Amanda Leiter

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

Background:Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel.Methods:We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel.Results:Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2–9.1), 4.0 (3.2–4.8), 4.1 (2.9–5.4) and 2.8 (2.5–3.2) months; median duration of enzalutamide was 9.1 (7.3–not reached), 4.7 (3.7–7.7), 5.4 (3.8–8.4) and 3.9 (3.0–4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7–16.5). 12-month OS was 78% (59–100%), 64% (45–90%), 77% (61–97%) and 51% (41–62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide.Conclusions:The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

Prostatic acid phosphatase is expressed in human prostate cancer bone metastases and promotes osteoblast differentiation

Prostate cancer (PCa) bone metastases are a major cause of morbidity and mortality. There are no effective therapies for PCa bone metastases that prolong survival. Prostatic acid phosphatase (PAP) is a secretory protein expressed by PCa cells. We demonstrate that PAP is strongly expressed in PCa bone metastases in 7/7 patients, while prostate‐specific antigen (PSA) is only weakly expressed. The human PCa cell line VCaP secretes PAP and induces an osteoblastic reaction in bone similar to that seen in human PCa bone metastases. Coculture of MC3T3 mouse preosteoblast cells with VCaP cells induces MC3T3 cell growth and differentiation as measured by alkaline phosphatase secretion, and this effect is inhibited by addition of the PAP‐inhibitor, l‐tartrate. Taken together, these data indicate that PAP is expressed in PCa bone metastases and may play a causal role in the osteoblastic phase of the disease.

Use of Crowdsourcing for Cancer Clinical Trial Development

Patient and physician awareness and acceptance of trials and patient ineligibility are major cancer clinical trial accrual barriers. Yet, trials are typically conceived and designed by small teams of researchers with limited patient input. We hypothesized that through crowdsourcing, the intellectual and creative capacity of a large number of researchers, clinicians, and patients could be harnessed to improve the clinical trial design process. In this study, we evaluated the feasibility and utility of using an internet-based crowdsourcing platform to inform the design of a clinical trial exploring an antidiabetic drug, metformin, in prostate cancer. Over a six-week period, crowd-sourced input was collected from 60 physicians/researchers and 42 patients/advocates leading to several major (eg, eligibility) and minor modifications to the clinical trial protocol as originally designed. Crowdsourcing clinical trial design is feasible, adds value to the protocol development process, and may ultimately improve the efficiency of trial conduct.

Clinical trial awareness: Changes over time and sociodemographic disparities

Background or aims: Lack of clinical trial awareness is a known obstacle to clinical trial enrollment. We sought to define the prevalence of clinical trial awareness in the US population, determine characteristics associated with increased trial awareness, and explore potential disparities in trial awareness. Methods: We utilized data from the Health Information National Trends Survey from 2008 and 2012. Logistic regression was utilized to assess predictors of clinical trial awareness, particularly sociodemographic variables and information-seeking preferences. Trial awareness and information-seeking preferences were compared in patient subgroups and between the two time periods. Results: Clinical trial awareness increased from 68% to 74% between 2008 and 2012. In the 2012 dataset, higher education level (odds ratio: 3.52, 95% confidence interval: 2.16–5.74), higher yearly income category (odds ratio: 1.84, 95% confidence interval: 1.17–2.89), and Internet use (odds ratio: 2.13, 95% confidence interval: 1.52–3.00) were significantly associated with clinical trial awareness. Hispanic ethnicity (odds ratio: 0.41, 95% confidence interval: 0.25–0.68) was significantly associated with decreased awareness. Clinical trial awareness increased in African-American/Blacks (Δ10.6%) and Hispanics (Δ10.7%) between 2008 and 2012, as did Internet use in both subgroups (Δ14.2%, Δ18.1%, respectively). Conclusion: Overall clinical trial awareness has increased between 2008 and 2012, although a large subset of the population still lacks general awareness of clinical trials. Racial and ethnic disparities in trial awareness exist, although disparities may be decreasing among the Black population. These findings may help target educational efforts and inform approaches to increasing trial awareness.

Obesity and Outcomes in Patients with Metastatic Urothelial Carcinoma1

Background: Obesity has been associated with worse outcomes in patients with clinically localized urothelial cancer. However, this impact has not been evaluated in metastatic disease. Objective: To assess the impact of obesity on outcomes of patients with metastatic urothelial cancer. Methods: Data from 537 patients were aggregated from eight phase II and phase III clinical trials investigating first-line cisplatin-based combination therapy in metastatic urothelial cancer. Chemotherapy regimen, adverse events, treatment response, and survival outcomes were compared across body mass index (BMI) and body surface area (BSA) categories. Results: BMI was classified according to WHO criteria (<18.5 underweight, 18.5–24.99 normal weight, 25–29.99 overweight, >30 obese). BSA was classified as either below or greater than or equal to (average for this cohort (1.87 m2 for males and 1.66 m2 for females). There was no significant difference in number of chemotherapy cycles, adverse events, and response rate or survival outcomes (overall and progression-free) across BMI and BSA categories. There was no significant difference in adverse events across BMI categories, but the incidences of embolic events and renal failure were higher in patients with an average or higher BSA than those with a lower than average BSA (6.6% vs. 3.1% for renal failure p = 0.06; 5.9% vs. 2.7% for renal failure, p = 0.07). There was no significant difference in response rate or survival outcomes (overall and progression-free) amongst BMI and BSA categories. Conclusions: Obese patients with metastatic urothelial cancer on cisplatin-based therapies have similar response rates, survival outcomes, and tolerability of cisplatin-based therapy to non-obese patients.

Targeting Vascular Endothelial Growth Factor Receptor Signaling in Renal Cancer: The Sooner the Better?

Over the past decade, the treatment of metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of antiangiogenic therapies. Five drugs are now approved by the US Food and Drug Administration and other regulatory agencies, directed at the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling axis: four orally bioavailable small molecule multikinase inhibitors with activity against VEGFR (sorafenib, sunitinib, pazopanib, and axitinib) and an intravenously administered monoclonal antibody that binds the VEGF ligand (bevacizumab). These regulatory approvals were largely based on improvements in time-to-event end points (eg, progressionfree survival) compared with placebo or control and were all based on trials completed in the metastatic setting. Consistent with an oncologic drug-development paradigm that has existed for>50 yr, after establishing the safety and efficacy of VEGFR-targeted agents in metastatic RCC, these drugs are now being studied in earlier clinical disease states in the hope of achieving an even greater impact on the natural history of the disease. In fact, a large number of randomized trials evaluating adjuvant VEGFR kinase inhibitors and collectively enrolling >7000 patients have been are ongoing or have completed accrual (Table 1). In this context, several critical questions emerge: Based on theirmechanism of action, is it reasonable to expect that the perioperative application of VEGFR-targeted therapies will increase the likelihood of cure in patients with clinically localized disease (or at least significantly delay recurrence)?What are the relative risks and benefits of application of these therapies in the neoadjuvant setting versus the adjuvant setting? What is the optimal antiangiogenic drug and duration of treatment in the perioperative setting? And,

Telemedicine-Enabled Clinical Trial of Metformin in Patients With Prostate Cancer

PURPOSE Clinical trials are critical to informing cancer care but often are hampered by slow accrual and lack of generalizability because of poor geographic accessibility. We tested the feasibility of replacing onsite study visits with telemedicine visits in a prospective clinical trial. METHODS Castration-naïve patients with prostate cancer and a rising serum prostate-specific antigen after definitive local therapy were eligible. Patients were required to have a single onsite visit for enrollment. Study treatment consisted of oral metformin 850 mg daily for 1 month followed by 850 mg twice daily for 5 months. Telehealth video visits (televisits) were conducted monthly by using a Health Insurance Portability and Accountability Act-compliant smartphone application. The primary objective was to determine the feasibility of telemedicine-enabled study visits. Secondary objectives were defining safety, anticancer activity, quality of life, and patient satisfaction. RESULTS Fifteen patients with a median age of 68 years (range, 57 to 83 years) and median one-way driving time to the study center of 71 minutes (range, 12 to 147 minutes) were enrolled. The patients completed 84 eligible televisits (completion rate, 100%; 95% CI, 0.80 to 1). Diarrhea was the most common adverse event but was limited to grade 1 in severity; a single patient experienced grade ≥ 3 adverse events. Seven patients (46.7%; 95% CI, 24.8% to 69.9%) had a ≤ 20% increase in prostate-specific antigen relative to baseline. Patients agreed or strongly agreed that they would participate in a telemedicine-enabled clinical trial in the future. CONCLUSION To our knowledge, this interventional oncology clinical trial is the first to be conducted through telemedicine. Telemedicine-enabled trials are feasible and may overcome geographic barriers to trial participation. Metformin was generally well tolerated but associated with modest anticancer activity.

Impact of obesity in patients with metastatic urothelial carcinoma.

346 Background: Obesity has been associated with worse outcomes in patients with clinically localized urothelial cancer. However, the impact of obesity on outcomes of patients with metastatic disease has not previously been evaluated. Methods: Data from 537 patients were aggregated from eight phase II and phase III clinical trials investigating first-line cisplatin-based combination therapy in metastatic urothelial cancer. Chemotherapy regimen, adverse events, treatment response, and survival outcomes were compared across body mass index (BMI) and body surface area (BSA) categories. Results: BMI was classified according to WHO criteria ( 30 obese (12.1%)). BSA was classified as either below (56.8% of patients) or greater than or equal to (43.2%) the European average (1.91 m2 for males and 1.71 m2 for females). There was no significant difference in number of chemotherapy cycles across BMI and BSA categori...