Clinical Outcomes of Patients with High-risk Metastatic Hormone-naïve Prostate Cancer: A 3-year Interim Analysis of the Observational J-ROCK Study.

BACKGROUND: Androgen deprivation therapy (ADT), administered alone, as combined androgen blockade (CAB) or as ADT plus androgen receptor signalling inhibitors (ARSIs) or ADT plus docetaxel, is the standard treatment for metastatic hormone-naïve prostate cancer (mHNPC) in Japanese real-world practice. OBJECTIVE: To investigate treatment patterns and clinical outcomes in LATITUDE criteria high-risk mHNPC. DESIGN, SETTING, AND PARTICIPANTS: The longitudinal, multicentre, J-ROCK registry study enrolled patients initiating ADT in Japan after May 2019, and categorised them as cohort 1 (ADT or CAB) or cohort 2 (ADT plus ARSIs or docetaxel). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) response, progression-free survival (PFS), time to castrate-resistant prostate cancer (CRPC), overall survival (OS), and safety were evaluated. PFS, time to CRPC, and OS were estimated via the Kaplan-Meier method and between-cohort comparisons via multivariate Cox regression models. RESULTS AND LIMITATIONS: In total, 974 patients were included (cohort 1: 38.1%, cohort 2: 61.9%). CAB was preferred (67.4%) to ADT alone in cohort 1, and abiraterone acetate plus prednisolone was used most frequently in cohort 2 (59.4%). The proportion of patients with ≥50%/≥90% PSA decline or who achieved PSA ≤0.2/≤0.1 ng/ml tended to be higher in cohort 2. PFS (adjusted hazard ratio 0.42; 95% confidence interval [CI] 0.31-0.55), time to CRPC (0.28; 95% CI 0.23-0.36), and OS (0.54; 95% CI 0.35-0.82) were longer in cohort 2. In cohorts 1 and 2, adverse drug reactions of special interest (ADRSIs) occurred in 1.3% and 15.1%, and fatal adverse events occurred in 1.9% and 1.7%, respectively. Limitations included nonrandomised design, varying time since marketing authorisation for ARSIs, and limited safety assessments. CONCLUSIONS: ADT plus ARSIs or docetaxel was used more frequently to treat high-risk mHNPC than standard ADT/CAB and was associated with more favourable clinical outcomes. Although ADRSIs were reported more in cohort 2, the safety profile was considered tolerable. PATIENT SUMMARY: Although many treatment options are available for high-risk metastatic prostate cancer, there are limited reports on real-world clinical experience with different therapies outside of the clinical trial setting. In this study, we compared clinical and safety outcomes with different treatment regimens, using a large series of patients with high-risk metastatic hormone-naïve prostate cancer across Japan. We found that androgen deprivation therapy in combination with newer androgen receptor signalling inhibitors resulted in improved response compared with androgen deprivation therapy alone or in combination with a first-generation antiandrogen.

Subcutaneous delivery of daratumumab in Japanese patients with relapsed/refractory multiple myeloma.

Subcutaneous daratumumab (DARA SC; daratumumab co-formulated with recombinant human hyaluronidase PH20) is administered in ~ 5 min and demonstrates safety and efficacy comparable to intravenous daratumumab, with low infusion-related reaction (IRR) rates in global populations. This open-label, multicenter, phase 1 study is the first evaluation of DARA SC in Japanese patients. Eligible patients had relapsed/refractory multiple myeloma (RRMM; ≥ 2 prior lines of therapy including a proteasome inhibitor and immunomodulatory drug). Patients (N = 6) received DARA SC 1,800 mg until progression (weekly for Cycles 1-2; every 2 weeks for Cycles 3-7; monthly for Cycles 7 + [28-day cycles]). The primary objective was to evaluate safety. Secondary objectives included efficacy and pharmacokinetics. Median time of administration was 3-4 min for all injections. No dose-limiting toxicity occurred, and no treatment-emergent adverse events were serious or led to discontinuation. No IRRs were observed; 4 (67%) patients had injection-site reactions (all grade 1). Overall response rate was 67%. Pharmacokinetics of DARA SC in Japanese patients were similar to findings from the global phase 1b PAVO study (NCT02519452). DARA SC at a flat dose of 1,800 mg was well tolerated in Japanese RRMM patients with comparable efficacy and pharmacokinetics to intravenous daratumumab. ClinicalTrials.gov identifier NCT03242889.

Efficacy and safety of abiraterone acetate plus prednisone in Japanese patients with newly diagnosed, metastatic hormone-naive prostate cancer: final subgroup analysis of LATITUDE, a randomized, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: LATITUDE was a randomized, double-blind, international and phase 3 study of abiraterone acetate plus prednisone in patients with high-risk metastatic hormone-naïve prostate cancer. In the first interim analysis of LATITUDE (clinical cutoff date: 31 October 2016), significant prolongation in overall survival and radiographic progression-free survival (co-primary endpoints) was observed when compared with placebo. The results of the Japanese subgroup analysis of LATITUDE first interim analysis were consistent with those of the overall population. In this study, overall survival and safety results from the final analysis of the Japanese subgroup of the LATITUDE study are presented (clinical cutoff date: 15 August 2018). METHODS: Abiraterone acetate (1000 mg/day) and prednisone (5 mg/day) were administered orally in the abiraterone acetate plus prednisone group, and matching placebos in the placebo group. RESULTS: Of the 1199 patients included in LATITUDE, 70 constituted the Japanese subgroup (abiraterone acetate plus prednisone: n = 35, placebo: n = 35). Following a median (range) follow-up of 56.6 (2.5, 64.2) months, the median overall survival was not reached in both the treatment arms of the Japanese subgroup (hazard ratio: 0.61; 95% confidence interval: 0.27-1.42; nominal P = 0.2502). A total of 23 deaths (abiraterone acetate plus prednisone: 9 [25.7%], placebo group: 14 [40.0%]) were reported in Japanese subgroup. Grade 3/4 adverse events were reported in 24 (68.6%) and 9 (25.7%) patients in the abiraterone acetate plus prednisone and placebo groups, respectively. CONCLUSIONS: In this Japanese subgroup analysis, addition of abiraterone acetate plus prednisone to androgen-deprivation therapy demonstrated favorable efficacy and safety outcomes in patients with newly diagnosed, high-risk metastatic hormone-naïve prostate cancer. Survival benefits observed in the Japanese subgroup first interim analysis were sustained long-term and were consistent with the overall population.

Daratumumab, lenalidomide, and dexamethasone in Japanese patients with transplant-ineligible newly diagnosed multiple myeloma: a phase 1b study.

Lenalidomide and dexamethasone (Rd) treatment is common for patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem-cell transplantation. Daratumumab plus Rd (D-Rd) is effective and well tolerated for treating relapsed or refractory multiple myeloma. In this ongoing phase 1b trial, transplant-ineligible Japanese patients with NDMM received daratumumab (16 mg/kg intravenously every week for 8 weeks, every 2 weeks for 16 weeks, then every 4 weeks until disease progression) plus Rd (R 25 mg on Days 1‒21 of 28-day cycle; d 40 mg weekly). The primary objective was to evaluate D-Rd tolerability and safety in Japanese patients with NDMM. Secondary objectives included daratumumab pharmacokinetics and response rate. During the dose-limiting toxicity (DLT) evaluation period, two DLTs occurred in seven (28.6%) patients, indicating D-Rd tolerability. At an 11.0-month median follow-up (interim analysis), grade 3/4 treatment-emergent adverse events occurred in six (85.7%) patients, including lymphopenia (71.4%), leukopenia (57.1%), and neutropenia (42.9%). Three (42.9%) patients experienced infusion-related reactions (IRRs). All IRRs were grade 2, occurred during the first daratumumab infusion, and resolved within 24 h. Pharmacokinetic findings were comparable to those in previous studies. A 100% overall response rate was achieved. These findings suggest D-Rd is tolerable in Japanese patients with transplant-ineligible NDMM. ClinicalTrials.gov identifier NCT02918331.

Efficacy and safety of apalutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a subgroup analysis of a randomized, double-blind, placebo-controlled, Phase-3 study.

BACKGROUND: In the global Phase-3 Selective Prostate Androgen Receptor Targeting with ARN-509 study, apalutamide plus ongoing androgen deprivation therapy (ADT) significantly increased metastasis-free survival (MFS) and improved other clinical outcomes in men with nonmetastatic castration-resistant prostate cancer (nm-CRPC) who were at high risk of developing metastases. In this subpopulation analysis of Selective Prostate Androgen Receptor Targeting with ARN-509 study, the efficacy and safety of apalutamide plus ADT were evaluated in Japanese patients with nm-CRPC. METHODS: The primary efficacy end point was MFS. Secondary efficacy end points were time to metastasis, progression-free survival, symptomatic progression, initiation of cytotoxic chemotherapy, and overall survival. Safety and pharmacokinetic parameters were also assessed. RESULTS: Fifty-five Japanese patients with ongoing ADT were randomized (apalutamide: n = 34, placebo: n = 21). Median treatment duration was 5.7 months in the apalutamide group and 11.0 months in the placebo group. Median MFS was not reached in the apalutamide group (95% confidence interval: 10.97, not estimable) and was 18.23 months (95% confidence interval: 11.04, 18.50) in the placebo group. Secondary end points were improved in the apalutamide group. The safety profile of apalutamide with ADT was comparable with the global population, and no new safety signals were identified in this Japanese subpopulation. Although, apalutamide exposure tended to be higher in the Japanese subpopulation compared with the non-Japanese population, this was likely to be explained by body weight and considered not clinically meaningful. CONCLUSION: In the Japanese subpopulation, treatment with apalutamide with ADT resulted in favorable efficacy outcomes with comparable benefit-risk profile to the global population with nm-CRPC who are at high-risk of developing metastases.

Repair Integrity and Functional Outcomes After Arthroscopic Suture Bridge Subscapularis Tendon Repair.

PURPOSE: This retrospective study aimed to report repair integrity and clinical outcomes after arthroscopic suture bridge subscapularis (SSC) tendon repair. METHODS: The subjects included 101 shoulders subjected to arthroscopic suture bridge repair for full-thickness SSC tear with a minimum of a 2-year follow-up. There were 57 men and 44 women with a mean age of 66 years (range, 32-85 years). The mean follow-up was 30 months (range, 24-71 months). Tenotomy or tenodesis was performed for the long head of the biceps in all cases. All patients were assessed for active range of motion; belly-press and bear-hug tests; University of California, Los Angeles score; and American Shoulder and Elbow Surgeons score preoperatively and at the final follow-up. Repair integrity and fatty degeneration of the SSC muscle were evaluated with magnetic resonance imaging at a mean 14 months (range, 12-58 months) after surgery. RESULTS: Flexion, internal rotation, and both functional scores significantly improved after surgery. Retears were found in 5 shoulders (5%). The shoulders with a retear showed significantly inferior functional scores compared with the intact shoulders. Fatty degeneration was significantly improved in the intact group, whereas there was no significant improvement in the retear group. Both belly-press and bear-hug test scores significantly improved after surgery; however, weakness persisted in shoulders with higher grade preoperative fatty degeneration even after successful repair. CONCLUSIONS: Arthroscopic suture bridge repair for SSC tears yielded good clinical outcomes and a very low retear rate, even for larger tears or shoulders with higher grade fatty degeneration. Fatty degeneration of the SSC muscle improved after successful repair, although internal rotation weakness persisted in shoulders with higher grade preoperative fatty degeneration. Arthroscopic suture bridge repair is a promising procedure for treating SSC tears. LEVEL OF EVIDENCE: Level IV, case series study.

Hill-Sachs lesion classification under arthroscopic findings.

BACKGROUND: The Hill-Sachs lesion (HSL) plays a role in recurrent glenohumeral joint instability. Currently, there are no studies based on the form characteristics of HSL. The purposes of this study were to report the HSL form characteristics and to determine whether they are correlated with number of prior subluxations and dislocations. METHODS: The study enrolled 134 consecutive patients diagnosed with anterior shoulder instability during an arthroscopic procedure. We classified the arthroscopic findings into 4 types, as follows: type 1, cyst type; type 2, gutter type; type 3, island type; and type 4, wide type. Subsequently, we investigated the correlation between each type and the number of shoulder subluxations and dislocations reported. The following data were analyzed: subluxation and dislocation history, arthroscopic findings, and maximum lesion size. RESULTS: Of the patients evaluated, 18, 32, 30, and 54 were classified as types 1 to 4, respectively. The mean numbers of shoulder dislocations were 3.3, 7.3, 6.0, and 12.0 for types 1 to 4, respectively. The wide type was correlated with more subluxations and dislocations than the other types (P = .001, .046, and .007, respectively). There were significant differences in mean width among all types (P < .0001). HSL width was correlated with lesion type and angle. CONCLUSION: We classified HSL into 4 types on the basis of visual inspection and found a correlation between lesion type and lesion size. However, HSL width was correlated with lesion type and angle; that is, the number of dislocations and subluxations does not affect HSL width.

Safety, tolerability, pharmacokinetics and antitumor activity of ganitumab, an investigational fully human monoclonal antibody to insulin-like growth factor type 1 receptor, combined with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer: a phase 1b study.

OBJECTIVE: Previous Phase 1 studies have shown the acceptable safety profile of ganitumab-a fully human monoclonal antibody to insulin-like growth factor Type 1 receptor-in patients with advanced solid tumors. However, ganitumab 20 mg/kg in combination with gemcitabine had not been administered to patients with metastatic pancreatic cancer. To evaluate the safety, tolerability, pharmacokinetics and antitumor activity of ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m(2) as first-line therapy in patients with metastatic pancreatic cancer, we conducted a Phase 1b study. METHODS: Eligible patients were adults with previously untreated metastatic adenocarcinoma of the pancreas. Patients received gemcitabine 1000 mg/m(2) on Days 1, 8 and 15 plus ganitumab 20 mg/kg on Days 1 and 15 of each 28-day cycle. Gemcitabine was administered intravenously over 30-60 min. Ganitumab was administered intravenously over 60 min after completing gemcitabine infusion. RESULTS: Six patients were enrolled and received the study treatment. All patients had thrombocytopenia and leukopenia. Other most common adverse events were neutropenia and nausea. One patient had a dose-limiting toxicity defined as Grade 3 neutropenia with fever. Exposure to ganitumab 20 mg/kg was not affected by the administration of gemcitabine. No apparent pharmacokinetic drug-drug interaction was observed. No anti-ganitumab antibodies were detected. Five patients had a measurable tumor region at baseline. Of these, four patients had a best response of stable disease. CONCLUSIONS: Ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m(2) was tolerable and showed an acceptable safety profile in patients with untreated metastatic pancreatic cancer.

Phase 1 study of trebananib (AMG 386), an angiogenesis targeting angiopoietin-1/2 antagonist, in Japanese patients with advanced solid tumors.

PURPOSE: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of trebananib (AMG 386)--a first-in-class angiopoietin-1/2 antagonist peptide-Fc fusion protein--in Japanese patients, we conducted a phase 1, dose escalation study. METHODS: Eligible patients were men or women, aged between 20 and 74 years, who had histologically or cytologically confirmed advanced solid tumors refractory to standard treatment. Trebananib (3, 10, and 30 mg/kg) was administered intravenously over 60 min in weekly cycles. RESULTS: From June 2009 to April 2010, a total of 18 patients (6 for each dose cohort) were enrolled into the study. Trebananib was tolerated at all dose levels. No dose-limiting toxicities were observed. The most common adverse events were peripheral edema, constipation, fatigue, and pyrexia. Exposure to trebananib appeared to increase according to the dose administered. Serum clearance appeared to be similar across the dose range with the mean terminal-phase half-life ranging from 93.9 to 95.9 h. No neutralizing antibodies were detected. Tumor response was assessed in 18 patients. Of these, one patient with colon cancer in the 3-mg/kg cohort and one with bladder cancer in the 30-mg/kg cohort had partial responses as their best responses. These 2 patients were on treatment at the time of data cutoff (January 17, 2012). CONCLUSION: Trebananib was tolerated and showed acceptable safety profile in Japanese patients with advanced solid tumors. The pharmacokinetic profiles were similar to those in the previous studies in the United States. Trebananib also showed evidence of durable antitumor activity in some patients.

Phase 1 study of ganitumab (AMG 479), a fully human monoclonal antibody against the insulin-like growth factor receptor type I (IGF1R), in Japanese patients with advanced solid tumors.

PURPOSE: This study was to investigate the safety and tolerability of ganitumab in Japanese patients with advanced solid tumors. METHODS: Patients were enrolled into 1 of 3 dose cohorts (6, 12, or 20 mg/kg) of single-agent ganitumab administered intravenously every 2 weeks. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of ganitumab in Japanese patients with advanced solid tumors. An exploratory pharmacodynamic analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF1R pathway (IGFBP-3 and total IGF-1). RESULTS: Nineteen patients with ECOG performance status 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of ganitumab. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCLC (2), thymic (2), and other cancers (6). No DLTs were observed. The most common grade ≥3 adverse events were neutropenia (21 %), leukopenia (16 %) and lymphopenia (11 %). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-ganitumab antibodies were detected during this study. Dose-linearity on PK of ganitumab was indicated in the dose range. Tumor response was assessed for 19 patients. Stable disease as best response was reported in 7 patients. CONCLUSIONS: Ganitumab up to 20 mg/kg was tolerable in Japanese patients with advanced solid tumors. The safety and PK profiles were similar to those previously observed in non-Japanese patients.