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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. High-risk patients who had radical prostatectomy received 12 cycles of apalutamide (240 mg daily; 28-day cycles) plus ADT. The primary end point was BCR-free survival. Secondary end points included testosterone recovery (≥150 ng/dL) and safety. RESULTS: One hundred eight patients were enrolled; median age was 66.0 years (range 46.0-77.0 years). Median preoperative PSA and baseline testosterone were 7.6 ng/mL (range 2.2-62.7 ng/mL) and 340.0 ng/dL (range 43.0-939.0 ng/dL), respectively. The BCR-free rate at 24 months (12 months after completion of planned therapy) was 100% (90% CI 93-100). Serum testosterone recovery rate (≥50 and ≥150 ng/dL) 12 months after treatment completion was 96% (95% CI 88-98) and 77% (95% CI 66-85), respectively. Overall, 107 (99%) patients experienced treatment-emergent adverse events, with 24 (22%) experiencing grade 3 to 4 events. CONCLUSIONS: In Apa-RP, BCR-free survival was 100% with 77% of patients having testosterone recovery (≥150 ng/dL) within 12 months of actual treatment completion and a manageable safety profile. These results provide proof of concept that treatment intensification with 12 cycles of apalutamide plus ADT could become an option for patients with high-risk localized prostate cancer who have undergone radical prostatectomy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04523207.
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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. SUBJECTS/METHODS: A prespecified rash management guide outlining recommended skin care practices was provided to all patients enrolled in Apa-RP (NCT04523207). Rash-related safety data from Apa-RP were compared descriptively with data from SPARTAN and TITAN. RESULTS: Patients in Apa-RP experienced improved rash-related outcomes vs those in SPARTAN and TITAN. CONCLUSIONS: Increased vigilance and proactive management may reduce the incidence, severity, and duration of rash during apalutamide treatment.
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OBJECTIVE: To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the 'Targeted Investigational Treatment Analysis of Novel Anti-androgen' (TITAN) study (ClinicalTrials.gov Identifier NCT02489318) with metastatic castration-sensitive prostate cancer (mCSPC). PATIENTS AND METHODS: Patients in the TITAN study with mCSPC were randomised to 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy. This post hoc analysis assessed the achievement of a PSA level of 0.2->0.02 ng/mL ('ultralow one' [UL1]) and ≤0.02 ng/mL ('ultralow two' [UL2]) vs >0.2 ng/mL with apalutamide treatment and its association with radiographic progression-free survival (rPFS), overall survival (OS), time to castration-resistant PC (TTCRPC), and time to PSA progression (TTPP). The landmark analysis and Kaplan-Meier methods were used. RESULTS: By 3 months, more patients achieved UL1 and UL2 with apalutamide (38% and 23%) vs placebo (15% and 5%). In the apalutamide-treated patients, UL2 vs PSA >0.2 ng/mL at landmark 3 months was associated with significantly longer rPFS (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.14-0.54), OS (HR 0.24, 95% CI 0.13-0.43), TTCRPC (HR 0.2, 95% CI 0.11-0.38), and TTPP (HR 0.11, 95% CI 0.04-0.27; nominal P values all <0.001); this association was also observed but less pronounced for UL1. Similar findings were observed at 6 months. Early onset of decline to UL2 by 3 months was associated with improved survival vs PSA >0.2 ng/mL anytime (HR 0.12, 95% CI 0.06-0.22; P < 0.001) in apalutamide-treated patients. CONCLUSIONS: In this post hoc analysis of TITAN, patients with the deepest PSA decline derived the greatest benefit. These results extend our findings of apalutamide efficacy in the overall TITAN population, underscoring the clinical value of PSA kinetics as a marker for treatment efficacy. PATIENT SUMMARY: Patients with metastatic prostate cancer that is sensitive to ongoing hormonal treatment benefited significantly from the addition of apalutamide compared with placebo. Those who achieved rapid and deep PSA reduction had the greatest survival benefit.
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BACKGROUND: Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant PC (nmCRPC) in the Phase 3 randomised TITAN and SPARTAN studies, respectively, and maintained health-related quality of life (HRQoL). Apalutamide treatment effect by patient age requires assessment. METHODS: Post-hoc analysis assessed patients receiving 240 mg/day apalutamide (525 TITAN and 806 SPARTAN) or placebo (527 TITAN and 401 SPARTAN) with ongoing ADT, stratified by age groups. Prostate-specific antigen declines, radiographic progression-free survival, metastasis-free survival, overall survival (OS), HRQoL and safety were assessed using descriptive statistics, Kaplan-Meier method, Cox proportional-hazards model and mixed-effects model for repeated measures. RESULTS: Hazard ratios (95% confidence intervals) generally favoured apalutamide plus ADT versus ADT alone across all endpoints regardless of age; e.g., OS values were 0.57 (0.40-0.80), 0.70 (0.54-0.91) and 0.74 (0.40-1.39) (TITAN) and 0.39 (0.19-0.78), 0.89 (0.69-1.16) and 0.81 (0.58-1.15) (SPARTAN) in patients aged <65, 65-79 and ≥80 years. Regardless of age, apalutamide also maintained HRQoL and was tolerated well with a potential trend in rates of adverse events increasing with age. Limitations include post-hoc nature and variability in sample size of age groups. CONCLUSIONS: Apalutamide plus ADT was an effective and well-tolerated option maintaining HRQoL in patients with mCSPC and nmCRPC regardless of age. CLINICAL TRIAL REGISTRATION: TITAN (NCT02489318); SPARTAN (NCT01946204).
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Anciano , Neoplasias de la Próstata Resistentes a la Castración/patología , Antagonistas de Andrógenos/uso terapéutico , Calidad de Vida , Tiohidantoínas/efectos adversosRESUMEN
WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from an additional (or post hoc) analysis of the TITAN study. The TITAN study looked at whether the prostate cancer treatment apalutamide could be used to treat individuals with metastatic castration-sensitive prostate cancer (or mCSPC). A total of 1052 participants with mCSPC were included in the TITAN study. Treatment with apalutamide was compared with treatment with placebo. All participants received androgen deprivation therapy (or ADT), which is a type of hormone therapy that has been part of the main treatment for mCSPC for many years. The results showed that apalutamide plus ADT increased the length of time that participants remained alive compared with placebo plus ADT. Apalutamide plus ADT also controlled the growth of the cancer for a longer length of time compared with placebo plus ADT. Additionally, participants who received apalutamide plus ADT experienced a greater reduction in the blood levels of prostate-specific antigen (or PSA), called a deep PSA decline, compared with those who received placebo plus ADT. An additional (or post hoc) analysis was carried out to understand whether a decrease in blood PSA levels, in response to treatment, was associated with improved outcomes, including longer survival time. WHAT WERE THE RESULTS OF THE ADDITIONAL ANALYSIS?: In participants who received apalutamide plus ADT, a deep PSA decline in response to treatment was associated with longer survival time and improved outcomes. WHAT DO THESE RESULTS MEAN FOR INDIVIDUALS WITH MCSPC?: These results demonstrate that individuals with mCSPC can benefit from treatment with apalutamide plus ADT. The association seen between deep PSA decline and the longer survival time and improved outcomes highlights how PSA measurements can be used to help monitor cancer disease evolution in response to treatment. Monitoring PSA levels will assist doctors and other healthcare professionals to understand how effectively a treatment is working for a patient and to tailor their treatment approach to improve PSA decline.
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Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Tiohidantoínas/efectos adversosRESUMEN
BACKGROUND: Adding apalutamide to androgen-deprivation therapy (ADT) resulted in a rapid (at 3- and 6-mo treatment) and deep prostate-specific antigen (PSA) decline (to ≤0.2 ng/ml or ≥90% from baseline), improved overall survival, reduced risk of disease progression, and prolonged health-related quality of life (HRQoL) in nonmetastatic castration-resistant prostate cancer (nmCRPC) in SPARTAN and metastatic castration-sensitive PC (mCSPC) in TITAN. OBJECTIVE: To evaluate the association of a rapid, deep PSA decline at 3 and 6 mo achieved with the addition of apalutamide to ADT with patient-reported outcomes (PROs) in SPARTAN and TITAN. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of SPARTAN and TITAN PRO data was performed. INTERVENTION: Apalutamide versus placebo plus concurrent ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PROs were assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P; SPARTAN and TITAN), Brief Pain Inventory-Short Form (BPI-SF; TITAN), and Brief Fatigue Inventory (BFI; TITAN) at baseline, prespecified cycles during treatment, and after progression for ≤1 yr. The association between a deep PSA decline at landmark 3 or 6 mo of apalutamide and the time to worsening of PROs was assessed using the Kaplan-Meier methodology and Cox proportional-hazard modeling. RESULTS AND LIMITATIONS: Among 806 SPARTAN and 525 TITAN apalutamide-treated patients, the median treatment duration was 32.9 and 39.3 mo, respectively. Patients achieving a deep PSA decline at 3 mo had longer time to worsening in FACT-P total, FACT-P physical well-being, BPI-SF worst pain intensity, or BFI worst fatigue intensity. The 6-mo PSA decline results were similar. Limitations of patient characteristics in clinical studies should be considered. CONCLUSIONS: Attaining a deep and rapid PSA decline at 3 mo with apalutamide plus ADT was associated with longer preservation of overall HRQoL and physical well-being in nmCRPC and mCSPC. PATIENT SUMMARY: Quality of life is maintained in individuals with advanced prostate cancer who achieve a deep prostate-specific antigen decline at 3 mo of apalutamide plus drugs that lower male sex hormones.
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BACKGROUND: Whether disease burden in patients with metastatic castration-sensitive prostate cancer (mCSPC) predicts treatment outcomes is unknown. We assessed apalutamide treatment effect in TITAN patients with mCSPC by disease volume, metastasis number and timing of metastasis presentation. METHODS: These protocol-defined and post hoc analyses of the phase III randomised TITAN study evaluated clinical outcomes in patients receiving 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy (ADT). Subgroups were defined by volume (high: visceral and ≥1 bone metastases or ≥4 bone lesions with ≥1 beyond vertebral column/pelvis), development of metastases per conventional imaging (synchronous: at initial diagnosis; metachronous: after localised disease) and oligometastases (≤5 bone-only metastases) or polymetastases (>5 in bone ± other locations or ≤5 in bone plus other locations). Overall survival (OS), radiographic or second progression-free survival, and time to prostate-specific antigen progression or castration resistance were assessed using Cox proportional hazards models. RESULTS: Of 1052 patients, 63%, 81%, 54%, 27%, 5.7%, and 8.0% had high-volume, synchronous, synchronous/high-volume, synchronous/low-volume, metachronous/high-volume, and metachronous/low-volume disease, respectively. The OS benefit favoured apalutamide plus ADT versus ADT alone in synchronous/high-volume (hazard ratio = 0.68 [95% confidence interval: 0.53-0.87]; p = 0.002), synchronous/low-volume (0.65 [0.40-1.05]; p = 0.08), metachronous/high-volume (0.69 [0.33-1.44]; p = 0.32) and metachronous/low-volume (0.22 [0.09-0.55]; p = 0.001) subgroups. Apalutamide improved other clinical outcomes regardless of subgroup, with similar safety profiles. Most favourable outcomes were observed in oligometastatic disease. CONCLUSION: TITAN patients derived a robust benefit with apalutamide plus ADT regardless of disease volume and timing of metastasis presentation without differences in safety, supporting early apalutamide intensification in mCSPC. CLINICAL TRIAL REGISTRATION: NCT02489318.
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The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.
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Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Antagonistas de Andrógenos/uso terapéutico , Antígeno Prostático Específico , Castración , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológicoRESUMEN
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. OBJECTIVE: The aim of this study was to evaluate whether the approved standard maintenance dose of relugolix in combination with apalutamide sustains castrate testosterone levels (< 50 ng/dL). PATIENTS AND METHODS: Twelve patients with HR-LPC who met all the main study criteria were included in the substudy. Patients received relugolix monotherapy for 2 weeks (loading dose [360 mg] at Day - 14 then 120 mg/day daily until Day - 1), then daily relugolix (120 mg) with apalutamide (240 mg) from Day 1 to Day 28. Endpoints were rate of maintained castration (testosterone < 50 ng/dL) through Day 28 (primary) and safety (secondary). RESULTS: All 12 patients received relugolix and apalutamide and achieved castrate testosterone levels after 2-week relugolix monotherapy (median testosterone 348.5 ng/dL and 8.7 ng/dL at Days - 14 and - 1). All 11 patients who had testosterone measured at Day 28 maintained castrate testosterone (median 10.0 ng/dL) without relugolix dose adjustment. Treatment-emergent adverse events (TEAEs) occurred in nine patients during relugolix monotherapy and in eight patients during relugolix + apalutamide coadministration. Hot flush was the most common TEAE reported, in six and four patients, respectively. CONCLUSIONS: Relugolix administered at approved standard doses concurrently with apalutamide was effective in maintaining castrate testosterone levels in HR-LPC without new safety signals. TRIAL REGISTRATION NUMBER AND DATE: NCT04523207, 21 August 2020.
The Apa-RP study evaluates the combination of apalutamide with drugs that lower male sex hormones for reducing the risk of prostate cancer recurrence. Patients in this study had their prostate gland surgically removed and were at high risk for disease recurrence. Relugolix, a newly approved oral drug for advanced prostate cancer, lowers blood testosterone (the primary male sex hormone) and, in combination with apalutamide, may reduce the risk of prostate cancer recurrence. The Apa-RP substudy goal was to test whether relugolix lowers blood testosterone and maintains these low levels when administered with apalutamide. Researchers looked at the testosterone levels of 12 patients with early prostate cancer who received standard doses of relugolix alone for 2 weeks followed by apalutamide and relugolix for an additional 28 days. Testosterone was measured before and after 2 weeks of relugolix treatment, and then again 28 days after apalutamide was added. All 12 substudy patients achieved low testosterone levels (< 50 ng/dL) after 2 weeks of relugolix treatment. Testosterone was measured at Day 28 of relugolix + apalutamide treatment in 11 patients, all of whom maintained low testosterone without adjustment of their relugolix dose. Adverse effects were consistent with those previously reported for each drug when administered alone. All 12 patients completed the substudy and moved onto the main study, the longer-term results of which will be reported in the future. In summary, relugolix administered at the same time as apalutamide was effective in maintaining low testosterone levels in patients with prostate cancer, without any new safety concerns.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/uso terapéutico , TestosteronaRESUMEN
BACKGROUND: The phase III SPARTAN study demonstrated that apalutamide significantly improves metastasis-free survival and overall survival vs. placebo in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). However, patients receiving apalutamide experienced falls more frequently vs. those receiving placebo (15.6% vs. 9.0%). METHODS: 806 patients with nmCRPC randomized to apalutamide in SPARTAN and treated with apalutamide in addition to ongoing androgen deprivation therapy (ADT) were included in this post-hoc analysis investigating clinical variables associated with a subsequent fall. Time to a fall was assessed with Cox proportional-hazards models adjusted for baseline characteristics and time-varying factors. Statistical inference was based on final multivariable models. RESULTS: Falls were reported for 125/803 (15.6%) patients treated with apalutamide and ADT. Most falls were grade 1 or 2 and did not require hospitalization. Median time from randomization to first fall was 9.2 months (range 0.1-25.3 months). In the final multivariable model of both baseline and after-baseline covariates, baseline patient characteristics (older age, poor Eastern Cooperative Oncology Group performance status, history of neuropathy, and α-blocker use before study treatment) remained significantly associated with fall; after-baseline clinical characteristics significantly associated with time to fall were development of neuropathy, arthralgia, and weight loss before fall. CONCLUSIONS: This analysis identified risk factors for fall among nmCRPC patients treated with apalutamide. Clinical management can minimize these identified risks while enhancing patient outcomes. Preventive interventions should be considered when the identified baseline conditions and post-treatment neuropathy, arthralgia, or weight decrease are present, to reduce risk of fall. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01946204.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/epidemiología , Antagonistas de Receptores Androgénicos/efectos adversos , Antagonistas de Andrógenos/uso terapéutico , Accidentes por Caídas , Artralgia/inducido químicamente , Artralgia/tratamiento farmacológicoRESUMEN
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. A post-hoc analysis was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic adverse events (AEs) in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT in both the studies. Anticoagulants were identified by WHO Drug Anatomical Therapeutic Chemical level 4 classifications. Thrombotic and embolic AEs were coded using the Medical Dictionary for Regulatory Activities Version 22.1. Data were analyzed from patients receiving concurrent OACs among all treated patients in SPARTAN (apalutamide + ADT: 95/803 [11.8%]; placebo + ADT: 48/398 [12.1%]) and TITAN (apalutamide + ADT: 31/524 [5.9%]; placebo + ADT: 28/527 [5.3%]). No consequential differences were observed in the occurrence of thrombotic and embolic events between apalutamide + ADT and placebo + ADT groups receiving concomitant OACs in SPARTAN (11.6% vs 12.5%) or TITAN (19.4% vs 21.4%). Grade 3/4 thrombotic and embolic AEs observed in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT were 6 (6.3%) vs 5 (10.4%) in SPARTAN and 3 (9.7%) vs 1 (3.6%) in TITAN. This analysis suggests that when necessary, concomitant OACs can be used with apalutamide with appropriate monitoring.
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BACKGROUND: Apalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). OBJECTIVE: To assess the relationships between PSA kinetics, outcomes, and molecular subtypes in SPARTAN. DESIGN, SETTING, AND PARTICIPANTS: The authors conducted a post hoc analysis of nmCRPC patients randomized to receive apalutamide (n = 806) or placebo (n = 401) plus ADT and a subset stratified by molecular classifiers. INTERVENTION: Apalutamide 240 mg/d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association between PSA kinetics and MFS, OS, time to PSA progression, and molecular subtypes was evaluated using the landmark analysis and Kaplan-Meier methods. RESULTS AND LIMITATIONS: By 3 mo, PSA decreased in most apalutamide-treated patients and increased in most placebo-treated patients. After apalutamide, the median time to PSA nadir, confirmed ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml were 7.4, 1.0, 1.9, and 2.8 mo, respectively. By 6 mo, 90%, 57%, and 32% of apalutamide patients had ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml, respectively, while only 1.5% of placebo patients experienced ≥50% PSA reduction. PSA reductions were observed within 3 mo and up to 12 mo of apalutamide treatment, and were similar across molecular subtypes. Deep PSA responses (≥90% PSA reduction or PSA ≤0.2 ng/ml) at landmark 6-mo apalutamide treatment were significantly associated with improved time to PSA progression (hazard ratio {HR} [95% confidence interval {CI}] 0.25 [0.18-0.33] or 0.13 [0.08-0.21]), MFS (0.41 [0.29-0.57] or 0.3 [0.19-0.47]), and OS (0.45 [0.35-0.59] or 0.26 [0.18-0.38]; p < 0.001 for all). CONCLUSIONS: Apalutamide plus ADT produced rapid, deep, and durable PSA responses by 6-mo treatment regardless of assessed molecular prognostic markers. An early PSA response with apalutamide was associated with clinical benefits, supporting prognostic value of PSA monitoring. PATIENT SUMMARY: In this report, we describe how prostate-specific antigen (PSA) levels relate to outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus androgen deprivation therapy (ADT). We found that treatment with apalutamide plus ADT resulted in rapid, deep, and durable PSA responses in the majority of patients, including those with high-risk molecular subtypes, which were associated with improved survival.
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Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/patología , TiohidantoínasRESUMEN
PURPOSE: To evaluate the efficacy and safety of ranibizumab 0.5 mg in adult patients with macular edema (ME) resulting from any cause other than diabetes, retinal vein occlusion, or neovascular age-related macular degeneration. DESIGN: A phase 3, 12-month, double-masked, randomized, sham-controlled, multicenter study. PARTICIPANTS: One hundred seventy-eight eligible patients aged ≥18 years. METHODS: Patients were randomized 2:1 to receive either ranibizumab 0.5 mg (n = 118) or sham (n = 60) at baseline and month 1. From month 2, patients in both arms received open-label individualized ranibizumab treatment based on disease activity. A preplanned subgroup analysis was conducted on the primary end point on 5 predefined baseline ME etiologies (inflammatory/post-uveitis, pseudophakic or aphakic, central serous chorioretinopathy, idiopathic, and miscellaneous). MAIN OUTCOME MEASURES: Changes in best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study letters) from baseline to month 2 (primary end point) and month 12 and safety over 12 months. RESULTS: Overall, 156 patients (87.6%) completed the study. The baseline characteristics were well balanced between the treatment arms. Overall, ranibizumab showed superior efficacy versus sham from baseline to month 2 (least squares mean BCVA, +5.7 letters vs. +2.9 letters; 1-sided P = 0.0111), that is, a treatment effect (TE) of +2.8 letters. The mean BCVA gain from baseline to month 12 was 9.6 letters with ranibizumab. The TE at month 2 was variable in the 5 predefined etiology subgroups, ranging from >5-letter gain to 0.5-letter loss. The safety findings were consistent with the well-established safety profile of ranibizumab. CONCLUSIONS: The primary end point was met and ranibizumab showed superiority in BCVA gain over sham in treating ME due to uncommon causes, with a TE of +2.8 letters versus sham at month 2. At month 12, the mean BCVA gain was high (9.6 letters) in the ranibizumab arm; however, the TE was observed to be variable across the different etiology subgroups, reaching a >1-line TE in BCVA in patients with ME resulting from inflammatory conditions/post-uveitis or after cataract surgery. Overall, ranibizumab was well tolerated with no new safety findings up to month 12.
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Inhibidores de la Angiogénesis/uso terapéutico , Edema Macular/tratamiento farmacológico , Ranibizumab/uso terapéutico , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Método Doble Ciego , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/etiología , Masculino , Persona de Mediana Edad , Ranibizumab/efectos adversos , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual/fisiologíaRESUMEN
BACKGROUND: Strains of 2 distinct influenza B lineages (Victoria and Yamagata) have cocirculated in the United States for over a decade, but trivalent influenza vaccines (TIVs) contain only 1 B-lineage strain. Each season, some or most influenza B disease is caused by the B lineage not represented in that season's TIV. Quadrivalent influenza vaccines (QIVs) containing a strain from each B lineage should resolve this problem. METHODS: This was a Phase III, randomized, multicenter trial in the United States among children 6 months to <9 years of age to evaluate the safety and immunogenicity of inactivated QIV compared with inactivated control TIVs containing opposite B-lineage strains. Participants were randomized at a ratio of approximately 4:1:1 to receive QIV, TIV containing a Victoria-lineage B strain or TIV containing a Yamagata-lineage B strain. Sera were collected pre- and 28-days post-final vaccination and safety was assessed for 6 months after the last injection. RESULTS: A total of 4363 participants were enrolled. QIV induced noninferior antibody responses to all A strains and corresponding B strains compared with the control TIVs and superior antibody responses to the noncorresponding B strain in each TIV. Rates of solicited reactions and unsolicited and serious adverse events were similar in all groups. CONCLUSIONS: This study demonstrated that QIV is safe and immunogenic among children 6 months to <9 years of age. These findings, along with data from 2 other studies of this QIV in adults, suggest that QIV should offer protection against both B lineages with a safety profile similar to TIV across all ages.
Asunto(s)
Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/inmunología , Vacunas de Productos Inactivados/efectos adversos , Vacunas de Productos Inactivados/inmunología , Anticuerpos Antivirales/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/epidemiología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Masculino , Orthomyxoviridae/inmunología , Estados Unidos/epidemiología , Vacunas de Productos Inactivados/administración & dosificaciónRESUMEN
This prospective, double-blind, multicenter trial compared the safety and tolerability of irbesartan/hydrochlorothiazide (HCTZ) fixed-dose combination therapy with irbesartan monotherapy in patients with severe hypertension (seated diastolic blood pressure (SeDBP) >or=110 mm Hg, mean BP 172/113 mm Hg at baseline). Patients were randomized 2:1 to 7 weeks' irbesartan/HCTZ 150/12.5 mg to 300/25 mg (n = 468) or irbesartan 150 mg to 300 mg (n = 227). The incidence of treatment-related adverse events (AEs) was similar with combination and monotherapy (11.3% and 10.1%), and most AEs were mild-to-moderate. The combined incidence of prespecified AEs was lower with irbesartan/HCTZ than with irbesartan (8.8% vs. 11.5%). There were no treatment-related serious AEs or deaths. At week 5, more patients achieved SeDBP < 90 mm Hg compared to irbesartan (47% vs. 33%; P = 0.0005). Despite more rapid and aggressive BP lowering, initial fixed-dose irbesartan/HCTZ demonstrated a comparable AE profile to irbesartan monotherapy in patients with severe hypertension.
Asunto(s)
Antihipertensivos/administración & dosificación , Compuestos de Bifenilo/administración & dosificación , Hidroclorotiazida/administración & dosificación , Hipertensión/tratamiento farmacológico , Tetrazoles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Antihipertensivos/efectos adversos , Compuestos de Bifenilo/efectos adversos , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Hidroclorotiazida/efectos adversos , Hipertensión/fisiopatología , Irbesartán , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de los Simportadores del Cloruro de Sodio/administración & dosificación , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Tetrazoles/efectos adversos , Adulto JovenRESUMEN
A post hoc pooled analysis of 2 multicenter, randomized, double-blind, active-controlled force-titration studies assessed the antihypertensive efficacy and tolerability of 7 to 8 weeks' once-daily fixed-dose irbesartan/hydrochlorothiazide (HCTZ) 300/25 mg in 796 stage 1 or 2 hypertensive patients according to age (65 years or older or younger than 65) (n=121 or 675) and presence or absence of obesity (n=378 or 414), type 2 diabetes (n=99 or 697), and high World Health Organization-defined cardiovascular risk (n=593 or 202). Systolic/diastolic blood pressure reductions (27-31/16-22 mm Hg) were similar regardless of age, obesity, and type 2 diabetes status and were greater in high- vs low-risk patients. Dizziness (2.0%-3.7%), hypotension (0%-0.7%), and syncope (0%) were rare and not centered in any subgroup. There was no hypotension in the elderly or in type 2 diabetics. Irbesartan/HCTZ provided consistent blood pressure lowering and tolerability regardless of age, obesity, and type 2 diabetes and greater efficacy in patients with high cardiovascular risk.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Tetrazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Antihipertensivos/efectos adversos , Compuestos de Bifenilo/efectos adversos , Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Femenino , Humanos , Hidroclorotiazida/efectos adversos , Irbesartán , Masculino , Persona de Mediana Edad , Obesidad , Factores de Riesgo , Tetrazoles/efectos adversos , Resultado del TratamientoRESUMEN
Severe hypertension is difficult to control. This prospective, randomized, double-blind, active-controlled, multicenter trial compared efficacy and safety of once-daily irbesartan/hydrochlorothiazide (HCTZ) combination therapy with irbesartan monotherapy in severe hypertension. Patients who were untreated or uncontrolled on monotherapy (seated diastolic blood pressure [BP] > or =110 mm Hg) received fixed-dose irbesartan 150 mg/HCTZ 12.5 mg combination therapy for 7 weeks, force-titrated to irbesartan 300 mg/HCTZ 25 mg at week 1 (n=468); or irbesartan 150 mg monotherapy, force-titrated to 300 mg at week 1 (n=269). Significantly more patients on combination therapy achieved seated diastolic BP <90 mm Hg at week 5 (primary end point) compared with monotherapy recipients (47.2% vs 33.2%; P=.0005). Likewise, significantly more patients attained goals per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (<140/90 mm Hg) at week 5 (34.6% vs 19.2%, respectively; P<.0001), while the mean difference between combination and monotherapy in seated diastolic BP and seated systolic BP was 4.7 mm Hg and 9.7 mm Hg (P<.0001). Greater and more rapid BP reduction with irbesartan/HCTZ was achieved without additional side effects.