Julia A. Batten

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.

Management of malignant gliomas during pregnancy: a case series.

Limited data are available on the management of glioma in pregnant women. Therefore, the aim of the current article was to describe the outcome of women with malignant gliomas who were exposed to chemotherapy early in the gestation period of their pregnancies.

Improvement of Psoriasis During Sunitinib Therapy for Renal Cell Carcinoma

Sunitinib is an oral tyrosine kinase inhibitor, which is indicated for the treatment of renal cell carcinoma and gastrointestinal stromal tumors. The authors report the case of a patient who underwent treatment for renal cell carcinoma and noted additional benefit by improvement in his psoriatic skin lesions. This may be attributed to the antiangiogenic activity of sunitinib by inhibition of vascular endothelial growth factor receptors.

Emerging molecularly targeted therapies in castration refractory prostate cancer.

Androgen deprivation therapy (ADT) with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC) and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR) signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700), and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.

Efficacy of Eplerenone in the Management of Mineralocorticoid Excess in Men With Metastatic Castration-resistant Prostate Cancer Treated With Abiraterone Without Prednisone

Background Abiraterone acetate has been approved for metastatic castration‐resistant prostate cancer (mCRPC). Coadministration with prednisone has been recommended to prevent the toxicity from secondary mineralocorticoid excess, such as hypertension, hypokalemia, and edema. However, the use of prednisone is often not desired by patients because of the potential for detrimental effects of long‐term therapy with corticosteroids, especially in those with comorbidities such as diabetes or who have received previous immunotherapeutic agents. Eplerenone is a nonsteroidal mineralocorticoid antagonist demonstrated to abrogate mineralocorticoid excess. In the present retrospective study, we report our real‐world experience with the use of eplerenone with abiraterone in men with mCRPC who wished to avoid concomitant prednisone therapy. Patients and Methods The incidence and grade (Common Terminology Criteria for Adverse Events, version 4) of mineralocorticoid excess toxicities, baseline demographics, disease characteristics, and progression‐free survival (PFS) were collected retrospectively. The patient population included men with mCRPC treated with abiraterone, who were not willing to receive corticosteroids, and thus received eplerenone. Their data were compared with the data from those treated with abiraterone and prednisone during the same period. Continuous variables were assessed using the Wilcoxon rank sum test or Student t test, and categorical variables were assessed using Fischers exact test or χ2 test, as appropriate. PFS was compared using the Kaplan‐Meier method. Results Of the 106 men treated with abiraterone, 40 received eplerenone and 66 received prednisone. The baseline and disease characteristics, incidence and grade of adverse events related to the syndrome of mineralocorticoid excess, and the median PFS were similar in both cohorts. Conclusion In a real‐world population of men with mCRPC treated with abiraterone, corticosteroids can be avoided by concomitant treatment with eplerenone. These data require further validation. Micro‐Abstract Prednisone is typically coadministered with abiraterone in the treatment of castrate‐resistant prostate cancer to prevent the toxicities of secondary mineralocorticoid excess. However, many patients do not desire or cannot tolerate chronic glucocorticoid therapy. In the present retrospective study, we report that eplerenone, a mineralocorticoid antagonist, can be safely used with abiraterone, obviating the need for concomitant prednisone in this patient population.

Abstract 1172: Phase I study of histone deacetylase inhibitor belinostat in combination with warfarin in patients with solid tumors or hematological malignancies.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: The family of Histone Deacetylase (HDAC) enzymes serves as important epigenetic regulators of gene expression through modulation of acetylation on important histone and non-histone proteins. Aberrant acetylation of histones can alter gene expression believed to be important in the tumorigenic process. Belinostat, a potent inhibitor of HDAC proteins has demonstrated anti tumor activity in animal models and in humans. The purpose of this study was to examine the pharmacokinetic and pharmacodynamic properties of warfarin in combination with belinostat and to evaluate the safety profile of belinostat with concomitant warfarin. Methods: Eligible patients enrolled on the study received 5 mg PO warfarin 14 days prior to administration of belinostat. Belinostat was administered as an iv infusion, 1000mg/m2 over 30 minutes for 5 consecutive days every 21 days. On day 3, cycle 1 of belinostat treatment, a second dose of 5mg PO warfarin was administered 2 hours prior to belinostat. Pharmacokinetic blood samples were obtained during cycle 1 of the study to measure warfarin and belinostat metabolism. Toxicities were monitored regularly throughout treatment and response was monitored according to standard of care guidelines. Results: 18 patients, with solid tumors or hematologic malignancies, treated with belinostat and warfarin were included in this analysis. Median age was 55 years (31-77). 11 (61%) patients were male and 7(39%) patients were female. The most common Grade 1 or 2, toxicities observed during the study were anemia (78%), fatigue (72%) and nausea (61%). The most frequent Grade 3 or 4 toxicities were nausea (11%) and hyperuricemia (11%). No Grade 3 or 4 thrombocytopenia or neutropenia were reported. No treatment related Grade 5 toxicities were reported. During cycle 1 no patient experienced treatment delays or discontinued study as result of treatment related toxicity. Conclusion: Belinostat was generally well tolerated in patients with solid tumors or hematologic malignancies with the major toxicity being anemia, fatigue or nausea. Pharmacokinetic results will be presented at the conference. Citation Format: Neeraj Agarwal, Mark L. Wade, Julia Batten, Cynthia Davidson, Show-Li Sun, Sunil Sharma. Phase I study of histone deacetylase inhibitor belinostat in combination with warfarin in patients with solid tumors or hematological malignancies. [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 1172. doi:10.1158/1538-7445.AM2013-1172

Effect of treatment dose reductions in the setting of hand-foot syndrome on survival outcomes in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor receptor inhibitors

Purpose Hand-foot syndrome is a common dose limiting toxicity of vascular endothelial growth factor receptor tyrosine kinase inhibitors used for treatment of patients with metastatic renal cell carcinoma. The effect of treatment dose reductions, in the context of hand-foot syndrome, on survival outcomes is reported. Methods This was a retrospective case series of patients receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors from 1 January 2004 to 31 October 2013. The main outcomes were progression-free and overall survival in these patients experiencing hand-foot syndrome and undergoing treatment dose reductions. Univariate and multivariate analyses were conducted utilizing Kaplan-Meier method and COX Proportional Hazard model with landmark analyses at 2 months. Results Of the 120 patients evaluated, treatment dose reductions for any reason were required in 68 (56.7%) patients. The most common reasons for treatment dose reductions were mucositis, hand-foot syndrome, and fatigue. The median progression-free survival and overall survival were significantly longer in patients with hand-foot syndrome with or without treatment dose reductions as compared to those without hand-foot syndrome. Conclusions An improvement in survival outcomes was observed in metastatic renal cell carcinoma patients with treatment-associated hand-foot syndrome despite treatment dose reductions. These data need validation in a larger cohort to confirm the hypothesis that treatment dose reductions in the setting of hand-foot syndrome do not negatively impatient survival.

Efficacy of eplerenone (Epe) in the management of mineralocorticoid excess (MCE) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (AA) without prednisone (P).

261Background: AA is approved for Mcrpc with co-administration with P to prevent MCE toxicity such as hypertension, hypokalemia and edema. However, use of P is often not desirable by the relatively asymptomatic patients because of potential for detrimental effects of long term corticosteroid therapy. Epe is a non-steroidal mineralocorticoid antagonist demonstrated to abrogate MCE. Here we report real world experience of use of Epe with AA in men with mCRPC who wished to avoid concomitant P. Methods: Incidence and grade (CTCAE v4) of MCE, along with baseline demographics, disease characteristics, and progression free survival (PFS) in men with mCRPC treated with AA (1000 mg daily), not willing to be treated with P (and thus received treatment with Epe 50 mg daily) were collected retrospectively, and compared with those treated with AA + P (10 mg daily) during the same time period (Table). Continuous variables were assessed by Wilcoxon rank sum or student t-test, and categorical variables were assessed by F...

Everolimus (EVE) versus temsirolimus (TEM) after first-line treatment with VEGF TKI in patients with metastatic renal cell carcinoma.

460 Background: Given the lack of affordability with an oral drug like EVE and/or preference in some patients (pts), TEM has been used after disease progression on a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). However, efficacy of TEM and EVE in this setting has not been evaluated in a randomized trial. Methods: Pts who were treated with a first VEGF TKI for metastatic renal cell carcinoma (mRCC) and then treated with either EVE or TEM upon progression were identified from two institutional databases. Survival estimates of progression free (PFS) and overall survival (OS) were assessed from initiation of second-line (2nd) treatment by Kaplan-Meier methodology. Results: 90 pts were eligible that received either EVE (n=59; 66%) or TEM (n=31; 34%) in 2nd setting. Pts and disease characteristics were similar in both groups. Median PFS was not different, but OS was significantly improved with EVE (Table). Conclusions: After progression on a 1st VEGFTKI, 2nd EVE and TEM have similar ...

Clinical outcomes and survival of patients (pts) with sarcomatoid metastatic renal cell carcinoma (smRCC).

535 Background: SmRCC is a rare variant of RCC associated with poor outcome. No definitive therapeutic recommendations exist. We present survival outcomes in pts with smRCC treated with systemic therapy. Methods: From a single institutional database (years 2000-2012), we identified 21 pts with documented sarcomatoid features who received systemic therapy. Survival was assessed in the overall cohort and in subgroups divided by clinicopathologic characteristics, including the extent of sarcomatoid features, and Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria. Sarcomatoid component of the tumor was classified by predominant (≥20%) and non-predominant (<20%). Immunohistochemistry (IHC) analysis was performed for mammalian target of rapamycin (mTOR) signaling, phosphorylated ribosomal protein S6, proviral integration site proteins (PIM 1,2,3), Beta-catenin, E-cadherin, phosphatase and tensin homolog (PTEN), U3 small nucleolar ribonucleoprotein (IMP-3), p53, and epithelial membrane antigen (EMA) on...