments. PK samples were collected at day 1, 8 and months 2, 3, 4. Log change in PSA response rate from baseline to week 12 was examined as the primary endpoint, with a non-inferiority design based on a non-inferiority margin of 15%. This margin corresponds to a 0.51 standard deviation (SD) difference in the mean log changes between the groups. Results: Accrual was completed with n = 36 on STD and n = 36 on LOW. Median (range) age was 74 (52-89) and baseline PSA was 39.2(range 0.6-1789). Mean log-change in PSA at 12 weeks was nominally greater in the LOW arm (-1.59 vs. -1.19). The 95% confidence for the difference (STD-LOW) ranged from -0.40 to 1.19, with lower limit corresponding to -0.24SD. Thus, non-inferiority of LOW was established. Median time to PSA progression was ~14 month in both arms (p = 0.53). Preliminary analysis of PK showed no difference in CMaxbeyond the first cycle with lower PK variability in the LOW arm. Conclusions: Low-dose (250mg/day) abiraterone acetate with a low-fat breakfast is non-inferior to standard dosing in a fasted state with respect to PSA and PK metrics. Although PSA response and progression are not clinically validated surrogates, given the pharmacoeconomic implications, these data warrant consideration by prescribers and payors. Clinical trial information: NCT01543776.
Racial disparities in prostate cancer outcome among prostate-specific antigen screening eligible populations in the United States.
Authors: Mahal Brandon Arvin Virgil , Chen Yu-Wei , Muralidhar Vinayak , Mahal Amandeep R. , Choueiri Toni K. , Hoffman Karen E. , Hu Jim C. , Sweeney Christopher , Beard Clair , Martin Neil E. , Feng Felix Yi-Chung , Kim Simon P. , Yu James B. , Trinh Quoc-Dien , Nguyen Paul L.
Published: March 2017

18

Background: In 2012, the United States Preventive Services Task Force (USPSTF) recommended against Prostate-Specific Antigen (PSA) screening, despite evidence that Black men are at a higher risk of prostate cancer-specific mortality (PCSM). We evaluated whether Black men of potentially screening-eligible age (55-69) are at a disproportionally high risk of poor outcomes. Methods: The SEER database was used to study 390,259 men diagnosed with prostate cancer in the United States between 2004-2011. Multivariable logistic regression modeled the association between Black race and stage of presentation, while Fine-Gray competing risks regression modeled the association between Black race and PCSM, both as a function of screening eligibility (age 55-69 vs not). Results: Black men were more likely to present with metastatic disease (adjusted odds ratio [AOR] 1.65; 1.58-1.72; P< 0.001) and were at a higher risk of PCSM (adjusted hazard ratio [AHR] 1.36; 1.27-1.46; P< 0.001) compared to Non-Black men. There were significant interactions between race and PSA-screening eligibility such that Black patients experienced more disproportionate rates of metastatic disease (AOR 1.76; 1.65-1.87 vs. 1.55; 1.47-1.65; Pinteraction< 0.001) and PCSM (AHR 1.53; 1.37-1.70 vs. 1.25; 1.14-1.37; Pinteraction= 0.01) in the potentially PSA-screening eligible group than in the group not eligible for screening. Conclusions: Racial disparities in prostate cancer outcome among Black men in are significantly worse in PSA-screening eligible populations. These results raise the possibility that Black men could be disproportionately impacted by recommendations to end PSA screening in the United States and suggest that Black race should inform clinical decisions on PSA screening.
Therapeutic targeting of tumor-associated macrophages through microscale engineering of the prostate cancer microenvironment.
Authors: Kosoff David , Yu Jiaquan , Schehr Jennifer L , Beebe David J. , Lang Joshua Michael
Published: March 2017

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Background: The tumor microenvironment (TME) plays integral roles in prostate cancer progression and is a high value therapeutic target. The development of effective TME-targeted therapies is limited by current technologies which are insufficient to replicate or analyze this complex environment. To address these challenges, we have developed a microfluidic cell culture platform known as STACKS, which permits co-culture of up to 6 patient-derived cell populations as well as compartmentalized, multiplexed analysis of gene expression, cell signaling, and matrix remodeling. We have focused on investigation of tumor-associated macrophages (TAMs), which have been implicated in prostate cancer growth, metastasis, survival, and therapeutic resistance. Methods: Using blood and prostate tissue obtained through biomarker studies at the University of Wisconsin, we isolated patient-derived cell populations for culture and analysis within the STACKS device. Monocytes obtained from peripheral blood were differentiated into tumor inhibitory (M1) and tumor promoting (M2) macrophages in the device. RNA, protein, and secretory factor expression were analyzed following manipulations of culture surface, cytokine exposure, and multi-cell culture with tumor and stromal cell populations. Results: We report that physical properties of the TME, such as topography and hydrophilicity, impact expression of tumor-promoting genes within macrophages. We also characterized macrophage expression of pro- and antitumor genes, including CCL18, CXCL10, CXCL11, IL-10, IL-12b, VEGF, and identified expression profiles that are dependent on tumor and stromal cell populations in co-culture and diverge from classical M1/M2 characterization. Conclusions: The STACKS platform is capable of advanced modeling and analysis of the prostate cancer TME. Investigation of patient-derived monocytes within STACKS has identified physical properties of the TME that affect tumor-related functions of macrophages and has also demonstrated that an M1/M2 classification spectrum may not be sufficient for characterizing TAMs. These findings represent new therapeutic targets for prostate cancer treatment.
A drug-drug interaction study on the combination of cabazitaxel with enzalutamide in patients with metastatic castration-resistant prostate cancer.
Authors: Belderbos Bodine P.S. , Bins Sander , van Leeuwen Roelof W.F. , De Hoop Esther Oomen , van der Meer Nelly , de Bruijn Peter , Hamberg Paul , Overkleeft Esther N.M. , van der Deure Wendy M. , Lolkema Martijn P. , De Wit Ronald , Mathijssen Ron H.J.
Published: March 2017

188

Background: Cabazitaxel and enzalutamide are effective single agent treatment options for metastatic castration resistant prostate cancer (mCRPC). Preclinical studies suggest enhanced efficacy of the combination of a taxane with enzalutamide. Recently, Morris et al. (CCR 2016) reported on an interaction study between docetaxel and enzalutamide: docetaxel mean exposure decreased by 12% during a short period of co-treatment with enzalutamide, probably due to enzyme (CYP3A4) induction. Since cabazitaxel is a CYP3A4 substrate, we investigated the influence of enzalutamide on cabazitaxel pharmacokinetics (PK) and toxicity during 3 chemotherapy cycles. Methods: We performed a cross-over study in 14 evaluable mCRPC patients who were treated with i.v. cabazitaxel Q3W (25 mg/m2). PK-sampling (over 24h) was conducted on day 1 of each cycle during 3 consecutive cabazitaxel cycles. From day 8 (±1) of the first cycle until day 8 (±1) of the third cycle, enzalutamide (160 mg/day) was administered concomitantly. Primary endpoint was the difference in geometric mean area under the curve (AUC0-24h) between the first and third cycle. Secondary endpoints included safety parameters and PSA response. Results: The AUC was 22% (95%CI 9-34%) lower during the third cycle (181 ng*h/mL, 95%CI 150-219 ng*h/mL) than during the first cycle (234 ng*h/mL, 95%CI 209-261 ng*h/mL; p = 0.005). No relevant adverse events occurred due to the drug combination. Nine patients (64%) received the full dose of cabazitaxel during the 3 study cycles. No enzalutamide dose reductions took place, and the combination was well tolerated. PSA response ( ≥ 50% decrease of baseline PSA ) was observed in 10 patients (71%). Conclusions: Cabazitaxel exposure is both statistically and clinically significantly reduced by concomitant enzalutamide use. Since the PROSELICA study (De Bono et al, ASCO 2016) may lead to an adapted standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be extensive, since it is likely to result in suboptimal exposures. We stimulate clinical studies with this combination, but these should include monitoring of the PK of cabazitaxel, and appropriate dose adaptations. Clinical trial information: NTR5164.
The association of androgen deprivation therapy and anxiety among 78,000 patients with localized prostate cancer patients.
Authors: Dinh Kathryn T , Reznor Gally , Muralidhar Vinayak , Martin Neil E. , Orio Peter F. , Trinh Quoc-Dien , Nguyen Paul L.
Published: March 2017

19

Background: Androgen deprivation therapy (ADT) has been associated with cognitive and psychological effects, including depression. ADT may also cause an increased incidence of anxiety; however, most studies have not considered anxiety as an individual outcome. We aimed to determine if receipt of any ADT or longer duration of ADT for prostate cancer is associated with increasing risk of being diagnosed with anxiety. Methods: We identified 78,552 men over 65 with stage I-III prostate cancer using the Surveillance, Epidemiology, and End Results-Medicare linked database from 1992-2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association of pharmacologic ADT with the diagnosis of anxiety using Cox-proportional hazard regression with propensity matching. Drug-data for treatment of anxiety was not available. Our secondary analysis was the association of ADT duration with a diagnosis of anxiety. Results: Overall, 43% (33,882) of patients who received ADT and had higher 3-year cumulative incidence of anxiety (4.1% vs. 3.5%) than patients without ADT (p < 0.001). Adjusted cox-analyses with propensity matching demonstrated patients with ADT had a 17% increased risk of anxiety (adjusted hazard ratio [AHR] = 1.17, 95% CI = [1.088-1.263]) compared to patients without ADT (p < 0.0001). The risk of anxiety increased with duration of ADT, from 4.5% with ≤ 6 months, 5.8% with 7-11 months, to 15.7% with ≥ 12 months (p-trend = 0.0123). Conclusions: Pharmacologic ADT is associated with an increased risk of anxiety in this large study of elderly men with localized prostate cancer. This risk increased with longer duration of ADT. Anxiety should be consider among the possible psychiatric effects of ADT and should be discussed along with depression prior to initiating ADT.
Clinical versus radiographic progression and overall survival for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) from COU-AA-302.
Authors: Ryan Charles J. , Kheoh Thian , Scher Howard I. , De Porre Peter , Yu Margaret K. , Morris Michael J.
Published: March 2017

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Background: COU-AA-302 evaluated abiraterone acetate plus prednisone (AA) vs prednisone (P) in chemotherapy-naïve mCRPC pts, with overall survival (OS) and radiographic progression-free survival (rPFS) as co-primary end points. Per study criteria, pts with radiographic progression (RAD) only were allowed to continue treatment, while those with unequivocal clinical progression (UCP) only were not, and were censored for rPFS. We evaluated the clinical significance of survival outcomes for pts with UCP only vs RAD only from the prospective COU-AA-302 trial. Methods: UCP was defined per protocol as ≥ 1 of the following: initiation of chronic opiates, ECOG performance status (PS) decline to ≥ 3, or initiation of chemotherapy, palliative radiation therapy, or surgery. OS was evaluated for each type of progression using Cox proportional hazard models. Results: 500 (92%) pts in the AA arm and 540 (100%) in the P arm discontinued study treatment. Of the 736 pts who discontinued treatment for a protocol-defined reason, 280 (38%) discontinued for UCP only, 332 (45%) for RAD only, and 124 (17%) for both UCP and RAD. Clinical events cited as the reason for discontinuation for UCP (AA vs P arm) included pain requiring opiates (22% vs 25%), ECOG PS ≥ 3 (4% vs 5%), and initiation of chemotherapy (50% vs 53%), radiation therapy (36% vs 27%) and surgery (3% vs 5%). UCP only pts had shorter median OS compared with RAD only pts (Table). Conclusions: UCP is a criterion used as an indicator for a censored event, yet appears to confer inferior survival relative to RAD. The high frequency of UCP implies that it may be an important determinant of clinical outcome. The events that drive UCP should be defined as part of the development of more informative interim trial end points, in line with the PCWG3-proposed “no longer clinically benefitting” outcome measure, which captures pts with UCP. Clinical trial information: NCT00887198. [Table: see text]
Outcomes for men under 65 with high-risk prostate cancer with Medicaid versus private insurance.
Authors: Mahal Amandeep R. , Mahal Brandon Arvin Virgil , Nguyen Paul L. , Yu James B.
Published: March 2017

198

Background: Increased Medicaid coverage, due to the Affordable Care Act, has been hypothesized to reduce racial disparities. We therefore examined the association between private insurance vs. Medicaid, race, and outcomes for the treatment of high-risk prostate cancer (CaP) among men < 65 years old. Methods: The Surveillance, Epidemiology, and End Results Program identified 116,853 men < 65 diagnosed with CaP from 2007-2011. Multivariable logistic regression modeled the association between insurance status (IS) and stage at presentation. Among men with high-risk CaP, the associations between IS and receipt of definitive therapy (DT) and prostate cancer-specific mortality (PCSM) were determined using multivariable logistic and Fine and Gray competing-risks regression models, respectively. Results: Compared to privately insured men, those with Medicaid were more likely to present with metastatic disease (Mets) (adjusted odds ratio (AOR) 5.79; 95% confidence interval (CI) 5.25-6.40; P < 0.001). Among men with high-risk disease, men with Medicaid were less likely to receive DT (AOR 0.55; 95% CI 0.51-0.60; P < 0.001) and had increased PCSM (adjusted hazard ratio (AHR) 1.8; 95% CI 1.27-2.54; P = 0.001). There were significant interactions (INT) between race and Medicaid for the outcomes of PCSM (PINT= 0.05) and Mets (PINT= 0.003). Specifically, gaps in PCSM and Mets were observed among privately insured men, with increased PCSM (AHR 1.51; 95% CI 1.18-1.94; P = 0.001) and Mets (AOR 1.33; 95% CI 1.20-1.48; P < 0.001), while there were no observed disparities among men with Medicaid with regards to PCSM (AHR 0.72; 95% CI 0.34-1.52; P = 0.387) and Mets (AOR 1.03 95% CI 0.86-1.24; P = 0.730). Conclusions: Among men with CaP, African American men are more likely to present with Mets, less likely to receive DT, and have increased PCSM compared to non-black men. These disparities are observed in heterogeneous privately insured cohorts. However, among men with Medicaid, outcomes were equally worse. Furthermore, there was a significant INT between race and IS, indicating more-than-additive effects. Our study suggests that while increased access to Medicaid could act to reduce disparities seen in CaP, outcomes need to be improved overall.
Taste and prostate cancer: Preliminary data on a novel patient-reported outcomes.
Authors: Chow Lydia D. , Cotogno Patrick , Ernst Emma M. , Manogue Charlotte , Ledet Elisa M. , Sartor Oliver
Published: March 2017

201

Background: Taste alterations are a common yet frequently under-assessed problem in cancer patients. Health-related quality-of-life (HRQOL) instruments for prostate cancer (PCa) patients (pts) do not assess taste despite these hypothetically being related to both appetite and weight loss. Herein we begin to assess taste using a novel instrument evaluating taste alterations with a focus on PCa. Methods: 61 PCa pts treated at Tulane Cancer Center were enrolled in this prospective study. An 18-item questionnaire assessed appetite, taste, smell, and diet. 127 questionnaires were completed (mean 2.1 responses/pt). In a subset of questionnaires, we compared self-reported taste, appetite, and weight loss over a 6-month period. In another subset, we compared taste and appetite to treatments with abiraterone, docetaxel, or enzalutamide. Non-parametric testing was performed. Results: Of the 61 participants with PCa, 18.0% reported poor taste, 17.1% reported poor appetite, and 6.6% reported nausea while eating. When asked to assess to what extent this was a perceived problem, 16.4% rated taste, 13.1% rated nausea, and 16.4% rated appetite as a “moderate” or “big” problem. Men with poor or very poor taste (1 or 2 on a 5 point Likert scale) had a significant association with poor appetite (OR = 7.9, P = 0.0002). There was no direct relationship observed between taste and weight loss. The population with poor appetite was more likely (OR = 21.25, P < 0.0001) to have had ≥ 5% weight loss as compared to those without a poor appetite. Those reporting at least some nausea were also (OR = 8.645, P = 0.0007) more likely to have ≥ 5% weight loss. In the treatment subset, pts on docetaxel at time of survey were 15.17 fold more likely to have poor taste as compared to those on abiraterone (p = 0.0145). Conclusions: We observed that perceived problems with taste were associated with loss of appetite which in turn was associated with weight loss. Weight loss is a known adverse prognostic factor in pts with advanced PCa. Further studies are warranted on this important patient-centric assessment.
Targeting reciprocal feedback inhibition: Apalutamide and everolimus in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rathkopf Dana E. , Slovin Susan F. , Morris Michael J. , Danila Daniel Costin , Delacruz Anthony , Shelkey Gregory , DeNunzio Mia , McLaughlin Brigit , Scher Howard I.
Published: March 2017

204

Background: Studies in xenograft CRPC and PTEN-deficient prostate cancer models have shown synergistic anti-tumor activity of next-generation anti-androgens such as apalutamide when combined with PI3K/mTOR inhibitors such as everolimus. (Carver B et al., Cancer Cell 2011) The primary hypothesis of this study was that the combination of apalutamide with everolimus would overcome resistance to prior hormonal therapy with abiraterone acetate and prednisone (AAP). Methods: The primary endpoint in mCRPC patients with prior AAP was to evaluate the safety, pharmacokinetics (PK), and recommended phase 2 dose (RP2D) of fixed dose apalutamide 240 mg po qd when combined with everolimus 5 mg po qd (cohort 1, n = 3) and everolimus 10 mg po qd (cohort 2, n = 6). The plan was to expand to treat 40 patients at the RP2D. Results: Nine patients were enrolled in phase 1. The PK for the combination was consistent with historical data of either drug given as monotherapy. The most common treatment related adverse events were < = grade 2 fatigue (67%), diarrhea (56%), and anorexia (56%). In cohort 2, 1 patient had a DLT of grade 3 rash. The median time on treatment was 17 weeks (range 7-51+). The best response was SD in all 9 patients. Patients came off study for: progression (n = 3), investigator choice (n = 3) and toxicity unrelated to treatment (n = 2). Seven patients had detectable CTCs at baseline (EPIC Sciences). One patient had a rise in CTC number that then converted to undetectable and remained on study 37 weeks. One out of 6 evaluable patients had PTEN loss in tissue at baseline (MSK IMPACT) and remained on study 12 weeks. One patient with prior AAP and enzalutamide exposure has remained on study 51+ weeks with a > 50% decline in PSA (PTEN pending). Conclusions: Although the combination of apalutamide and everolimus was safe and well tolerated, the treatment response was similar to historical data of AAP followed by apalutamide alone. (Rathkopf D et al., ASCO 2014) We elected to close this study before expansion in favor of evaluating novel AR/PI3K pathway combinations in patients who have not yet been exposed to AAP. Drug provided by Janssen and Novartis. Trial support: PCF and MSK Experimental Therapeutics Center. Clinical trial information: NCT02106507.
Real-world outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving second-line (2L) chemotherapy (CT) vs alternative androgen receptor-targeted agents (ARTA) after lack of response to first-line (1L) ARTA in US community oncology practices.
Authors: Oh William K. , Cheng Wendy Y. , Miao Raymond , Vekeman Francis , Gauthier-Loiselle Marjolaine , Duh Mei Sheng , Drea Edward , Szatrowski Ted P.
Published: March 2017

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Background: The relationship between treatment sequence and mCRPC outcomes is unclear. This retrospective study assessed if 2L CT vs alternative ARTA is associated with improved outcomes in pts with lack of response to 1L ARTA in the US community oncology setting. Methods: Using Altos electronic medical records, we identified 345 mCRPC pts with lack of response to 1L ARTA (abiraterone or enzalutamide) who received 2L docetaxel or cabazitaxel (CT cohort N = 147), or alternative ARTA (ARTA cohort N = 198) from May 2011 to Oct 2014. Outcomes were evaluated from start of 2L therapy and compared for 2L CT vs ARTA cohorts using one-sided tests. Prostate-specific antigen (PSA) response ( ≥ 50% reduction) and overall survival (OS) were assessed using logistic and Cox proportional hazard regression models adjusted for year, age, metastases, opioid use, ECOG performance score, PSA, hemoglobin (Hb), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and albumin (Alb) levels. Results: At start of 2L therapy, pts receiving CT vs ARTA were younger (median age, 74 vs 79 yr) and had a worse prognosis: higher mean PSA (439 vs 231 ng/mL), LDH (344 vs 234 U/L) and ALP (241 vs 166 U/L), lower mean Hb (11 vs 12 g/dL), higher mean Halabi risk score (159 vs 137; JCO 2014:32;671–7), increased opioid use (42 vs 22%), and more pts had Alb < lower limit of normal (LLN; 25 vs 15%); all p < 0.01. More pts in the CT vs ARTA cohort had a PSA response (adjusted odds ratio = 2.27, p = 0.005) and there was a non-statistically significant trend toward improved OS for 2L CT vs ARTA (adjusted hazard ratio [aHR] = 0.81, p = 0.148). Among pts with poor prognostic features, those in the CT cohort had significantly improved OS (Halabi intermediate–high risk score: aHR = 0.55 p = 0.009; Hb < 11 g/dL: aHR = 0.41 p = 0.002; LDH > upper limit of normal: aHR = 0.18 p = 0.014; Alb < LLN: aHR = 0.42 p = 0.020), compared with those in the ARTA cohort. Conclusions: Treatment with 2L CT, vs 2L ARTA, may be more suitable for pts with a lack of response to 1L ARTA, particularly in pts with a poor prognosis. Funding: Sanofi Genzyme.
The use of five-alpha reductase inhibitors and their association with reclassification and pathologic outcomes in the Canary Prostate Active Surveillance Study (PASS).
Authors: Kearns James T , Faino Anna V , Newcomb Lisa F , Brooks James D. , Carroll Peter , Dash Atreya , Ellis William J , Fabrizio Michael , Gleave Martin , Morgan Todd Matthew , Nelson Peter S , Thompson Ian Murchie , Wagner Andrew , Zheng Yingye , Lin Daniel W.
Published: March 2017

22

Background: The outcomes of patients who enroll in active surveillance (AS) programs for prostate cancer (PCa) while currently taking five-alpha reductase inhibitors (5-ARIs) have not been well defined. Previous studies suggest that the initiation of 5-ARIs after enrolling in AS decreases the rate of reclassification and/or treatment for PCa, but there is still an FDA black box warning about the risk of grade risk prostate cancer while on 5-ARI. The objective of this study was to evaluate the safety of remaining on a 5-ARI after initiating AS for PCa. Methods: All men were enrolled in PASS. Inclusion criteria were current or never 5-ARI user, Gleason 3+3 or 3+4 PCa at diagnosis, ≤ 34% core ratio at diagnosis and ≥ 1 surveillance biopsy. Reclassification was defined as an increase in Gleason score and/or ratio of biopsy cores positive for cancer to ≥ 34%. Results: 1045 men were included in this study, 938 who had never used a 5-ARI and 107 5-ARI users. 5-ARI users had larger prostate volume (51 cc vs 40 cc, p < 0.01), a higher rate of BPH (77% vs 29%, p < 0.01) and older age (65 vs 62 years, p < 0.01). All other clinical parameters, including serum PSA, were statistically similar. Kaplan Meier analysis of any reclassification is shown in the figure. There was no significant difference in any reclassification (p = 0.12). The use of 5-ARI at diagnosis was significantly protective for reclassification in a proportional hazards model (HR 0.68, p = 0.03); this difference was not significant after accounting for serum PSA, BMI, prostate size and positive cores ratio at diagnosis (HR 0.78, p = 0.18). There was no significant effect on adjusted analysis when evaluating for disease upgrading. 171 patients underwent radical prostatectomy (RP), 158 never 5-ARI users and 13 5-ARI users. There were no statistically significant differences when evaluating for Gleason grade or adverse pathology. 5-ARI users had a longer median time to RP (3.6 vs 2.1 years, p = 0.045). Conclusions: There is no association between 5-ARI use at diagnosis and reclassification on AS for men in the Canary PASS cohort. 5-ARI users have a longer median time to RP and do not have more severe PCa at RP.
Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-t alone in patients with metastatic castrate resistant prostate cancer.
Authors: Twardowski Przemyslaw , Wong Jeffrey Y.C. , Pal Sumanta K. , Frankel Paul Henry , Franklin Kelly , Junqueira Maribel , Prajapati Manisha R. , Harwood Deborah , Agarwal Neeraj
Published: March 2017

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Background: Sipuleucel-T (sip-T) is an autologous cellular vaccine indicated for patients (pts) with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC). Since radiation therapy (RT) can suppress the bone marrow function and immune response, previous studies evaluating sip-T excluded pts who received RT less than or equal to 28 days prior to sip-T therapy. Recent evidence suggests that RT may act synergistically with immunotherapy to enhance and broaden antitumor immune response. Methods: Pts who met standard criteria for sip-T were randomized to receive sip-T alone (Arm A) or sip-T initiated 1 week after completing sensitizing RT to single metastatic site (Arm B). RT was delivered at 300cGy/day to 3000 cGy total. The primary endpoint was the ability to safely combine sip-T preceded by RT and generate sip-T product with adequate immune activation parameters. Secondary endpoints included the measurement of immune responses to prostatic acid phosphatase (PAP) and PA20204 (recombinant fusion protein utilized in the generation of sip-T). Results: 51 pts were enrolled, 2 did not receive any sip-T because of vascular access problems and were excluded. 24 were treated on Arm A, 25 on Arm B. 47/49 pts received all 3 sip-T infusions. Median age was 66 yrs (range 45-90). Sip-T product parameters including: total nucleated cell (TNC) count, antigen presenting cell (APC) count and APC activation were similar in both groups. 2 pts on Arm A demonstrated PSA response. Median progression free survival (PFS) was 3.0 months on Arm A and 4.6 months on Arm B (p = 0.19). Both arms showed similar increases in humoral responses to PA2024 and PAP. IFN-ƴ ELISPOT T-cell activation responses to PA20204 were observed in both arms, but were more robust in the Arm A (p = 0.04). Both arms were well-tolerated, with fatigue as the most common grade 2 adverse event (1 pt in Arm A and 3 pts in Arm B). Conclusions: Sensitizing RT completed 1 week before generation of sip-T did not affect product parameters and the ability to deliver sip-T therapy. RT did not enhance the humoral and cellular responses associated with sip-T therapy. Clinical trial information: NCT01807065.
Comprehensive genomic sequencing of prostate sarcomatoid carcinoma tumors identifies differences in genomic alterations compared to prostate adenocarcinoma tumors.
Authors: Millis Sherri Z. , Stephens Philip J. , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj Mahamed , Wang Jue
Published: March 2017

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Background: Sarcomatoid carcinoma of the prostate is a rare variant of prostatic cancer and has a significantly worse prognosis. The genomic features underpinning this rare subtype of malignancy are not well understood, and at present, there are no effective therapies. Methods: Tissue from 1417 prostate cancer patients was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling identified different patterns in GAs between prostate adenocarcinoma (1409) and prostate sarcomatoid carcinoma (8) (table), most notably in the commonly identified alterations in prostate cancers: TP53, RB1, and TMPRSS2-ERG. Additionally, the PI3K/mTOR pathway was altered in 50% of the sarcomatoid carcinoma cohort. None of the sarcomatoid carcinoma patients had a high TMB, while 4% of the prostate adenocarcinomas had TMB greater than 19 mutations/Mb. The sarcomatoid carcinoma cohort also had on average 8 GAs, while the prostate adenocarcinoma cohort had an average of 13 GAs. Conclusions: Genomic profiles of tumors from patients with prostate cancers reveal that those with sarcomatoid carcinoma features are more likely to have genomic alterations in TP53, RB1, and TMPRSS2 but fewer overall GA’s. Based on rearrangements and the sarcoma profile, utilization of a broad CGP panel that includes analysis of a larger panel of rearrangements identifies more commonly rearranged genes that would not be identified in non-comprehensive panels that do not evaluate these rearrangements. These findings may contribute to a better understanding of the oncogenesis of sarcomatoid prostate carcinoma and for defining novel systemic treatment options. [Table: see text]
Predictors of long-term response to abiraterone acetate with prednisone and cabazitaxel after first-line docetaxel in patients with metastastic castration-resistant prostate cancer (mCRPC): Subgroup analysis of a prospective observational study.
Authors: Sala Nuria , Méndez-Vidal María José , Pinto Alvaro , Puente Javier , Rodriguez Sanchez Angel , Cuevas Sanz Jose Miguel , Vazquez-Estevez Sergio , Muñoz del Toro Jacobo , Ruiz Pedro , Garcia Angela , Gonzalez del Alba Aranzazu
Published: March 2017

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Background: Recently treatment options for mCRPC have increased considerably. It remains unclear if there is any predictive factor to recognize which patients (pts) could obtain the most benefit in second line (2L) mCRPC. Recent data have been published addressing long-term predictive factors in a retrospective cohort in 2L1. We aim to reproduce it in this prospective study. Methods: The CAPRO study is a prospective multicenter national observational descriptive study. The primary endpoint was to describe the management in 2L mCRPC pts after DOC in routine clinical practice. To characterize which factors are associated with a better response in 2L mCRPC, we performed a multivariant analysis in the subgroup of pts with a long-term response (long-term responders (LTR): pts receiving abiraterone acetate + prednisone (AA) or Cabazitaxel (CB) for > 12 mo). Results: 150 patients were recruited (Jul 2013-Jan 2015). We identified 36 LTR (29/100 with AA: (29%) and 7/44 (15.9 %) with CB as 2L. No statistical differences in the number of LTR treated with AA vs CB (p = 0.095) were observed. LTR group (before starting 2L): median age 77.2 (51-87) median PSA 56.7 ng/dL (5.3-2627 ng/dL), alkaline phosphatase 92.5 IU/L (44-630 IU/L) and LDH 221.5 IU/L (147-445 IU/L). At median follow-up of 7.8 mo (IQR 4.2- 12.8), median PFS (clinical and/or radiological) was significantly longer in LTR AA group (not yet reached) vs LTR CB group 18.14 [95% CI 12.67-23.6]; HR 0·29 [95% CI 0,092 – 0,918; p = 0.025]. In a multivariate analysis two factors were significantly associated with LTR in 2L mCRPC: Gleason score < 7 (OR: 0.22 95% CI 0.065-0.745, p = 0.015) and normal LDH ( < 250 IU/L) (OR: 0.235, 95% CI 0.093-0.595, p = 0.002). No differences in safety profile between LTR vs non LTR of AA group and CB group were found. Conclusions: In this final subgroup analysis we observed Gleason score < 7 and LDH < 250 IU/L are predictors of long term response in 2L mCRPC. Median PFS in LTR treated with AA was significantly longer than LTR treated with CB. These findings need to be validated in further larger prospective studies.
Assessment of urologists experience with abiraterone acetate and with a real-world trial: Results obtained from a Canadian Observational Study in Metastatic Cancer of the Prostate (COSMiC).
Authors: Feifer Andrew , Fradet Vincent , Drachenberg Darrel , Gotto Geoffrey , Rendon Ricardo A. , Sabbagh Robert , Shayegan Bobby , Danielson Brita Lavender , Casey Richard , Zardan Anousheh , Camacho Fernando , Hew Huong
Published: March 2017

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Background: Abiraterone Acetate (AA) is a selective inhibitor of the androgen biosynthesis and has significantly improved OS for mCRPC patients. Canadian Observational Study in Metastatic Cancer of the Prostate (COSMiC) is a Non-Interventional Observational Study pPhase IV clinical trial; NCT02364531) specifically designed to (1) collect real-world drug-specific outcomes (clinical and patient reported outcomes) and (2) assess urologists experience with incorporation of AA in their practice. Here we report data collected from COSMiC trial on the success of AA integration into the urology practice and physicians experience in participating in the trial. Methods: (1) A comprehensive questionnaire was developed to assess urologists experience with (a) integration and usage of AA in their practice and (b) COSMiC trial. (2) Questionnaire was sent to the active trial sites (47 sites) and collected data from 30 sites is summarized here. Results: 93.3% of participants in COSMiC trial were urologists (63.3% community vs. 30% academic). The ease of use and success in integration of AA in urology practice was rated easy by 50% of the participants, easy once they overcame few barriers by 46.7% and challenging by 3.3%. Drug-related barriers identified included time involvement (50%), resource issues such as nursing support (23.3%), and lack of appropriate infrastructure (33.3%). 90% of the active sites indicated that treating mCRPC patients with AA will be part of their practice post-trial. As part of this report we also assessed and identified physicians barriers in participating in COSMiC trial. 86.7% of the sites reported that trials such as COSMiC will add value to the therapeutic area and 93.3% of the sites reported interest in participating in trials of this nature in future. Conclusions: This report indicates that integration of AA in urology practices is considered easy and manageable for most urologists, in some cases after overcoming few initial barriers. There is high interest in participating in future real-world trials of this nature among urologists and such studies add value to the therapeutic area. Clinical trial information: NCT02364531.
National, centralised hospital datasets can inform clinical trial outcomes in prostate cancer: A pilot study in the STAMPEDE trial.
Authors: Mintz Harriet Paige , Evison Felicity , Parsons Helen M , Sydes Matthew Robert , Spears Melissa Ruth , Patel Prashant , James Nicholas D. ,   The STAMPEDE Trial Group
Published: March 2017

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Background: Hospital Episode Statistics (HES) are routinely collected data describing National Health Service (NHS) hospital visits in England, with procedure & disease codes. This study, embedded in STAMPEDE, aimed to build a model using HES, linked to primary medical records & trial case report forms (CRFs) to identify progressive disease events (PDEs), including skeletal-related events (SREs). Methods: Analysis of 5 STAMPEDE patients (pts) in 2 stages (data to Jul 16). 1: Detailed manual note review of 3 pts’ PDEs were compared to HES & CRFs to build model. 2: Used model to use HES to identify possible PDEs in 2 pts, verified by note review & compared to CRFs. Created algorithm rules to identify PDEs per 8 week interval plus further analysis of HES coding to find SREs. Results: Prostate cancer PDEs coincided with clustering of HES events. HES found 4 PDEs omitted from CRFs but missed 2 (total PDEs: HES 10, CRFs 8). HES found a false positive CRF PDE. Compared with note review HES missed 4 PDEs (false negatives), with 2 missed & 2 upgraded to PDEs post-standard query procedures, plus HES found 3 false positives (1 STAMPEDE treatment & 2 delayed treatments post-PDE). Hence HES found 71% of PDEs in note review (HES 10, note review 14).CRFs found 57% of PDEs compared to note review (CRFs 8, note review 14). Hence HES found 14% more PDEs than were recorded in CRFs compared to note review. HES identified 4 additional SREs not recorded in CRFs but missed 2. Conclusions: Hospital record review revealed site staff may miss reporting major clinical efficacy outcome events on CRFs, especially nearer end-of-life. HES successfully identified most PDEs (often found as a cluster of SREs), plus additional trial events not reported on CRFs compared to note review and as predicted HES & CRFs found less PDEs. PDEs & SREs missed from CRF recording can be identified in HES.This confirmed use of HES to detect PDEs is feasible. HES-identified events have potential as a primary data source when subsequently verified by standard data queries. Future work will test this model prospectively in the forthcoming BladderPath trial. It may offer a superior, cost-effective method of primary data collection compared to traditional CRF recording.
An update on clinical outcome data for a phase II randomized study comparing androgen deprivation therapy plus docetaxel versus androgen deprivation therapy alone in men with locally advanced/metastatic hormone sensitive prostate cancer.
Authors: Hassani Adam , Frew John A. , McMenemin Rhona Margaret , Azzabi Ashraf S. , Pedley Ian D.
Published: March 2017

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Background: Androgen deprivation therapy has been the standard of care for advanced prostate cancer for many years. However recent studies have reported a survival benefit for upfront docetaxel chemotherapy in men with hormone sensitive prostate cancer. The GenTax trial was a single institution phase II study investigating clinical outcome and gene profiling for patients with treatment naïve prostate cancer treated with either docetaxel chemotherapy plus androgen deprivation therapy (D+ADT) or androgen deprivation therapy alone (ADT). We report on updated clinical outcome data for this trial. Methods: Patients with newly diagnosed T3/T4, PSA ≥ 50ng/ml or Gleason score ≥ 8, or metastatic disease were enrolled. Patients were randomised to ADT or D+ADT (docetaxel 75mg/m2 q21 days for 6 cycles). Data were analysed for overall survival, toxicities, time to second line treatment and number of subsequent treatments. Results: 30 patients were randomly assigned to ADT (n = 15) or D+ADT (n = 15) between 10/13/2005 and 12/02/2009. 7 patients in each arm had metastatic disease. Grade 3-4 toxicities were infrequent in D+ADT arm and were not noted in the ADT arm. There were no significant differences between treatment arms for overall survival (log rank p = 0.977) or time to second line treatment (log rank p = 0.954). Median overall survival was 98 months (95% CI 72.3 - 123.7) for ADT and 87 months (95% CI 71.5 - 102.5) for D+ADT. Median time to second line treatment was 45 months (95% CI 13.4 - 76.6) for ADT and 46 months (95% CI 13.2 – 78.8) for D+ADT. Number of subsequent treatments ranged from 0-6 (mean 2.40) for ADT-only and 0-5 (mean 2.13) for D+ADT. Conclusions: The combination of docetaxel and ADT in the hormone sensitive setting is well tolerated, as previously reported. This study was not sufficiently powered to detect statistically significant differences in survival. Patients proceeded to receive a number of subsequent lines of therapy although the order in which these were given was variable. There is a need to establish optimal sequencing of treatments in the upfront docetaxel era. Clinical trial information: 2004-004874-96.