Apalutamide for High-Risk Localized Prostate Cancer Following Radical Prostatectomy (Apa-RP).

Purpose: Approximately 25% to 50% of patients with high-risk localized prostate cancer experience biochemical recurrence (BCR) within 2 years of radical prostatectomy. The Apa-RP study (NCT04523207) investigated whether adjuvant apalutamide plus androgen deprivation therapy (ADT) in high-risk patients who have undergone radical prostatectomy improved BCR-free survival.

Materials And Methods: Apa-RP was a multicenter, open-label, single-arm, phase 2 study conducted in community urology practices in the US.

Impact of a rash management guide in patients receiving apalutamide for high-risk localized prostate cancer in the Apa-RP study.

Background/objectives: Based on the SPARTAN and TITAN studies, apalutamide is approved for patients with nonmetastatic castration-resistant and metastatic castration-sensitive prostate cancer. Skin rash was a common adverse reaction across indications. We hypothesized that earlier identification and intervention could improve rash outcomes.

Coadministration of Apalutamide and Relugolix in Patients with Localized Prostate Cancer at High Risk for Metastases.

Background: The single-arm, open-label, multicenter, phase II Apa-RP study evaluates the biochemical recurrence (confirmed prostate-specific antigen [PSA] > 0.2 ng/mL)-free rate in patients with high-risk localized prostate cancer (HR-LPC) after radical prostatectomy following adjuvant apalutamide and androgen-deprivation therapy. In this substudy, relugolix, an oral gonadotropin-releasing hormone antagonist, was evaluated in combination with apalutamide.

Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies.

Apalutamide, an androgen receptor signaling inhibitor, in combination with androgen-deprivation therapy (ADT), is approved for treatment of patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer, based on the data from the phase 3 SPARTAN and TITAN studies respectively. Apalutamide is an inducer of cytochrome P450 enzymes and P-glycoprotein, which are involved in the metabolism of oral anticoagulants (OACs) and may thus have potential drug-drug interactions when co-administered with OACs. Concomitant use of certain OACs such as apixaban, rivaroxaban, edoxaban, dabigatran, and warfarin was allowed in the SPARTAN and TITAN studies.

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.

Background: As with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.

Methods: Patient data for multiple cardiac-related treatment-emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).

Data on prior pegylated liposomal doxorubicin (PLD) treatment in recurrent ovarian cancer: Post-hoc data analysis from the phase 3 randomized, open-label study comparing trabectedin and PLD versus PLD alone in patients with recurrent ovarian cancer.

The data presented herein are supplementary to our published primary article "A phase 3 randomized, open-label, multicenter trial for safety and efficacy of combined trabectedin and pegylated liposomal doxorubicin therapy for recurrent ovarian cancer"[1]. The exploratory analysis evaluated the impact of prior pegylated liposomal doxorubicin (PLD) therapy in patients who participated in a randomized, open-label study comparing combination therapy of trabectedin and PLD vs PLD alone in third-line recurrent ovarian cancer (ROC). These exploratory analyses showed that prior treatment with PLD in ROC does not impact the response and survival rates nor does it increase toxicities or negatively influence survival and response rates in both treatment groups.

A phase 3 randomized, open-label, multicenter trial for safety and efficacy of combined trabectedin and pegylated liposomal doxorubicin therapy for recurrent ovarian cancer.

Objective: This phase 3 study aimed to compare overall survival (OS) of women with platinum-sensitive, recurrent ovarian cancer (ROC) treated with third-line trabectedin (T) + pegylated liposomal doxorubicin (PLD) vs. PLD monotherapy.

Methods: Women with advanced-relapsed epithelial ovarian cancer were randomly assigned 1: 1 to intravenous infusions of either T + PLD (trabectedin 1.

Safety and efficacy of trabectedin when administered in the inpatient versus outpatient setting: Clinical considerations for outpatient administration of trabectedin.

Background: The results of the randomized, phase 3 ET743-SAR-3007 trial demonstrated that trabectedin had a significantly longer progression-free survival (PFS) compared with dacarbazine in patients with advanced leiomyosarcoma/liposarcoma after the failure of prior chemotherapy. Patients randomized to trabectedin received a 24-hour intravenous infusion either in an inpatient or outpatient setting. Herein, the authors reported the safety, efficacy, and patient-reported outcomes based on first infusion site of care.

Results of a Real-world Study of Enzalutamide and Abiraterone Acetate With Prednisone Tolerability (REAAcT).

Background: The objective of this study was to evaluate differences in tolerability in patients with metastatic castration-resistant prostate cancer treated with enzalutamide (ENZA) or abiraterone acetate plus prednisone (AA+P).

Patients And Methods: This was a phase IV, prospective, open-label, multicenter, real-world study. Patients were prescribed ENZA or AA+P at the treating physician's discretion.

The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer.

Purpose: We evaluated the use of abiraterone acetate (1,000 mg) plus prednisone (5 mg) in patients with high risk, nonmetastatic, castration resistant prostate cancer.

Materials And Methods: Patients considered at high risk for progression to metastatic disease (prostate specific antigen 10 ng/ml or greater, or prostate specific antigen doubling time 10 months or less) received abiraterone acetate plus prednisone daily in 28-day cycles. The primary study end point was the proportion of patients in whom a 50% or greater prostate specific antigen reduction was achieved during cycles 1 to 6.

Low Incidence of Corticosteroid-associated Adverse Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to Patients with Metastatic Castration-resistant Prostate Cancer.

Background: Abiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs the survival of patients with metastatic castration-resistant prostate cancer (mCRPC). AA plus prednisone (P) (AA+P) is approved for the treatment of patients with mCRPC.

Objective: To investigate whether long-term use of low-dose P with or without AA leads to corticosteroid-associated adverse events (CA-AEs) in mCRPC patients.

Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial.

Background: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy.

Methods: We did a multicentre, open-label, early-access protocol trial in 23 countries.

A phase II clinical trial of pegylated liposomal doxorubicin and carboplatin plus bevacizumab in patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer.

Objective: To assess the safety and efficacy of pegylated liposomal doxorubicin (PLD), carboplatin, plus bevacizumab in patients with ovarian, fallopian tube, or primary peritoneal cancer.

Methods: Patients with platinum-sensitive, recurrent disease received PLD 30 mg/m(2) and carboplatin area under the curve (AUC) 5 on Day 1 plus bevacizumab 10mg/kg on Days 1 and 15 of every 28-day cycle, for a maximum of 10 cycles. The primary endpoint was objective response rate (ORR) [complete+partial response]; additional endpoints were safety, duration of response, progression-free survival (PFS), and time to progression (TTP).

Pirfenidone for diabetic nephropathy.

Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²).

An open-label, randomized, multicenter, controlled study of epoetin alfa for the treatment of anemia of chronic kidney disease in the long term care setting.

Objective: To evaluate the safety and efficacy of epoetin alfa administered in extended-dosing intervals to a target hemoglobin (Hb) level not exceeding 12.0 g/dL for the treatment of anemia in subjects with chronic kidney disease (CKD) not on dialysis.

Design: An open-label, randomized, multicenter, controlled study consisting of a 1-week screening phase and a 26-week open-label treatment phase.

Pirfenidone is renoprotective in diabetic kidney disease.

Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix.

Pharmacokinetic and pharmacodynamic profiles of extended dosing of epoetin alfa in anemic patients who have chronic kidney disease and are not on dialysis.

Background And Objectives: Emerging evidence suggests that epoetin alfa can be administered at extended intervals of up to 4 wk. This open-label, randomized study was performed to characterize the pharmacokinetic and pharmacodynamic profiles of four dosing regimens of epoetin alfa administered subcutaneously in anemic patients who had chronic kidney disease and were not on dialysis.

Design, Setting, Participants, & Measurements: Thirty-eight patients, enrolled from nine centers in the United States, were > or =18 yr of age and had hemoglobin <11.

A randomized study of extended dosing regimens for initiation of epoetin alfa treatment for anemia of chronic kidney disease.

Background And Objectives: Although epoetin alfa is commonly initiated weekly (QW) in anemic chronic kidney disease (CKD) patients, recent evidence indicates that it can be initiated every 2 wk (Q2W) and used in maintenance therapy every 4 wk (Q4W). This study examined the feasibility of initiating epoetin alfa Q4W in anemic CKD patients not receiving dialysis.

Design, Setting, Participants, & Measurements: This open-label study randomized subjects (1:2:2:2) to treatment with epoetin alfa 10,000 IU QW, 20,000 IU Q2W, 20,000 IU Q4W, or 40,000 IU Q4W for 16 wk.

Stimulation of urinary TGF-beta and isoprostanes in response to hyperglycemia in humans.

TGF-beta and oxidant stress have been considered to play key roles in the pathogenesis of diabetic vascular complications; however, the stimulus for these factors in humans is not clear. The purpose of this in vivo study was to determine whether transient hyperglycemia in humans is sufficient to increase renal production of TGF-beta1 and urinary isoprostanes in normal humans. A hyperglycemic clamp procedure was performed on 13 healthy volunteers.

Transforming growth factor-beta: a clinical target for the treatment of diabetic nephropathy.

Diabetic nephropathy is continuing to rise in incidence, despite awareness of tight glycemic control and blood pressure. The identification that matrix accumulation is driven by transforming growth factor-beta (TGF-beta) has led to a concerted effort to apply antifibrotic strategies for this disorder. Recent studies have not only demonstrated the beneficial effects of blocking TGF-beta on matrix accumulation but have also found that blocking TGF-beta may have important hemodynamic effects that are relevant to diabetic complications.

Chronic kidney disease: issues and establishing programs and clinics for improved patient outcomes.

The spectrum of chronic kidney disease (CKD) extends from the point at which there is slight kidney damage, but normal function, to the point at which patients require either a renal transplant or renal replacement therapy to survive. Epidemiological studies suggest there are approximately 20,000,000 patients with various stages of CKD. These patients have many comorbidities, including cardiovascular disease, hypertension, diabetes, anemia, nutritional and metabolic derangements, and fluid overload.

TGF-beta-induced Ca(2+) influx involves the type III IP(3) receptor and regulates actin cytoskeleton.

Ca(2+) influx has been postulated to modulate the signaling pathway of transforming growth factor-beta (TGF-beta); however, the underlying mechanism and functional significance of TGF-beta-induced stimulation of Ca(2+) influx are unclear. We show here that TGF-beta stimulates Ca(2+) influx in mesangial cells without Ca(2+) release. The influx of Ca(2+) is prevented by pharmacological inhibitors of inositol 1,4,5-trisphosphate receptors (IP(3)R) as well as specific antibodies to type III IP(3)R (IP(3)RIII) but not to type I IP(3)R (IP(3)RI).