Treatment Option For Postmenopausal Women Research Articles

Cost-effectiveness intervention thresholds for romosozumab and teriparatide in the treatment of osteoporosis in the UK.

To estimate the 10-year probability of a major osteoporotic fracture (MOF) at which sequential treatment with romosozumab or teriparatide followed by alendronate, compared with alendronate alone, becomes cost-effective in a UK setting. A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), in women receiving sequential treatment with either romosozumab or teriparatide followed by alendronate, compared with alendronate alone. Patients aged 50 to 90years with a recent MOF, hip or spine fracture were followed from the start of a 5-year treatment until the age of 100years or death. The analysis had a healthcare perspective. Efficacy of romosozumab, teriparatide and alendronate was derived from phase III randomised controlled trials. Resource use and unit costs were derived from the literature. Cost-effectiveness intervention threshold (CEIT), defined as the 10-year probability of a major osteoporotic fracture at which treatment becomes cost-effective, was compared with clinically appropriate intervention thresholds for bone-forming treatment in women with very high fracture risk as recommended by the UK National Osteoporosis Guideline Group (NOGG). The base case analysis showed that sequential romosozumab-to-alendronate treatment was cost-effective from a 10-year MOF probability of 18-35% and above depending on age and site of sentinel fracture at a willingness to pay (WTP) of £30,000. For teriparatide-to-alendronate, treatment was cost-effective at a 10-year MOF probability of 27-57%. The results were sensitive to pricing of the drugs but relatively insensitive to treatment duration, romosozumab persistence assumptions, and site of sentinel fracture. The CEITs for romosozumab-to-alendronate treatment were lower than the clinical thresholds from the age of 70years meaning that treatment could be considered both cost-effective and aligned with the NOGG treatment guidelines. By contrast, for teriparatide-to-alendronate the CEITs were higher than the clinical thresholds irrespective of age. However, cost-effective scenarios were found in the presence of strong clinical risk factors in addition to a recent sentinel fracture. The results of this study indicate that sequential romosozumab-to-alendronate or teriparatide-to-alendronate treatment can be a cost-effective treatment option for postmenopausal women at very high risk of fracture.

Abstract 3863: Aminoflavone confers activity against aromatase inhibitor-resistant breast cancer cells in part via miR125b2-3p restoration

Abstract Aromatase inhibitor therapy is the most crucial adjuvant treatment option for postmenopausal women with hormone receptor-positive (HR+) non-metastatic breast cancer. However, up to 30% of these patients will experience relapse due in part to aromatase inhibitor resistance. We recently identified miR125b2-3p as a putative tumor suppressor in HR+ breast cancer. We also found that small molecule Aminoflavone (AF) induces miR125b2-3p expression in HR+ breast cancer cells. In the current study, we hypothesized that AF confers anticancer actions in breast cancer cells resistant to aromatase inhibitors via miR125b2-3p reactivation. Using the Alamar Blue and colony forming assays, we discovered that AF demonstrated anticancer activity in estrogen-deprived resistant (EDR) cells designed to mimic aromatase inhibitor resistance. AntagomiR125b2-3p enhanced, while miR125b2-3p mimics diminished colony formation of EDR cells. AF-mediated suppression of colony formation in EDR cells was attenuated during co-treatment with antagomiR125b2-3p and was enhanced during co-treatment with miR125b2-3p mimics. Both miR125b2-3p mimics and AF suppressed EDR cell migration. AntagomiR125b2-3p counteracted AF-mediated suppression of cell migration. Our in silico profiling studies identified the alpha6-integrin, a mediator of breast cancer stem cell activity and metastasis, as one miR-125b2-3p target. Immunohistochemistry of patient tumor samples revealed that alpha 6-integrin protein expression intensified following relapse on the aromatase inhibitor anastrozole. MCF-7 cells transfected to overexpress the alpha 6-integrin were less responsive to anastrozole than those transfected with empty vector. These data suggest that AF restores the tumor suppressor function of miR125b2-3p to inhibit the alpha 6-integrin and confer activity against aromatase inhibitor-resistant breast cancer. Citation Format: Eileen J. Brantley, Nicole Mavingire, Salma Khan, Gayathri Nagaraj, Shawnee Angeloni, Charles Wang, Ubaldo Soto. Aminoflavone confers activity against aromatase inhibitor-resistant breast cancer cells in part via miR125b2-3p restoration. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3863.

Safety and effectiveness of a novel home-use therapeutic ultrasound device for the treatment of vaginal dryness in postmenopausal women: a pilot study.

Abstract A home-use, therapeutic ultrasound device was safe and effective for treating vaginal dryness after 12 weeks, and effectiveness was maintained to 1 year. Therapeutic ultrasound could offer a new, nonhormone treatment option for postmenopausal women with vulvovaginal atrophy. Objective To evaluate safety and effectiveness of therapeutic ultrasound for treatment of postmenopausal vaginal dryness. Methods In a pilot study, postmenopausal women with self-reported vaginal dryness were randomized (1:1) to double-blind ultrasound treatment (n = 21) or sham (n = 21) for 12 weeks. Primary effectiveness endpoint was change from baseline to week 12 in Vaginal Assessment Scale symptoms (dryness, soreness, irritation, dyspareunia). Secondary effectiveness endpoint was scoring of clinician-reported Vaginal Health Index (elasticity, fluid, pH, mucosa, moisture). After 12 weeks, participants received open-label ultrasound treatment to 1 year. Safety endpoint was treatment-emergent adverse events. Results In the modified intent-to-treat population, women showed (mean ± standard error) reduction in Vaginal Assessment Scale with ultrasound treatment versus sham (n = 15, −0.5 ± 0.2 vs n = 15, −0.4 ± 0.3; P = 0.9) and improved Vaginal Health Index (n = 9, 2.7 ± 0.9 vs n = 9, 0.6 ± 1.4; P = 0.3). In the per-protocol analysis population, ultrasound treatment (n = 9) versus sham (n = 8) significantly reduced symptoms score (−0.6 ± 0.3 vs −0.0 ± 0.4; P = 0.05) and significantly improved Vaginal Health Index (2.7 ± 0.9 vs −0.4 ± 1.2; P = 0.03). Improvement in effectiveness endpoints were seen at 1 year compared with baseline. There were no differences in treatment-emergent adverse events between ultrasound treatment versus sham and no serious adverse events. Conclusions Home-use ultrasound was safe and effective for treating vaginal dryness after 12 weeks. Effectiveness was maintained to 1 year. Therapeutic ultrasound could offer a new, nonhormonal treatment option for postmenopausal women with vulvovaginal atrophy.

Effect of Chamomile Vaginal Gel on the Sexual Function in Postmenopausal Women: A Double-Blind Randomized Controlled Trial

Female sexual dysfunction (FSD) is a common complaint among postmenopausal women, which is largely because of the genitourinary syndrome in these women (GSM). Considering the phytoestrogenic effects of chamomile, the present study was primarily aimed to investigate the effect of chamomile vaginal gel on the sexual function of postmenopausal women. The side effects of these drugs were evaluated as a secondary outcome of the study. This randomized double-blind clinical trial and placebo-controlled study was conducted on postmenopausal women with sexual dysfunction (FSFI ≤26.55). To this aim, 96 postmenopausal women were randomly assigned into three groups (n = 32 each) including women receiving (i) chamomile vaginal gel 5%, (ii) conjugated estrogen vaginal cream, and (iii) placebo vaginal gel, for 12 weeks (ie, every night in the first 2 weeks, and 2 nights per week in the next 10 weeks, each night 1 g was used). The sexual function was measured using female sexual function index (FSFI) before and after the intervention. Data analysis was performed by chi-square, one-way ANOVA, descriptive statistics, analysis of covariance (ANCOVA), and paired t test using SPSS software version 22. P < .05 was considered statistically significant. The main study outcome measure was evaluate the effects of vaginal administration of chamomile gel in comparison with conjugated estrogen cream and placebo gel on postmenopausal FSD using the FSFI. The findings showed that chamomile vaginal gel in compared to placebo vaginal gel caused a significant improvement in all six sexual function domains and the total FSFI score (effect size = +2.9 [95% CI, +2.1 to +3.6], P < .001). Also, there was no significant difference between the chamomile vaginal gel and conjugated estrogen vaginal cream groups in terms of the total score and all sub-domains of sexual function with the exception of orgasm (effect size = +0.13 [95% CI, -0.36 to +0.63], P = .02) and sexual satisfaction (effect size = 0 [95% CI, -0.49 to +0.49], P = .04). Two women in the chamomile group and one in the placebo group experienced a burning sensation (P = .345). This treatment can be considered as a treatment option for postmenopausal women with sexual dysfunction who have contraindications to the use of hormone therapy. This study is the first study to investigate the effectiveness of chamomile vaginal gel on sexual function in postmenopausal women. However, in this study, treatment duration was 12 weeks and no follow up was performed beyond this time. Based on the results of this study, the use of vaginal chamomile gel improved sexual function in postmenopausal women.

Cost-effectiveness of romosozumab for the treatment of postmenopausal women with severe osteoporosis at high risk of fracture in Sweden

SummaryRomosozumab is a novel bone-building drug that reduces fracture risk. This health economic analysis indicates that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture.PurposeTo estimate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate (“romosozumab-to-alendronate”) compared with alendronate alone in patients with severe osteoporosis at high risk of fracture in Sweden.MethodsA microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), for women treated with romosozumab-to-alendronate or alendronate alone. Patients aged 74 years with a recent major osteoporotic fracture (MOF) were followed from the start of treatment until the age of 100 years or death. Treatment with romosozumab for 12 months was followed by alendronate for up to 48 months or alendronate alone with a maximum treatment duration of 60 months. The analysis had a societal perspective. Efficacy of romosozumab and alendronate were derived from phase III randomized controlled trials. Resource use and unit costs were collected from the literature. Cost-effectiveness was estimated using incremental cost-effectiveness ratio (ICER) with QALYs as effectiveness measures.ResultsThe base case analysis showed that sequential romosozumab-to-alendronate treatment was associated with 0.089 additional QALYs at an additional cost of €3002 compared to alendronate alone, resulting in an ICER of €33,732. At a Swedish reference willingness-to-pay per QALY of €60,000, romosozumab-to-alendronate had a 97.9% probability of being cost-effective against alendronate alone. The results were most sensitive to time horizon, persistence assumptions, patient age, and treatment efficacy.ConclusionThe results of this study indicate that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture.

17β-estradiol/progesterone in a single, oral, softgel capsule (TX-001HR) significantly increased the number of vasomotor symptom-free days in the REPLENISH trial.

Objective:To examine responder rates and vasomotor symptom-free days with oral 17β-estradiol/progesterone (E2/P4; TX-001HR) versus placebo in the REPLENISH trial.Methods:REPLENISH (NCT01942668) was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial, evaluating single, oral, softgel E2/P4 capsules in postmenopausal women (40-65 y) with a uterus and vasomotor symptoms (VMS). Women with moderate to severe hot flushes (≥7/d or ≥50/wk) were randomized (VMS substudy) to daily E2/P4 (mg/mg) of 1/100, 0.5/100, 0.5/50, 0.25/50, or placebo. Proportions of women with ≥50% or ≥75% reductions in moderate to severe VMS (responders), and those with no severe VMS as well as the weekly number of days without moderate to severe VMS with TX-001HR versus placebo were determined. Mixed model repeated measures was used to analyze data and Fisher exact test was employed to compare E2/P4 versus placebo.Results:Seven hundred twenty-six women were eligible for the VMS efficacy analysis (E2/P4 1/100 [n = 141], 0.5/100 [n = 149], 0.5/50 [n = 147], 0.25/50 [n = 154], or placebo [n = 135]). Significantly more women treated with all E2/P4 doses versus placebo were ≥50% responders and ≥75% responders at weeks 4 and 12 (P < 0.05) and also had significantly more days per week without moderate to severe VMS at week 12 (1.9-3.0 d for E2/P4 versus 1.3 d for placebo; P < 0.05). The proportion of women without severe hot flushes at week 12 was 43% to 56% for all E2/P4 doses versus 26% for placebo (P ≤ 0.01).Conclusions:Women treated with E2/P4 had a greater response to treatment with more VMS-free days than with placebo. The E2/P4 1/100 dose (Bijuva [E2 and P4] capsules) represents an oral treatment option for postmenopausal women with moderate to severe VMS and a uterus.

Medroxyprogesterone opposes estradiol-induced renal damage in midlife ovariectomized Long Evans rats.

Our laboratory previously published that long-term administration of estradiol (E2) was detrimental to the kidneys of midlife ovariectomized Long Evans rats, contrasting clinical studies in showing that menopausal hormone therapy is associated with decreased albuminuria. However, it is unknown whether this renal benefit was due to estrogen and/or the combination with progestogen. Therefore, the objective of the current study was to determine the impact of medroxyprogesterone (MPA) on E2-mediated renal damage using a rodent model. Female Long Evans retired breeders underwent ovariectomy at 11 months of age and were treated for 40 days with subcutaneous E2, E2+MPA or vehicle at doses mimicking that of menopausal hormone therapy (N = 5-7 per group). Systolic blood pressure was measured along with indices of renal damage and function to investigate the impact of MPA on E2-mediated renal outcomes. Renal estrogen receptor alpha and G protein-coupled estrogen receptor transcript copy numbers were measured in all treatment groups through droplet digital PCR. Middle-aged female Long Evans rats displayed spontaneous hypertension with similar systolic blood pressures and heart weights between groups. Even though blood pressure was comparable, E2 reduced glomerular filtration rate and increased proteinuria indicating pressure-independent renal damage. Coadministration with MPA prevented E2-induced glomerular filtration rate impairment and proteinuria by promoting renal hypertrophy and preventing renal interstitial fibrosis. Both E2 and E2+MPA reduced renal estrogen receptor alpha (ERα) and increased renal G protein-coupled estrogen receptor mRNA, but neither ERα nor ERß protein was different between groups. MPA was protective against E2-induced renal damage and dysfunction in middle-aged female Long Evans rats. Assessing the impact of hormone therapy on renal outcomes may be an important clinical factor when considering treatment options for postmenopausal women.

Romosozumab: A first-in-class sclerostin inhibitor for osteoporosis.

The purpose of this article is to review the pharmacology, efficacy, and safety of the sclerostin inhibitor romosozumab for the treatment of osteoporosis, including data from clinical trials of the drug. A review of the literature was performed by searching PubMed and MEDLINE for all relevant articles published between January 2014 and February 2020 using the keywords romosozumab, romosozumab-aqqg, osteoporosis, and fracture. All relevant English-language articles evaluating the pharmacology, efficacy, or safety of romosozumab for the treatment of osteoporosis in humans were included; poster presentations were excluded. Romosozumab has been approved by the Food and Drug Administration and is considered both safe and effective for the treatment of osteoporosis in high-risk postmenopausal females. Phase 2 and phase 3 clinical trials have shown a statistically significant decrease in new vertebral fractures and an increase in bone mineral density with romosozumab use, as compared with both placebo use and use of alternative osteoporosis therapies. The primary safety concern is a potential risk of cardiovascular events; additionally, hypocalcemia must be corrected prior to initiation. Romosozumab is the first anabolic medication that both increases bone formation and decreases bone resorption. Data suggest that romosozumab is more effective than oral bisphosphonates in preventing osteoporotic fractures, though cost and safety concerns must be considered. Romosozumab is a novel, 12-month treatment option for postmenopausal women at high risk for osteoporotic fracture that both increases bone formation and decreases bone resorption.

Economic Evaluation of Senshio® (Ospemifene) for the Treatment of Vulvovaginal Atrophy in Scotland.

Local oestrogens, the current treatment for vulvar and vaginal atrophy (VVA), are not suitable for all women. Standard of care (SoC) consists of over-the-counter lubricants and moisturisers. Senshio® (ospemifene) provides a treatment option for postmenopausal women who are not candidates for local vaginal oestrogen therapy who would otherwise have an unmet clinical need. The aim of this study was to estimate the cost-effectiveness of ospemifene, a selective oestrogen receptor modulator, for the treatment of moderate to severe symptomatic VVA in postmenopausal women who are not candidates for local vaginal oestrogen therapy. The Scottish Medicines Consortium (SMC) recently evaluated the clinical and cost-effectiveness evidence of ospemifene plus SoC compared with SoC alone. A cost-effectiveness study, from a National Health Service (NHS) Scotland perspective over a lifetime time horizon, was submitted to the SMC. The cohort-based Markov model used robust clinical evidence from two large pivotal phase III randomised controlled studies and included four health states classified by dyspareunia symptom severity: none, mild, moderate and severe. The movement of women between health states was dependent on the effectiveness of treatment in reducing dyspareunia. Extensive sensitivity analyses were undertaken to assess the level of confidence associated with the base-case results. Treatment with ospemifene was associated with an additional cost of £847 per patient and an increase in quality-adjusted life-years (QALY) of 0.06 per patient. Ospemifene had an incremental cost-effectiveness ratio of £14,138 per QALY. In the probabilistic sensitivity analysis, there was a probability of 89% that ospemifene was cost-effective at a threshold of £20,000 per QALY gained. Ospemifene remained cost-effective under all scenario analyses. The SMC reviewed the clinical and economic evidence and judged that the evidence demonstrated a robust case to support prescribing ospemifene in NHS Scotland. Ospemifene is a cost-effective intervention that has recently been accepted by the SMC for the treatment of postmenopausal women with moderate to severe VVA who are not candidates for local oestrogen.

Pharmacoeconomic analysis of using cyclin-dependent kinase 4 and 6 inhibitors in the first line treatment of HR-positive HER2-negative advanced breast cancer

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib and abemaciclib are the new treatment options for postmenopausal women with locally advanced or metastatic hormone-receptor (HR) positive human epidermal growth factor receptor 2 (HER2) negative BC. The aim of the current study is to conduct complex pharmacoeconomic evaluation of using CDK4/6 inhibitors palbociclib and ribociclib that are included in Vital and Essential Drug List (VEDL) in combination with letrozole in first line treatment from the Russian healthcare system prospective. Methods . Pharmacoeconomic evaluation consisted of two parts: clinical and economic study and budget impact analysis. We used cost minimization method for the clinical and economic study, since palbociclib and ribociclib are equally or comparably effective, according to earlier literature. Time horizon of clinical and economic study was 5 years. Direct medical costs including medications and adverse event treatments were considered. We accounted for treatment discontinuation and CDK4/6 inhibitors dose modifications. Budget impact analysis was performed for the three-year period of 2020-2022. All patients who can be treated with palbociclib or ribociclib were considered. Results . Mean direct medical costs of using palbociclib + letrozole were 2 082 333 RUB per patient, which were 505 016 RUB or 19.5% lower, compared to ribociclib + letrozole. According to current trends of BC morbidity, 8 098-8 221 newly diagnosed patients will be ready to start treatment with CDK4/6 inhibitors in 2020-2022 in Russia annually. Using palbociclib in this patient population lowers 3-year budget costs by 9 087 million RUB or by 22.5%, compared to ribociclib. Conclusions . Using palbociclib is the cost-saving treatment option for postmenopausal women with locally advanced or metastatic HR-positive HER2-negative BC, compared to ribociclib.

Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Guideline Update.

The objective is to provide an update of the 2019 Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline for the pharmacological management of osteoporosis in postmenopausal women using romosozumab. We reviewed findings from the meta-analysis and primary clinical trials assessing the efficacy of romosozumab, a monoclonal antibody targeting sclerostin, for the prevention of fractures and concluded that this agent can be considered a treatment option for postmenopausal women at very high risk for osteoporotic fracture. The romosozumab label has a boxed warning, recommending careful consideration by the treating clinician as to cardiovascular risk profile in the individual woman who might receive this agent, since clinical trial data from an active comparator study show an imbalance in serious cardiovascular adverse events between romosozumab and alendronate.

Early metabolic response of breast cancer to neoadjuvant endocrine therapy: comparison to morphological and pathological response

BackgroundNeoadjuvant endocrine therapy (NET) has shown efficacy in terms of clinical response and surgical outcome in postmenopausal patients with estrogen receptor-positive / HER2-negative breast cancer (ER+/HER2- BC) but monitoring of tumor response is challenging. The aim of the present study was to investigate the value of an early metabolic response compared to morphological and pathological responses in this population.MethodsThis was an ancillary study of CARMINA 02, a phase II clinical trial evaluating side-by-side the efficacy of 4 to 6 months of anastrozole or fulvestrant. Positron Emission Tomography/Computed Tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) scans were performed at baseline (M0), early after 1 month of treatment (M1) and pre-operatively in 11 patients (74.2 yo ± 3.6). Patients were classified as early “metabolic responders” (mR) when the decrease of SUVmax was higher than 40%, and “metabolic non-responders” (mNR) otherwise. Early metabolic response was compared to morphological response (palpation, US and MRI), variation of Ki-67 index, pathological response according to the Sataloff classification and also to Preoperative Endocrine Prognostic Index (PEPI) score. It was also correlated with overall survival (OS) and recurrence-free survival (RFS).ResultsTumor size measured on US and on MRI was smaller in mR than mNR, with the highest statistically significant difference at M1 (p = 0.01 and 7.1 × 10− 5, respectively). No statistically significant difference in the variation of tumor size between M0 and M1 assessed on US or MRI was observed between mR and mNR. mR had a better clinical response: no progressive disease in mR vs 2 in mNR and 2 partial response in mR vs 1 partial response in mNR. One patient with a pre-operative complete metabolic response had the best pathological response. Pathological response did not show any statistically significant difference between mR and mNR. mR had better OS and RFS (Kaplan-Meier p = 0.08 and 0.06, respectively). All cancer-related events occurred in mNR: 3 patients died, 2 of them from progressive disease.ConclusionsFDG-PET/CT imaging could become a “surrogate marker” to monitor tumor response, especially as NET is a valuable treatment option in postmenopausal women with ER+/HER2- BC.

PCN246 BUDGET IMPACT OF RIBOCICLIB PLUS LETROZOLE FOR THE TREATMENT OF POST-MENOPAUSAL WOMEN WITH HORMONE RECEPTOR-POSITIVE (HR+), HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2- NEGATIVE (HER2-) ADVANCED OR METASTATIC BREAST CANCER IN DENMARK

To estimate cost and budget impact of establishing ribociclib+letrozole (ribociclib) as a first-line treatment option for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer compared to palbociclib+letrozole (palbociclib) in Denmark. A two-year budget impact model with a Danish national payer perspective was developed to calculate the incremental cost of introducing ribociclib in patients with HR+/HER2- breast cancer eligible for treatment. Progression-free survival, incidence and type of adverse events and dose distributions were all from the registration trial MONALEESA-2. Acquisition costs (pharmacy purchasing price), monitoring, health state cost (progression-free and post-progression) and cost associated with relevant grade 3 and 4 adverse events, were included based on Danish tariffs. 270 patients were assumed eligible for treatment every year, based on clinical experts. New patients would enter the model each year and patients could exit due to death. The budget impact was calculated based on two treatment mixes, one where ribociclib is not considered as standard treatment and one where ribociclib is considered standard treatment. In a cohort of 270 patients per year, the inclusion of ribociclib would be associated with a total saving of approximately DKK 4.3 million for a time horizon of two years. Ribociclib has a lower acquisition cost for the lower doses of 400 and 200 mg, while palbociclib has a flat acquisition cost for all three doses. Hence, the cost-savings related to ribociclib are mostly due to reduced drug costs due to down dosing. Increased costs were observed for adverse events and monitoring; however, based on clinical feedback, the payer’s appraisal assumed no difference in these. The budget impact of introducing ribociclib as standard treatment in Denmark is cost-saving compared to palbociclib for the first line treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer.

A Cost Minimization Analysis of Treatment Options for Postmenopausal Women With Dysuria

(Abstracted from Am J Obstet Gynecol 2019; doi: 10.1016/j.ajog.2019.04.031) The most common type of bacterial infection seen in an outpatient setting is urinary tract infection (UTI). In the United States, the overall lifetime prevalence of UTIs in women is greater than 50%.

A cost-minimization analysis of treatment options for postmenopausal women with dysuria

Empiric therapy for urinary tract infection is difficult in postmenopausal women because of the higher rates of confounding lower urinary tract symptoms and differential resistance profiles of uropathogens in this population. The objective of the study was to determine the least costly strategy for treatment of postmenopausal women with the primary complaint of dysuria. We performed a cost minimization analysis modeling the following clinical options: (1) empiric antibiotic therapy followed by urine culture, (2) urinalysis with empiric antibiotic therapy only if positive nitrites and leukocyte esterase, or (3) waiting for culture prior to initiating antibiotics. For all strategies we included nitrofurantoin, trimethoprim/sulfamethoxazole, fosfomycin, ciprofloxacin, or cephalexin. Pathogens included Escherichia coli, Enterococcus faecalis, Klebsiella pneumonaie, or Proteus mirabalis. Pathogens, resistance, treatment success, and medication side effects were specific to postmenopausal women. Cost minimization modeling with TreeAge Pro assumed 73.4% of urinary tract infections were caused by Escherichia coli with 24.4% resistance to nitrofurantoin, trimethoprim/sulfamethoxazole. With our assumptions, empiric antibiotics with nitrofurantoin, trimethoprim/sulfamethoxazole was the least costly approach ($89.64/patient), followed by waiting for urine culture ($97.04/patient). Except for empiric antibiotics with fosfomcyin, empiric antibiotics was always less costly than using urinalysis to discriminate antibiotic use. This is due to the cost of urinalysis ($38.23), high rate of both urinary tract infection (91%), and positive urinalysis (69.3%) with dysuria in postmenopausal women and resultant high rate of antibiotic use with or without urinalysis. Options with fosfomycin were the most expensive because of the highest drug costs ($98/dose), and tornado analyses showed fosfomycin cost was the most impactful variable for model outcomes. Sensitivity analyses showed empiric fosfomycin became the least costly option if drug costs were $25.80, a price still more costly than almost all modeled baseline drug costs. This outcome was largely predicated on low resistance to fosfomycin. Conversely, ciprofloxacin was never the least costly option because of higher resistance and side effect cost, even if the drug cost was $0. We modeled 91% positive urine culture rate in postmenopausal women with dysuria; waiting for the urine culture prior to treatment would be the least costly strategy in a population with a predicted positive culture rate of <65%. The least costly strategy was empiric antibiotics with nitrofurantoin and trimethoprim/sulfamethoxazole, followed by waiting on culture results. Local resistance patterns will have an impact on cost minimization strategies. Empiric fosfomycin would be least costly with reduced drug costs, even at a level at which drug costs were higher than almost all other antibiotics. In a population with high posttest probability of positive urine culture, urinalysis adds unnecessary cost. Antibiotic stewardship programs should continue efforts to decrease fluoroquinolone use because of high resistance, side effects, and increased cost.

22: A cost minimization analysis of treatment options for postmenopausal women with dysuria

Our objective was to determine the least costly strategy for treatment of postmenopausal (PMP) women with the primary complaint of dysuria. We performed a cost minimization analysis modeling the following clinical options: (1) empiric antibiotic therapy (eABX) followed by urine culture (Ucx), (2) urinalysis (U/A) with eABX only if positive nitrites/leukocyte esterase, or (3) waiting for Ucx prior to initiating antibiotics. For all strategies we included nitrofurantoin, trimethoprim/sulfamethoxazole (TMP/SMX), fosfomycin, ciprofloxacin, or cephalexin. Pathogens included E. coli, E. faecalis, K. pneumonaie, or P. mirabalis. Pathogens, resistance, treatment success, and medication side effects were specific to postmenopausal women. In terms of our results, we assumed 73.4% of UTIs were caused by E.coli strains with a 24.4% resistance to TMP/SMX. With our assumptions, eABX TMP/SMX was the least costly approach ($89.64/patient, Table 1), followed by waiting for Ucx($97.04/patient). For any given antibiotic, eABX was always less costly than using U/A first. This is due to cost of U/A ($38.23), high rate of UTI (90%) in PMP women with dysuria, and resultant high rate of ABX with or without U/A. Options with fosfomycin were the most expensive due to highest drug costs($98/dose), and tornado analyses showed fosfomycin cost was the most impactful variable for model outcomes. Sensitivity analyses showed eABX fosfomycin became the least costly option if drug costs were $25.80. This outcome was largely predicated on low resistance to fosfomycin. Conversely, ciprofloxacin was never the least costly option due to higher resistance and side effect cost, even if the drug cost was $0. In conclusion, the least costly strategy was eABX TMP/SMX, followed by waiting on Ucx. Local resistance patterns will impact cost minimization strategies. Fosfomycin eABX would be least costly with reduced drug costs. In a population with high post-test probability of positive Ucx, U/A adds unnecessary cost. Antibiotic stewardship should continue efforts to decrease fluoroquinolone use due to high resistance, side effects, and increased cost.

Budget impact of including ribociclib in combination with letrozole on US payer formulary: first-line treatment of post-menopausal women with HR+/HER2− advanced or metastatic breast cancer

Objectives: The combination of a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor with the aromatase inhibitor letrozole is a safe and effective alternative to letrozole monotherapy for first-line hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. This study evaluates the budget impact of using the CDK 4/6 inhibitor ribociclib plus letrozole as a first-line treatment option for postmenopausal women with HR+/HER2− advanced breast cancer, from a United States (US) payer perspective.Methods: A cohort-based budget impact model was used to calculate the incremental cost of introducing ribociclib plus letrozole over three years for the target population. The analysis compared two scenarios: treatment options excluding or including ribociclib plus letrozole. Market shares were derived from market research and the assumption was the introduction of ribociclib plus letrozole would only displace existing CDK-based therapies. Treatment duration was based on the median time to treatment discontinuation or median progression-free survival for first-line treatment, and on clinical trial data for second- and third-line treatment. Acquisition costs were based on wholesale acquisition costs and considered co-payment. Costs for drug administration and monitoring, subsequent therapy, and relevant adverse events were included.Results: Of 1 million insured members, 263 were eligible for CDK 4/6 inhibitor treatment. Cumulative total savings with ribociclib plus letrozole were $3.01M over three years, corresponding to a cumulative incremental cost saving of $318.11 per member treated per month.Conclusions: In the US, ribociclib plus letrozole represents a cost-saving first-line treatment option for postmenopausal women with HR+/HER2− advanced breast cancer.

ACTIVExtend: 24 Months of Alendronate After 18 Months of Abaloparatide or Placebo for Postmenopausal Osteoporosis.

PurposeIn women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO).MethodsWomen who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only.ResultsFive hundred fifty-eight women from ACTIVE’s ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan–Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group.ConclusionsEighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures.

Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer). The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. clinicaltrials.gov Identifier: NCT01698918.

Denosumab: A Review in Postmenopausal Osteoporosis.

Denosumab (Prolia®; Pralia®) is a human monoclonal antibody targeting the key bone resorption mediator RANKL. The drug is administered via subcutaneous injection once every 6months and is approved for various indications, including the treatment of postmenopausal (PM) women with osteoporosis at increased/high risk of fracture or failure/intolerance of other osteoporosis therapies (indications featured in this review). Denosumab showed benefit in several phase 3 or 4 studies in PM women with osteoporosis or low bone mineral density (BMD), including the pivotal 3-year double-blind FREEDOM trial and its 7-year open-label extension. Denosumab reduced the risk of vertebral, nonvertebral and hip fractures and increased BMD across skeletal sites versus placebo in FREEDOM, with these benefits maintained over up to 10years' therapy in the extension. The drug was also more effective in improving BMD than bisphosphonates, including in women switched from a bisphosphonate regimen, in 1-year trials; however, whether these differences translate into differences in anti-fracture efficacy is unclear. Denosumab was generally well tolerated over up to 10years' treatment, although an increased risk of multiple vertebral fractures was observed after discontinuation of the drug. Thus, denosumab is a key treatment option for PM women with osteoporosis who have an increased/high risk of fracture or failure/intolerance of other osteoporosis therapies, although the potential for multiple vertebral fractures to occur after discontinuation of the drug requires consideration of subsequent management options.