Phase 1/2 multicenter trial of acalabrutinib in Chinese patients with relapsed/refractory mantle cell lymphoma.

Acalabrutinib studies have limited Asian participation. This phase 1/2 study (NCT03932331) assessed acalabrutinib in Chinese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). Overall, 34 patients were enrolled. Most patients were men (88%); median age was 63 years and 59% had ≥3 prior treatments. Median treatment duration was 14 months (range, 1-24). Any-grade adverse events (AEs) and grade ≥3 AEs occurred in 85.3% and 44.1% of patients, respectively. AEs causing treatment discontinuation were aplastic anemia, thrombocytopenia, and gastrointestinal infection (n = 1 each). Fatal AEs occurred in 2 patients (aplastic anemia and multiple organ dysfunction syndrome [n = 1 each]). BICR-assessed ORR was 82.4% (95% confidence interval [CI]: 65.5, 93.2); 12 (35.3%) patients achieved complete response. Estimated 12-month OS was 84.5% (95% CI: 66.6, 93.3). Acalabrutinib yielded tolerable safety and high response rates in Chinese patients with R/R MCL.

Drug-drug interaction potential among patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with novel androgen receptor inhibitors.

BACKGROUND: Nonmetastatic castration-resistant prostate cancer (nmCRPC) patients are often older and use concurrent medications that increase the potential for drug-drug interactions (pDDIs). This study assessed pDDI prevalence in real-world nmCRPC patients treated with apalutamide, darolutamide, or enzalutamide. RESEARCH DESIGN AND METHODS: Castrated prostate cancer patients without metastases prior to androgen receptor inhibitor initiation were identified retrospectively via Optum Clinformatics Data Mart claims data (8/2019-3/2021). The top 100 concomitant medications were assessed for pDDIs. RESULTS: Among 1,515 patients (mean age: 77 ± 8 years; mean Charlson Comorbidity Index: 3 ± 3), 340 initiated apalutamide, 112 darolutamide, and 1,063 enzalutamide. Common concomitant medication classes were cardiovascular (80%) and central nervous system (52%). Two-thirds of the patients received ≥5 concomitant medications; 30 (30/100 medications) pDDIs were identified for apalutamide and enzalutamide each and 2 (2/100 medications) for darolutamide. Most pDDIs had risk ratings of C or D, but four for apalutamide were rated X. Approximately 58% of the patients on apalutamide, 5% on darolutamide, and 54% on enzalutamide had ≥1 identified pDDI. CONCLUSIONS: Results showed a higher frequency of pDDIs in patients receiving apalutamide and enzalutamide vs darolutamide. The impact of these could not be determined retrospectively. DDI risk should be carefully evaluated when discussing optimal therapy for patients with nmCRPC.

Epigenetic HDAC5 Inhibitor Reverses Craniofacial Neuropathic Pain in Mice.

Identifying and resolving molecular complexities underlying chronic neuropathic pain is a significant challenge. Among the numerous classes of histone deacetylases, Class I (HDAC 1-3) and Class III (sirtuins) have been best studied in experimental pain models where inhibitor pre-treatments but not post-treatments abrogate the development of pain-related behaviors. Post-treatment here in week 3 with less well-studied Class IIa HDAC4/5 selective inhibitor LMK235 diminishes the trigeminal ganglia increases of HDAC5 RNA and protein in two chronic orofacial neuropathic pain models to levels measured in naïve mice at week 10 post-model induction. HDAC4 RNA reported in lower limb inflammatory pain models is not evident in the trigeminal models. Many other gene alterations persisting at week 10 in the trigeminal ganglia (TG) are restored to naïve levels in mice treated with LMK235. Important pain-related upregulated genes Hoxc8,b9,d8; P2rx4, Cckbr, growth hormone (Gh), and schlafen (Slfn4) are greatly reduced in LMK235-treated mice. Fold increase in axon regeneration/repair genes Sostdc1, TTr, and Folr1 after injury are doubled by LMK235 treatment. LMK235 reduces the excitability of trigeminal ganglia neurons in culture isolated from nerve injured mice compared to vehicle-treated controls, with no effect on neurons from naïve mice. Electrophysiological characterization profile includes a shift where ∼20% of the small neurons recorded under LMK235-treated conditions are high threshold, whereas none of the neurons under control conditions have high thresholds. LMK235 reverses long-standing mechanical and cold hypersensitivity in chronic trigeminal neuropathic pain models in males and females (5,10 mg/kg), preventing development of anxiety- and depression-like behaviors. PERSPECTIVE: Data here support HDAC5 as key epigenetic factor in chronic trigeminal neuropathic pain persistence, validated with the study of RNA alterations, TG neuronal excitability, and pain-related behaviors. HDAC5 inhibitor given in week 3 restores RNA balance at 10 weeks, while upregulation remains for response to wound healing and chronic inflammation RNAs.

Advanced glycated end-products inhibit dilation through constitutive endothelial RAGE and Nox1/4 in rat isolated skeletal muscle arteries.

OBJECTIVE: This study investigated the actions of advanced glycated end-products (AGE), their receptors (RAGE), and NAD(P)H oxidase (Nox) subtypes 1, 2, and 4 on mechanisms of endothelium-dependent dilation of the rat cremaster muscle artery (CMA). METHODS: Immunofluorescence studies were used to examine expression of RAGE in rat arteries. ROS accumulation was measured using luminescence and fluorescence assays. Functional studies were performed using pressure myography. RESULTS: High levels of RAGE expression were shown in the endothelial cells of the CMA, compared with low endothelial expression in middle cerebral and mesenteric arteries and the aorta. Exogenous AGE (in vitro glycated bovine serum albumin) stimulated H2O2 accumulation in CMA, which was prevented by the RAGE antagonist FPS-ZM1, the NAD(P)H oxidase (Nox) inhibitor apocynin and inhibited by the Nox1/4 inhibitor setanaxib, but not the Nox2 inhibitor GSK2795039. In functional studies, AGE inhibited vasodilation of CMA stimulated by acetylcholine, sodium nitroprusside, and the BKCa activator NS1619, but not adenosine-induced dilation. FPS-ZM1, apocynin, and setanaxib prevented the inhibitory effects of AGE on responses to acetylcholine and NS-1619. CONCLUSION: These observations suggest RAGE are constitutively expressed in the endothelium of the rat CMA and may be activated by AGE to stimulate Nox1/4 and ROS formation with resulting inhibition of NO and BKCa-mediated endothelium-dependent dilation.

Orally Delivered Connexin43 Hemichannel Blocker, Tonabersat, Inhibits Vascular Breakdown and Inflammasome Activation in a Mouse Model of Diabetic Retinopathy.

Diabetic retinopathy (DR), a microvascular complication of diabetes, is associated with pronounced inflammation arising from the activation of a nucleotide-binding and oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome. Cell culture models have shown that a connexin43 hemichannel blocker can prevent inflammasome activation in DR. The aim of this study was to evaluate the ocular safety and efficacy of tonabersat, an orally bioavailable connexin43 hemichannel blocker, to protect against DR signs in an inflammatory non-obese diabetic (NOD) DR mouse model. For retina safety studies, tonabersat was applied to retinal pigment epithelial (ARPE-19) cells or given orally to control NOD mice in the absence of any other stimuli. For efficacy studies, either tonabersat or a vehicle was given orally to the inflammatory NOD mouse model two hours before an intravitreal injection of pro-inflammatory cytokines, interleukin-1 beta, and tumour necrosis factor-alpha. Fundus and optical coherence tomography images were acquired at the baseline as well as at 2- and 7-day timepoints to assess microvascular abnormalities and sub-retinal fluid accumulation. Retinal inflammation and inflammasome activation were also assessed using immunohistochemistry. Tonabersat did not have any effect on ARPE-19 cells or control NOD mouse retinas in the absence of other stimuli. However, the tonabersat treatment in the inflammatory NOD mice significantly reduced macrovascular abnormalities, hyperreflective foci, sub-retinal fluid accumulation, vascular leak, inflammation, and inflammasome activation. These findings suggest that tonabersat may be a safe and effective treatment for DR.

Effect of Roflumilast Cream vs Vehicle Cream on Chronic Plaque Psoriasis: The DERMIS-1 and DERMIS-2 Randomized Clinical Trials.

Importance: Once-daily roflumilast cream, 0.3%, a potent phosphodiesterase 4 inhibitor, demonstrated efficacy and was well tolerated in a phase 2b trial of patients with psoriasis. Objective: To evaluate the efficacy of roflumilast cream, 0.3%, applied once daily for 8 weeks in 2 trials of patients with plaque psoriasis. Design, Setting, and Participants: Two phase 3, randomized, double-blind, controlled, multicenter trials (DERMIS-1 [trial 1; n = 439] and DERMIS-2 [trial 2; n = 442]) were conducted at 40 centers (trial 1) and 39 centers (trial 2) in the US and Canada between December 9, 2019, and November 16, 2020, and between December 9, 2019, and November 23, 2020, respectively. Patients aged 2 years or older with plaque psoriasis involving 2% to 20% of body surface area were enrolled. The dates of final follow-up were November 20, 2020, and November 23, 2020, for trial 1 and trial 2, respectively. Interventions: Patients were randomized 2:1 to receive roflumilast cream, 0.3% (trial 1: n = 286; trial 2: n = 290), or vehicle cream (trial 1: n = 153; trial 2: n = 152) once daily for 8 weeks. Main Outcomes and Measures: The primary efficacy end point was Investigator Global Assessment (IGA) success (clear or almost clear status plus ≥2-grade improvement from baseline [score range, 0-4]) at week 8, analyzed using a Cochran-Mantel-Haenszel test stratified by site, baseline IGA score, and intertriginous involvement. There were 9 secondary outcomes, including intertriginous IGA success, 75% reduction in Psoriasis Area and Severity Index (PASI) score, and Worst Itch Numeric Rating Scale score of 4 or higher at baseline achieving 4-point reduction (WI-NRS success) at week 8 (scale: 0 [no itch] to 10 [worst imaginable itch]; minimum clinically important difference, 4 points). Results: Among 881 participants (mean age, 47.5 years; 320 [36.3%] female), mean IGA scores in trial 1 were 2.9 [SD, 0.52] for roflumilast and 2.9 [SD, 0.45] for vehicle and in trial 2 were 2.9 [SD, 0.48] for roflumilast and 2.9 [SD, 0.47]) for vehicle. Statistically significantly greater percentages of roflumilast-treated patients than vehicle-treated patients had IGA success at week 8 (trial 1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3%-46.9%]; trial 2: 37.5% vs 6.9%; difference, 28.9% [95% CI, 20.8%-36.9%]; P < .001 for both). Of 9 secondary end points, statistically significant differences favoring roflumilast vs vehicle were observed for 8 in trial 1 and 9 in trial 2, including intertriginous IGA success (71.2% vs 13.8%; difference, 66.5% [95% CI, 47.1%-85.8%] and 68.1% vs 18.5%; difference, 51.6% [95% CI, 29.3%-73.8%]; P < .001 for both), 75% reduction in PASI score (41.6% vs 7.6%; difference, 36.1% [95% CI, 28.5%-43.8%] and 39.0% vs 5.3%; difference, 32.4% [95% CI, 24.9%-39.8%]; P < .001 for both), WI-NRS success (67.5% vs 26.8%; difference, 42.6% [95% CI, 31.3%-53.8%] and 69.4% vs 35.6%; difference, 30.2% [95% CI, 18.2%-42.2%]; P < .001 for both). The incidence of treatment-emergent adverse events was 25.2% with roflumilast vs 23.5% with vehicle in trial 1 and 25.9% with roflumilast vs 18.4% with vehicle in trial 2. The incidence of serious adverse events was 0.7% with roflumilast vs 0.7% with vehicle in trial 1 and 0% with roflumilast vs 0.7% with vehicle in trial 2. Conclusions and Relevance: Among patients with chronic plaque psoriasis, treatment with roflumilast cream, 0.3%, compared with vehicle cream resulted in better clinical status at 8 weeks. Further research is needed to assess efficacy compared with other active treatments and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifiers: NCT04211363, NCT04211389.

Lycopene enhances the sensitivity of castration-resistant prostate cancer to enzalutamide through the AKT/EZH2/ androgen receptor signaling pathway.

Enzalutamide is an effective drug for the treatment of castration-resistant prostate cancer (CRPC), but acquired enzalutamide resistance is usually unavoidable within the short term in many patients. Lycopene, a safe and effective phytochemical, has been documented to have anticancer activity in a variety of tumors, especially for prostate cancer (PCa). The aim of this study was to provide data support for the combination of lycopene and enzalutamide in the treatment of CRPC. To this end, tissues from patients with primary prostate cancer (PPC) and CRPC were examined by immunohistochemical analysis and found that p-AKT and p-EZH2 were overexpressed in CRPC. Furthermore, Kaplan-Meier survival analysis showed that the high expression of p-AKT and p-EZH2 may be related to the poor prognosis of patients. In addition, the expression of p-AKT, p-EZH2 and androgen receptor (AR) were significantly down-regulated in 22RV1 and C4-2B cells and the proliferation and invasion of CRPC cells were inhibited after treatment with lycopene, while SC79 (an AKT agonist) markedly rescue this effect. Of note, a combination of lycopene and enzalutamide significantly inhibited the proliferation and invasion of CRPC cells in vitro, as well as tumor growth and bone metastasis in vivo. These results suggest that the enhanced antitumor effects of enzalutamide by lycopene may be related to the reduction of AR protein levels through lycopene-mediated inhibition of AKT/EZH2 pathway, which may provide a new approach to improve the efficacy of enzalutamide in CRPC.

Combined inhibition of IL­6 and IL­8 pathways suppresses ovarian cancer cell viability and migration and tumor growth.

Ovarian cancer is the most lethal gynecological cancer type in the United States. The success of current chemotherapies is limited by chemoresistance and side effects. Targeted therapy is a promising future direction for cancer therapy. In the present study, the efficacy of co­targeting IL­6 and IL­8 in human ovarian cancer cells by bazedoxifene (Baze) + SCH527123 (SCH) treatment was examined. ELISA, cell viability, cell proliferation, cell migration, cell invasion, western blotting and peritoneal ovarian tumor mouse model analyses were performed to analyze the expression levels of IL­6 and IL­8, tumor growth, tumor migration and invasion, and the possible pathways of human ovarian cancer cell lines (SKOV3, CAOV3 and OVCAR3) and patient­derived OV75 ovarian cancer cells. Each cell line was treated by monotherapy or combination therapy. The results demonstrated that IL­6 and IL­8 were secreted by human ovarian cancer cell lines. Compared with the DMSO control, the combination of IL­6/glycoprotein 130 inhibitor Baze and IL­8 inhibitor SCH synergistically inhibited cell viability in ovarian cancer cells. Baze + SCH also inhibited cell migration and invasion, suppressed ovarian tumor growth and inhibited STAT3 and AKT phosphorylation, as well as survivin expression. Therefore, co­targeting the IL­6 and IL­8 signaling pathways may be an effective approach for ovarian cancer treatment.

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial.

BACKGROUND AND OBJECTIVES: Masitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active. METHODS: This randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18-75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0-6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12-W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients. RESULTS: A total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of -0.097 (97% CI -0.192 to -0.002); p = 0.0256. Safety was consistent with masitinib's known profile (diarrhea, nausea, rash, and hematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed. DISCUSSION: Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data. TRIAL REGISTRATION INFORMATION: The first participant was randomized to study AB07002 on August 25, 2011. The trial was registered with the European Clinical Trials Database (#EudraCT 2010-021219-17) on July 1, 2011 (clinicaltrialsregister.eu/ctr-search/trial/2010-021219-17/ES) and with ClinicalTrials.gov (#NCT01433497) on September 14, 2011 (clinicaltrials.gov/ct2/show/NCT01433497). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that masitinib 4.5 mg/kg/d decreased progression of disability, measured by the EDSS, in adults with PPMS or patients with nSPMS (with no exacerbations in the last 2 years).

Follicular Lymphoma: a Focus on Current and Emerging Therapies

Follicular lymphoma (FL) is the most common indolent lymphoma and is characterized by a relapsing and remitting course. In addition to significant biologic heterogeneity, the clinical trajectory for patients is variable, with some being observed for many years, and others having aggressive disease requiring multiple treatment courses. Unfortunately, FL remains incurable, and continues to cause early mortality. Improved understanding of the genetic and immune biology of FL has led to several FDA-approved therapies in the relapsed and refractory setting, including PI3K inhibitors; immunomodulatory agents; the EZH2 inhibitor, tazemetostat; and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel. This review outlines the current approach to the diagnosis and treatment of FL with a focus on emerging investigational therapies, including targeted protein inhibitors, antibody-drug conjugates, monoclonal antibodies, bispecific antibodies, and novel combination strategies.

In vitro inhibition of phosphodiesterase type 4 enhances rat corpus cavernosum nerve-mediated relaxation induced by gasotransmitters.

AIMS: Nitric oxide (NO) and hydrogen sulfide (H2S) are involved in nerve-mediated corpus cavernosum (CC) relaxation. Expression of phosphodiesterase type 5 (PDE5) and type 4 (PDE4), cyclic guanosine monophosphate (cGMP)- and cyclic adenosine monophosphate (cAMP)-specific, respectively, has been described and PDE5- and PDE4-inhibitors induce cavernous smooth muscle relaxation. Whereas the NO/cGMP signaling pathway is well established in penile erection, the cAMP-mediated mechanism is not fully elucidated. The aim of this study is to investigate the localization and the functional significance of PDE4 in rat CC tone regulation. MAIN METHODS: We performed immunohistochemistry for the detection of the PDE4A isoenzyme. Isometric tension recordings for roflumilast and tadalafil, PDE4 and PDE5 inhibitors, respectively, electrical field stimulation (EFS) and ß-adrenoceptor agonist isoproterenol and endogenous H2S production measurement. KEY FINDINGS: A marked PDE4A expression was detected mainly localized in the nerve cells of the cavernous smooth muscle. Furthermore, roflumilast and tadalafil exhibited strong corpus cavernous relaxations. Endogenous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isoproterenol- and EFS-induced relaxations were increased by roflumilast. SIGNIFICANCE: These results indicate that PDE4A is mainly expressed within the nerves cells of the rat CC, where roflumilast induces a potent corpus cavernous relaxation per se and potentiates the response induced by ß-adrenoceptor activation. The fact that roflumilast enhances H2S production, as well as EFS-elicited responses suggests that PDE4 inhibitors modulate, in a positive feedback fashion, nerve-mediated relaxation induced by gasotransmitters, thus indicating a key role for neuronal PDE4 in penile erection.

Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial.

Early clinical data indicate that some patients with castration-resistant prostate cancer may benefit from program death ligand-1 (PD-L1) inhibition, especially with enzalutamide. The IMbassador250 trial (no. NCT03016312) enrolled 759 men with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The addition of atezolizumab to enzalutamide in an open-label randomized trial did not meet the primary endpoint of improved overall survival in unselected patients (stratified hazard ratio 1.12, 95% confidence interval (0.91, 1.37), P = 0.28), despite an acceptable safety profile. In archival tumor samples, prostate tumors showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, phosphatase and tensin homolog status and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant prostate cancers. In planned biomarker analysis, longer progression-free survival was seen with atezolizumab in patients with high PD-L1 IC2/3, CD8 expression and established immune gene signatures. Exploratory analysis linked progression-free survival in the atezolizumab arm with immune genes such as CXCL9 and TAP1, together with other potentially relevant biomarkers including phosphatase and tensin homolog alterations. Together these data indicate that the expected biology associated with response to immune checkpoint inhibitors is present in prostate cancer, albeit in fewer patients. Careful patient selection may be required for immune checkpoint inhibitors to identify subgroups of patients who may benefit from this treatment approach.

Medication adherence among patients with advanced prostate cancer using oral therapies.

Aims: In light of the extended overall survival and improved quality of life provided by advanced prostate cancer (PC) oral therapies, this study aimed to describe treatment adherence to advanced PC oral therapies and evaluate associated patient characteristics and subsequent healthcare resource utilization (HRU). Patients & methods: Patients with advanced PC initiating apalutamide, enzalutamide or abiraterone acetate were identified from administrative data (October 1, 2014-September 30, 2019). Adherence and persistence at six months postinitiation were used to evaluate patient factors and HRU. Results: Aged ≥75 years, Black race, chemotherapy use and higher pharmacy paid amounts were associated with poor adherence/persistence, which translated to higher HRU. Conclusions: Strategies to increase adherence and persistence may improve patient outcomes and associated HRU.

Lay abstract This study included 27,262 patients with advanced prostate cancer who started taking one of three oral cancer medications (apalutamide, enzalutamide or abiraterone acetate) between October 2014 and September 2019. Patients who were black, aged 75 years or older, who had chemotherapy or who had higher prescription costs had the most difficulty following dosing guidelines or staying on treatment. Patients who did not follow dosing guidelines required more healthcare services. In light of the extended survival and improved quality of life that oral cancer medication for advanced prostate cancer provides, helping patients to take the correct medication dose, at the right time, and for the recommended length of time may improve their outcomes and reduce medical costs.

Real-world outcomes of second novel hormonal therapy or radium-223 following first novel hormonal therapy for mCRPC.

Aim: To evaluate real-world clinical outcomes of radium-223 or alternative novel hormonal therapy (NHT) following first-line NHT for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: Retrospective analysis of the US Flatiron database (ClinicalTrials.gov identifier: NCT03896984). Results: In the radium-223 cohort (n = 120) versus the alternative NHT cohort (n = 226), proportionally more patients had prior symptomatic skeletal events and bone-only metastases, and first-line NHT duration was shorter. Following second-line therapy, 49 versus 39% of patients received subsequent life-prolonging therapy; of these, 47 versus 76% received taxane. Median overall survival was 10.8 versus 11.2 months. Conclusion: Real-world patients with mCRPC had similar median overall survival following second-line radium-223 or alternative NHT after first-line NHT. Many patients received subsequent therapy, with less taxane use after radium-223.

Lay abstract Patients with metastatic castration-resistant prostate cancer are often first treated with novel hormonal therapy (NHT) using abiraterone or enzalutamide. To aid decisions about what treatment to use next, we reviewed information about patients who were treated with an alternative NHT (226 patients) or the nuclear medicine radium-223 (120 patients) after the first NHT. Most patients given radium-223 had cancer that had spread to their bones only, whereas many patients given an alternative NHT had cancer in their bones and other parts of their body. Around one in four patients given radium-223 and one in five given an alternative NHT had symptoms related to their bone metastases after starting treatment. Five in every ten patients given radium-223 received further therapy, including chemotherapy in 50% of these patients, while four in every ten patients given an alternative NHT received further therapy, including chemotherapy in 75%. On average, patients lived for almost a year after starting radium-223 or an alternative NHT.

Role of Roflumilast Combined with ESHAP Chemotherapy in Relapsed/Refractory Patients with Diffuse Large B-Cell Lymphoma.

PURPOSE: There are unmet needs associated with the current treatment strategies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) due to the poor treatment outcomes of these strategies. Roflumilast, a selective phosphodiesterase-4 inhibitor used for treating chronic obstructive pulmonary disease, is effective against B-cell malignancy via phosphoinositide 3-kinase (PI3K)-activity suppression. We analyzed the effects of roflumilast combined with ESHAP (etoposide, cisplatin, methylprednisolone, and cytarabine) chemotherapy in experimental and clinical settings. MATERIALS AND METHODS: An in vitro study using lymphoma cell lines and a pilot study on relapsed/refractory DLBCL patients were conducted to investigate the effects and mechanism of the combination of roflumilast and chemotherapy. The complete response (CR), overall response rate (ORR), and 1-year progression-free survival (PFS) were analyzed. RESULTS: We found that roflumilast is efficient when combined with other chemotherapy drugs, especially cytarabine. Synergistic effects between these two drugs influence the translation of mammalian target of rapamycin and myeloid cell leukemia 1, resulting in apoptosis and inhibition of B-cell lymphoma proliferation. In clinical setting, the roflumilast group showed better rates of CR (46.2% vs. 34.6%), ORR (76.9% vs. 53.8%), and 1-year PFS (50.0% vs. 25.9%) compared with the control group, though not statistically significant. The roflumilast group showed a higher incidence of asthenia and gastrointestinal adverse events. However, grade 3 or 4 adverse events were similar in both groups. CONCLUSION: We found that roflumilast, when combined with ESHAP chemotherapy, for relapsed/refractory DLBCL was clinically active and well tolerated. This combined treatment was able to suppress PI3K activity, which is correlated with the degree of clinical response.

Phase II study of enzalutamide in androgen receptor positive, recurrent, high- and low-grade serous ovarian cancer.

OBJECTIVES: We sought to determine the safety and efficacy of the oral androgen receptor antagonist enzalutamide in patients with previously treated, recurrent, AR-positive (AR+) ovarian cancer. METHODS: This was a single-institution phase II study of patients with AR+ ovarian cancer with measurable disease with 1-3 prior lines of chemotherapy; patients were screened for enrollment from 11/2013-7/2018. Following consent, archival tissue was evaluated for AR+. Enrolled patients received daily enzalutamide 160 mg until progression of disease or treatment discontinuation. Adverse events were graded by CTCAE v4.0. Co-primary endpoints were 6-month progression-free survival (PFS6) and overall response rate (ORR) by RECIST 1.1 criteria. RESULTS: During the study period, 160 patients were screened and 59 (45 high-grade serous [HGS] and 14 low-grade serous [LGS]) consented to treatment on study. There was 1 confirmed and 1 unconfirmed partial response. The ORR was 1.7% (90% CI: 0.2-100%). The overall PFS6 rate (as binary) was 22% (90% CI: 15.1-100%). The 6-month PFS rate (as time to event) was 19.8% for HGS patients (90% CI: 12.7-100%) and 38.5% (90% CI: 21.7%-100%) for LGS patients. Grade 3 toxicities occurred in 6 patients (one toxicity (Grade 3 rash) was considered a dose-limiting toxicity). One patient died of cardiac arrest after 42 days on treatment of a cardiac arrest not attributed to study drug. CONCLUSIONS: The study met its primary endpoint, with a PFS6 rate of 22% (n = 13); however, the overall response rate was low. Enzalutamide was well tolerated and may be a potential treatment option in select patients.