Effectiveness of leuprolide acetate administered monthly compared to three-monthly in the treatment of central precocious puberty: evaluation at the end of treatment.

Introduction: Gonadotropin-releasing hormone (GnRH) analogs are the standard treatment for central precocious puberty (CPP). Although there are numerous varieties of GnRH agonists, the effectiveness of 1-monthly compared with 3-monthly Leuprolide acetate is still restricted. The objective of this study was to evaluate the outcomes of CPP treatment with Leuprolide acetate at a 1-monthly dosage of 3.75 mg, in comparison to a dosage of 11.25 mg administered every 3 months. Method: This retrospective cohort study involved 143 girls diagnosed with CPP with 72 of them receiving the monthly treatment regimen and 71 receiving the 3-monthly treatment regimen. Anthropometric measurements were compared at the start and end of the therapy. The rates and level of LH suppression were assessed six months after therapy. Results: The regimen administered every 3 months showed more significant suppression of LH. The 3-monthly group showed lower actual height and degree of bone age advancement at the end of therapy. However, the predicted adult height (PAH) remained comparable in both groups. Conclusion: The 3-monthly treatment showed greater hormonal and growth suppression effects, but there was no significant difference in PAH between the two groups.

Timing of onset of menses after GnRH agonist treatment for central precocious puberty.

OBJECTIVES: To understand possible predictors of the onset of menses after gonadotropin-releasing hormone agonist treatment cessation in girls with central precocious puberty (CPP). METHODS: This exploratory post hoc analysis of a phase 3 and 4 trial of girls with CPP treated with once-monthly intramuscular leuprolide acetate examined onset of menses after treatment completion using a time-to-event analysis. Pretreatment and end-of-treatment chronologic age (CA), bone age (BA)/CA ratio, and Tanner breast stage; pretreatment menses status; and end-of-treatment BA and body mass index (BMI) were studied as potential factors influencing the onset of menses. RESULTS: Median time to first menses after stopping treatment was 18.3 months among 35 girls (mean age at onset of treatment, 6.8 years) examined. Of 26 girls experiencing menses, 11 (42 %) menstruated at 16-21 months after stopping treatment. Most girls with pretreatment BA/CA≥1.4 started menstruating very close to 18 months after stopping treatment; those with less advanced BA/CA experienced menses at 9-18 months. End-of-treatment BA/CA≥1.2 was associated with a quicker onset of menses (14.5 vs. 18.5 months for BA/CA<1.2, p=0.006). End-of-treatment BA≥12 years predicted longer time to menses. No relationship with time to menses was observed for pretreatment menarche status, pretreatment or end-of-treatment Tanner breast stage (<3/≥3) or CA (<6/≥6 or ≤11/>11), or end-of-treatment BMI percentiles (<85.6/≥85.6 and <92.6/≥92.6). CONCLUSIONS: Pretreatment menarche status or CA do not appear to predict onset of menses, but pre- and end-of-treatment BA/CA may be helpful in anticipating time to first menses after stopping treatment.

Systemic and Tumor-directed Therapy for Oligorecurrent Metastatic Prostate Cancer (SATURN): Primary Endpoint Results from a Phase 2 Clinical Trial.

Nearly all men with metastatic hormone-sensitive prostate cancer treated with intermittent androgen deprivation therapy (ADT) experience recurrence within 6 mo of testosterone recovery. We conducted a single-arm phase 2 trial to evaluate whether addition of dual androgen receptor pathway inhibitors (ARPIs) and metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT improves recurrence rates for men with between one and five nonvisceral, extrapelvic metastases on prostate-specific membrane antigen positron emission tomography/computed tomography after prior radical prostatectomy. Patients received 6 mo of androgen annihilation therapy (AAT; leuprolide, abiraterone acetate plus prednisone, and apalutamide) and metastasis-directed SBRT. The primary endpoint was the percentage of patients with prostate-specific antigen (PSA) <0.05 ng/ml 6 mo after testosterone recovery (≥150 ng/dl), with the study powered to detect an improvement from 1% to 12%. We enrolled 28 men between March 2021 and June 2022. Median follow-up was 20 mo (interquartile range 16-22). Twenty-six patients (93%) completed SBRT with 6 mo of hormone therapy, of whom six discontinued at least one ARPI; two patients withdrew prematurely. At 6 mo after testosterone recovery, PSA was maintained at <0.05 ng/ml in 13/26 patients (50%, 95% confidence interval 32-67%). Rates of grade 2 and 3 AAT toxicity were 21% and 21%. The results confirm that addition of metastasis-directed SBRT to highly potent systemic therapy can maintain low PSA after testosterone recovery, although further studies are needed to clarify the optimal systemic therapy regimen. PATIENT SUMMARY: We tested a combination of intensified hormone therapy (called androgen annihilation therapy) and radiotherapy targeted at metastases in men with recurrence of metastatic prostate cancer. We found that half of patients were recurrence-free 6 months after their testosterone level recovered, and that less than a quarter of patients experienced a severe drug-related side effect. Overall, this appears to be an effective therapy with acceptable side effects. This trial is registered on ClinicalTrials.gov as NCT03902951.

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer.

Importance: Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. Objective: To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. Design, Setting, and Participants: This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Interventions: Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Main Outcomes and Measures: Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Results: Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). Conclusions and Relevance: The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

The effect of antiangiogenic agent aflibercept on surgically induced endometriosis in a rat model.

OBJECTIVE: The aim of the study is to show for the first time how aflibercept affects endometriosis lesions. MATERIAL AND METHODS: Surgically induced endometriosis in Wistar albino female rats. Rats with endometriosis were randomly divided into three groups: control (Co), aflibercept (Af), and leuprolide acetate (Le). Then, Af, aflibercept, and Le received leuprolide acetate. The control group was not treated. The weights and changes in intra-abdominal adhesions of the rats before and after treatment were recorded according to the Blauer adhesion score. Blood extracted for sacrifice was analyzed. Endometriotic lesions were evaluated for size, volume, histology, and immunohistochemistry (vascular endothelial growth factor [VEGF] and CD31). Significance level was accepted as p < 0.05. RESULTS: Aflibercept significantly reduced endometrial implant volume (p = 0.002). The explant epithelial histological score showed a significant difference between aflibercept and leuprolide acetate (p = 0.006) and between aflibercept and control groups (p = 0.002). Aflibercept decreased VEGF-H and CD31 expression (p = 0.001) more than leuprolide acetate. Aflibercept improved adhesions (p = 0.006). CONCLUSION: Aflibercept is more successful than leuprolide acetate in the treatment of endometriosis.

OBJETIVO: Mostrar por primera vez cómo afecta aflibercept a las lesiones de endometriosis. MATERIAL Y MÉTODOS: Endometriosis inducida quirúrgicamente en ratas hembras albinas Wistar. Las ratas con endometriosis se dividieron aleatoriamente en tres grupos: control (Co), aflibercept (Af) y acetato de leuprolida (Le). Luego, Af, aflibercept y Le recibieron acetato de leuprolida. El grupo de control no fue tratado. Los pesos y cambios en las adherencias intraabdominales de las ratas antes y después del tratamiento se registraron de acuerdo con la puntuación de adherencia de Blauer. La sangre extraída para el sacrificio fue analizada. Las lesiones endometriósicas se evaluaron en tamaño, volumen, histología e inmunohistoquímica (factor de crecimiento endotelial vascular [VEGF] y CD31). El nivel de significación se aceptó como p < 0.05. RESULTADOS: Aflibercept redujo significativamente el volumen del implante endometrial (p = 0.002). La puntuación histológica epitelial (EHS) del explante mostró una diferencia significativa entre aflibercept y acetato de leuprolida (p = 0.006) y entre los grupos de aflibercept y control (p = 0.002). Aflibercept disminuyó la expresión de VEGF-H y CD31 (p = 0.001) más que el acetato de leuprolida. Aflibercept mejoró las adherencias (p = 0.006). CONCLUSIÓN: Aflibercept tiene más éxito que el acetato de leuprolide en el tratamiento de la endometriosis.

Postradical prostatectomy prostate-specific antigen outcomes after 6 versus 18 months of perioperative androgen-deprivation therapy in men with localized, unfavorable intermediate-risk or high-risk prostate cancer: Results of part 2 of a randomized phase 2 trial.

BACKGROUND: Patients with localized, unfavorable intermediate-risk and high-risk prostate cancer have an increased risk of relapse after radical prostatectomy (RP). The authors previously reported on part 1 of this phase 2 trial testing neoadjuvant apalutamide, abiraterone, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. The results demonstrated favorable pathologic responses (tumor <5 mm) in 20.3% of patients (n = 24 of 118). Herein, the authors report the results of part 2. METHODS: For part 2, patients were randomized 1:1 to receive either AAPL for 12 months (arm 2A) or observation (arm 2B), stratified by neoadjuvant therapy and pathologic tumor classification. The primary end point was 3-year biochemical progression-free survival. Secondary end points included safety and testosterone recovery (>200 ng/dL). RESULTS: Overall, 82 of 118 patients (69%) enrolled in part 1 were randomized to part 2. A higher proportion of patients who were not randomized to adjuvant therapy had a favorable prostatectomy pathologic response (32.3% in nonrandomized patients compared with 17.1% in randomized patients). In the intent-to-treat analysis, the 3-year biochemical progression-free survival rate was 81% for arm 2A and 72% for arm 2B (hazard ratio, 0.81; 90% confidence interval, 0.43-1.49). Of the randomized patients, 81% had testosterone recovery in the AAPL group compared with 95% in the observation group, with a median time to recovery of <12 months in both arms. CONCLUSIONS: In this study, because 30% of patients declined adjuvant treatment, part B was underpowered to detect differences between arms. Future perioperative studies should be biomarker-directed and include strategies for investigator and patient engagement to ensure compliance with protocol procedures.

Effects of different treatment methods on clinical efficacy and fertility outcomes of patients with adenomyosis.

OBJECTIVE: This trial was to investigate the effect of different treatment methods on the clinical efficacy and fertility outcome of patients with adenomyosis. METHODS: In total, 140 patients with adenomyosis were evenly and randomly allocated into group A (laparoscopic surgery), group B (laparoscopic surgery combined with gonadotropin-releasing hormone analogs [GnRH-a]), group C (ultrasound-guided percutaneous radiofrequency ablation), and group D (ultrasound-guided percutaneous radiofrequency ablation combined with GnRH-a). On the 3rd day after surgery, patients in group B and group D were subcutaneously injected with GnRH-a (Leuprorelin Acetate SR for Injection) at 3.75 mg/time, once every 4 weeks, for a total of 3 months. The therapeutic effects of the 4 groups were compared, including menstrual volume, dysmenorrhea score, uterine volume, clinical efficacy, luteinizing hormone (LH), estradiol (E2), and follicle-stimulating hormone (FSH) levels, CA125 levels, recurrence, pregnancy status, and pregnancy outcomes. RESULTS: After treatment, the menstrual volume of 4 groups was lowered, dysmenorrhea, Visual Analog Scale (VAS) score, LH, FSH, E2, and CA125 levels were reduced, and uterine volume was decreased. The menstrual volume, VAS score, levels of LH, FSH, E2, and CA125, and uterine volume were reduced in groups B, C, and D compared with group A, and the decrease was more significant in group D. The total effective rate of group D was 100.00%, which was higher than that of group A (71.43%), group B (80.00%), and group C (82.86%). After one year of drug withdrawal, the recurrence of hypermenorrhea, dysmenorrhea, uterine enlargement, and excessive CA125 in group D was significantly lower than that in groups A, B and C, and the recurrence in groups B and C was significantly lower than that in group A (P < 0.05). Compared with groups A, B, and C, group D had a higher pregnancy rate, natural pregnancy rate, and lower in vitro fertilization-embryo transfer rate (P < 0.05), but showed no significant difference in pregnancy outcomes. CONCLUSION: Ultrasound-guided percutaneous radiofrequency ablation combined with Leuprorelin Acetate is effective in the treatment of adenomyosis, which can effectively relieve clinical symptoms, protect postoperative ovarian function, reduce recurrence rate, alleviate pain, and improve quality of life.

Longitudinal assessment of auxological parameters, adult height outcome and its determinants in leuprolide-treated Indian girls with idiopathic central precocious puberty.

OBJECTIVES: To assess auxological parameters, adult height outcome and its determinants in Indian girls with idiopathic central precocious puberty (iCPP) treated with gonadotropin-releasing hormone analogues (GnRHa). METHODS: Retrospective study. Inclusion: data on girls with iCPP from initiation to stopping GnRHa (n=179). Exclusion: boys, peripheral, organic central precocity. RESULTS: Mean age of starting GnRHa: 8.2± 1.1 years, duration: 2.8± 1.2 years. 11.7 % had attained menarche at first presentation. The difference between bone (BA) and chronological (CA) ages reduced significantly from 2.6± 0.9 years (onset) to 1.6± 0.8 years (cessation). Weight, BMI Z-scores increased (p<0.01), height Z-scores decreased (0.8 vs. 0.6; p<0.01), predicted adult height (PAH) and Z-scores improved by 3.5 cm, 0.5 SDS following treatment (p<0.01). Overweight/obese girls (vs. normal BMI) were taller, with more advanced BA at starting (height Z-score: 0.7 vs. 1.0, BA-CA: 2.2 vs. 2.9 years), stopping (height Z-score: 0.5 vs. 0.9, BA-CA: 1.4 vs. 1.9 years) treatment, but showed no difference in PAH at starting, stopping treatment. Adult height data (n=58) revealed 1.9 cm gain above target height. Adult height Z-scores significantly exceeded target height Z-scores (p<0.01). Mean adult height (157.1± 5.8 cm) crossed PAH at starting treatment (155.9± 6.4 cm) but remained 1.6 cm lesser than PAH at cessation. Adult weight, BMI Z-scores (-0.2± 1.3, -0.1± 1.2) were significantly lower (p<0.01) than those at stopping GnRHa. Height gain adjusted for age at starting GnRHa correlated negatively with height, weight, BMI, Tanner-staging, BA, FSH, Estradiol at treatment onset, BA at cessation, and correlated positively with treatment duration. CONCLUSIONS: GnRHa treatment in Indian girls with iCPP resulted in improved PAH, decelerated bone age advancement and growth velocity. Most girls achieved adult height within target range, surpassing PAH at treatment initiation. Lesser anthropometric, sexual, skeletal maturity, lower baseline FSH, estradiol, longer treatment duration, less advanced BA at stopping GnRHa may translate into better adult height outcomes.

The multifactorial aetiology and management of premenstrual dysphoric disorder with leuprorelin acetate.

Up to 18% of women of reproductive age may experience symptoms during the luteal phase of the menstrual cycle known as premenstrual syndrome (PMS) or its more severe form, premenstrual dysphoric disorder (PMDD). A plethora of symptoms have been described, but both are commonly associated with other mood-related disorders such as major depression causing significant life impairment. Originally known as late luteal phase dysphoric disorder in the DSM-III-R (American Psychiatric Association 1987), the syndrome was renamed PMDD in the DSM-IV (American Psychiatric Association 1994). Between 3% and 8% of women meet the diagnostic criteria for PMDD. Currently, there is no consensus on its aetiology although it is thought to be multifactorial. Biological, genetic, psychological, environmental and social factors have all been suggested. However, an altered sensitivity to the normal hormonal fluctuations that influence functioning of the central nervous system is thought most likely. PMDD is identified in the DSM-5 by the presence of at least five symptoms accompanied by significant psychosocial or functional impairment. During evaluation, it is recommended that clinicians confirm symptoms by prospective patient mood charting for at least two menstrual cycles. Management options include psychotropic agents, ovulation suppression and dietary modification. Selective serotonin reuptake inhibitors (SSRIs) are considered primary therapy for psychological symptoms. Ovulation suppression is another option with the combined oral contraceptive pill (COCP) or GnRH (gonadotropin-releasing hormone) agonists. Rarely symptoms warrant a bilateral oophorectomy and a 6-month trial of GnRH agonists prior to surgery may be prudent to determine its potential efficacy. The authors present the case of a multiparous woman in her mid-30s experiencing severe symptoms during the luteal phase of her menstrual cycle. A trial of the contraceptive pill and SSRIs were unsuccessful. Treatment with leuprorelin acetate (Prostap) improved her symptoms. She therefore elected to undergo a bilateral oophorectomy with resolution of her symptoms. She started hormone replacement therapy (HRT). This case demonstrates the multifactorial aetiology of PMDD and the challenges in its management. Women with PMDD suffer functional impairments comparable with other depressive disorders and yet PMDD and its impact remain under-recognised. As the psychological nature and consequences of PMDD often seem indistinguishable from symptoms of other mental health difficulties, this condition presents distinct diagnostic challenges for healthcare professionals. It is crucial to establish the correct diagnosis using clearly defined criteria because if it is left untreated, it can cause considerable impairment to the woman's quality of life.

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown. METHODS: In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety. RESULTS: A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures. CONCLUSIONS: In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.).

Puberty Suppression Followed by Testosterone Therapy Does Not Impair Reproductive Potential in Female Mice.

More adolescents are coming out as transgender each year and are put on puberty blockers to suppress natal puberty, which is then followed by cross-hormone treatment to achieve puberty of the desired gender. Studies to examine the effects of puberty suppression and virilizing therapy on future reproductive potential among transgender males are lacking. This study used a translational murine in vitro fertilization model to examine the effects of female puberty suppression with depot leuprolide acetate (LA), followed by virilizing therapy with testosterone cypionate (T), on embryologic and pregnancy outcomes. LA effectively inhibited puberty when mice were treated beginning at 3 weeks of age. LA treatment was associated with higher mouse weight but lower ovarian weight. LA-treated mice ovulated developmentally competent eggs in response to gonadotropin administration, albeit at a higher dose than controls. Ovaries from mice treated with LA and T produced oocytes that had morphologically normal meiotic spindles after in vitro maturation and responded to gonadotropin stimulation. Eggs from mice treated with LA and T were fertilizable and produced developmentally competent embryos that led to births of fertile pups. These results suggest that fertility may not be impaired after puberty suppression and cross-hormone therapy for transgender males.

Efficacy and safety of different subsequent therapies after fertility preserving surgery for endometriosis: A systematic review and network meta-analysis.

BACKGROUND: Endometriosis (EMT) is a benign and common estrogen-dependent disease. Hormonal therapy improves pain symptoms in most women with EMT. However, in many cases, laparoscopic fertility preservation surgery is considered a common treatment for EMT. The present study aimed to evaluate the efficacy and safety of dienogest, leuprolide, danazol, gestrinone, mifepristone and levonorgestrel intrauterine system (LNG-IUS) in relieving symptoms and delaying the recurrence of EMT cysts after fertility protection surgery. METHODS: We searched PubMed, the Cochrane Library, Web of Science, EMBase, China National Knowledge Infrastructure, VIP Database, China Biology Medicine disc, WanFang Data databases to collect randomized controlled trials (RCT) related to dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS as a follow-up treatment after fertility preserving surgery for EMT. After literature screening, data extraction and quality evaluation, effective rate, recurrence rate, pregnancy rate and adverse reaction rate were used as outcome indicators to evaluate the efficacy and safety of drugs. Evidence networks included in the study were drawn and publication bias was assessed. The drugs most likely to be the best postoperative treatment were explored through mixed comparison of different drugs and efficacy ranking. RESULT: Effective rate: dienogest, leprerelin, gestrinone and LNG-IUS were better than placebo after EMT fertility preservation surgery; dienogest was superior to mifepristone and danazol. LNG-IUS is superior to danazol. LNG-IUS has the highest potential for improving the effectiveness of EMT symptoms. Recurrence rate: the application of dienogest, leuprolide, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was lower than that of placebo; dienogest and LNG-IUS were lower than danazol. The recurrence rate of dinorgestrel was the last place with the highest performance. Pregnancy rate: in the cases with fertility requirements, dienogest and,leuprolide were better than placebo after EMT fertility preservation surgery; dienogest was superior to danazol, gestrinone and mifepristone. Leuprolide is superior to danazol and gestrinone. The first rank of dienogest pregnancy rate was the highest. Adverse reaction rate: the application of dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was higher than that of placebo. After placebo, LNG-IUS had the highest adverse reaction rate. CONCLUSION: For patients after fertility preserving surgery for EMT, the recurrence rate of dienogest was the last place with highest preference. The first rank of dienogest pregnancy was the highest.

Effect of Leuprolide Acetate, a GnRH Agonist, on Neuroinflammation and Anxiety-Like Behavior after Mild Hypoxic-Ischemic Encephalopathy in Rat Model.

BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is a condition that predisposes to negative outcomes such as neuroanatomical injury, mood disorders, and motor or cognitive disabilities. The neuroinflammation plays an important role in the neurological damage; therefore, reducing it could provide neuroprotection. The leuprolide acetate (LA) has shown to have neuroregenerative and immunomodulator properties in other nervous system injuries. OBJECTIVE: The aim of this study was to evaluate the immunomodulatory effect of LA in the acute phase of mild HIE and its effects in motor activity and behavior in a subacute phase. METHOD: Forty-five Wistar rats on postnatal day 7 were divided into Sham, HIE treated with saline solution (HIE-SS), and HIE-LA. The HIE was performed cutting of the right carotid artery followed by 60 min of hypoxia. The expression of the inflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and the chemokine CXCL-1 were evaluated 72 h after HIE by RT-qPCR and the motor activity and behavior were evaluated by open field test at postnatal day 33. RESULTS: HIE-SS animals showed increased expression of IL-1ß, TNF-α, IFN-γ, and CXCL-1 genes in injured tissue. However, the HIE-LA group exhibited similar expression levels of IL-1ß and TNF-α to the Sham group, while IFN-γ and CXCL-1 mRNA expression were attenuated with LA treatment. LA treatment also prevented anxiety-like behavior in the open field test. CONCLUSION: Treatment with LA partially reverses HIE-induced neuroinflammation and prevents anxiety-like behavior in neonatal rats.

Trastuzumab, leuprorelin, letrozole, and palbociclib as first-line therapy in HER2-positive and hormone receptor-positive metastatic breast cancer: A case report.

RATIONALE: Cyclin-dependent kinase 4/6 inhibitors are promising candidates for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, current international guidelines recommend endocrine therapy alone or with HER2-targeted therapy to treat HER2-positive and hormone receptor (HR)-positive metastatic breast cancer in patients who cannot tolerate first-line chemotherapy. Moreover, data on the effectiveness and safety of cyclin-dependent kinase 4/6 inhibitors combined with trastuzumab and endocrine therapy as a first-line treatment for HER2-positive and HR-positive metastatic breast cancer are limited. PATIENT CONCERNS: A 50-year-old premenopausal woman was with epigastric pain for more than 20 days. Ten years ago, she was diagnosed with left breast cancer and underwent surgical treatment, chemotherapy, and endocrine therapy. DIAGNOSES: After relevant examination, the patient was diagnosed with liver, lung, and left cervical lymph node metastatic HER2-positive and HR-positive carcinoma from the left breast after systemic therapy. INTERVENTIONS: The laboratory investigations showed that the patient's liver function was seriously damaged due to the liver metastases, and the patient was assessed as unable to tolerate chemotherapy. She was treated with trastuzumab, leuprorelin, letrozole, and piperacillin combined with percutaneous transhepatic cholangic drainage. OUTCOMES: The patient's symptoms were relieved, her liver function returned to normal, and the tumor showed partial response. Neutropenia (Grade 3) and thrombocytopenia (Grade 2) occurred during treatment but improved after symptomatic treatment. To date, the progression-free survival of the patient is over 14 months. LESSONS: We believe that trastuzumab, leuprorelin, letrozole, and palbociclib is a feasible and effective treatment for HER2-positive and HR-positive metastatic breast cancer in premenopausal patients who cannot tolerate first-line chemotherapy.

LBA02-09 EMBARK: A Phase 3 Randomized Study of Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in High-risk Biochemically Recurrent Prostate Cancer.

Volume 209, Supplement 4, Page e1190: The abstract text is as given below. This erratum also includes the additional disclosure, conflict of interest, and acknowledgments that were not included in the original publication. The online and PDF versions of the article have been updated. INTRODUCTION AND OBJECTIVE: Within 10 years following definitive therapy for prostate cancer, ∼20-50% of patients (pts) experience biochemical recurrence (BCR) characterized by rising prostate-specific antigen (PSA) levels. Pts with high-risk BCR have an increased risk of mortality and improved therapies are needed. The objective of EMBARK was to evaluate the efficacy and safety of enzalutamide (enza) + androgen deprivation therapy (ADT) and enza monotherapy (mono) in pts with high-risk BCR. METHODS: EMBARK is a randomized, phase 3 study of pts with BCR considered high-risk: PSA doubling time ≤9 months and PSA ≥2 ng/mL above nadir post-radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) ± postoperative RT. Pts were randomized (1:1:1) to enza 160 mg/day + leuprolide acetate (LA) (double-blind), placebo (pbo) + LA (double-blind), or enza mono (open-label). LA 22.5 mg was administered every 12 weeks. If the PSA at week 36 was <0.2 ng/mL, therapy was stopped at week 37 and restarted when PSA was ≥2 ng/mL for pts with primary RP, and ≥5 ng/mL for pts without RP. The primary endpoint, determined by blinded, independent central review (BICR), was metastasis-free survival (MFS) with enza + LA vs pbo + LA. Key secondary endpoints were MFS of enza mono vs pbo + LA, time to PSA progression, time to antineoplastic therapy, and overall survival (OS) of enza + LA or enza mono vs pbo + LA. RESULTS: 1068 pts were randomized into the study (enza + LA, n=355; pbo + LA, n=358; enza mono, n=355). After median follow-up of 60.7 months, per BICR, MFS for enza + LA (HR 0.42; 95% CI 0.30-0.61; p<0.0001) and enza mono (HR 0.63; 95% CI 0.46-0.87; p=0.0049) were statistically superior to pbo + LA. Statistically significant improvements were also observed in risk of PSA progression (enza + LA: HR 0.07; 95% CI, 0.03-0.14; enza mono: HR 0.33; 95% CI, 0.23-0.49; both p<0.0001) and time to first use of new antineoplastic therapy (enza + LA: HR 0.36; 95% CI, 0.26-0.49; enza mono: HR 0.54; 95% CI, 0.41-0.71; both p<0.0001). Interim OS data trended in favor enza + LA (HR 0.59; 95% CI, 0.38-0.91; p=0.0153, did not cross interim efficacy boundary) and enza mono (HR 0.78; 95% CI, 0.52-1.17; p=0.2304). Fatigue and hot flash were the most common adverse events; no new safety signals were observed. CONCLUSIONS: In pts with high-risk BCR, enza + ADT and enza mono demonstrated a statistically significant and clinically meaningful improvement in MFS vs pbo + ADT. The safety profile of enza was consistent with results from previous clinical studies. CLINICAL TRIAL REGISTRATION NUMBER: NCT02319837. SOURCE OF FUNDING: Pfizer Inc. and Astellas Pharma Inc.Conflict of Interest and Disclosure Statement:Neal D. Shore reports grant support and consulting fees from AbbVie, Amgen, Astellas Pharma Inc., AstraZeneca, Bayer, Clovis Oncology, Dendreon Pharmaceuticals LLC, Ferring Pharmaceuticals, GenesisCare, Janssen Oncology, Merck, Myovant Sciences, Pfizer Inc., Sanofi-Genzyme, and Tolmar Pharmaceuticals, Inc. Murilo de Almeida Luz reports receiving speaker honoraria from Astellas Pharma Inc., Bayer, Janssen, Merck Sharp & Dohme, and Pfizer Inc.; being an advisory board member for Astellas Pharma Inc., Bayer, and Janssen; sponsored research from Bayer, Bristol Myers Squibb, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen, and Roche; receiving travel expenses from AstraZeneca, Bayer, Janssen, and Pfizer Inc. Ugo De Giorgi reports serving as a consultant for Janssen, Astellas Pharma Inc., Sanofi, Bayer, Pfizer Inc., Bristol Myers Squibb, Novartis, Ipsen, and Merck Sharp & Dohme. Martin Gleave reports stock or ownership interest in OncoGenex Technologies Inc., Sustained Therapeutics Inc., and Sikta Biopharma; is a consultant to Astellas Pharma Inc., AstraZeneca, Bayer, Genova Diagnostics (GDx), Janssen, Pfizer Inc., Roche, Sanofi, and TerSera Therapeutics LLC; and holds patents for OGX-011, OGX-427, ST-CP, and ST-POP. Geoffrey T. Gotto reports receiving honoraria from Amgen, Astellas Pharma Inc., Bayer, Ferring Pharmaceuticals, Janssen, and Merck; being a consultant or advisory board member for Amgen, Astellas Pharma Inc., Bayer, Janssen, and Merck; providing expert testimony for Janssen; and receiving support for travel, accommodation, and expenses from Janssen. Gabriel P. Haas reports being an employee of and shareholder in Astellas Pharma Inc. Miguel Ramirez-Backhaus reports serving as a consultant or advisory board member for Astellas Pharma Inc., Bayer, Janssen, and Karl Storz; receiving speaker honoraria from Astellas Pharma Inc., Bayer, Janssen, and GP Pharm. Antti Rannikko reports being a board member for the Ida Montin Foundation, and Orion Research Foundation; being an advisory board member for Bayer, Janssen, and Orion Pharma; being a stockholder and clinical advisor for Aqsens Health; being a clinical investigator for Astellas Pharma Inc., Bayer, Janssen, Orion Pharma, and RhoVac AB; and receiving competitive state research funding from HUS Helsinki University Hospital, Finnish Cancer Organizations, and the Jane and Aatos Erkko Foundation. Jamal Tazari, Yiyun Tang, and Fabian Zohren are employees of and shareholders in Pfizer Inc. Swetha Sridharan reports no conflicts of interest. Jennifer Sugg is an employee of Astellas Pharma Inc., and a shareholder in AstraZeneca. Ronald F. Tutrone, Jr. reports being an advisory board member for Bayer; and receiving speaker honoraria from Astellas Pharma Inc., Exosome Diagnostics, Inc., Myovant Sciences, and Pfizer Inc. Balaji Venugopal reports receiving honoraria from Bristol Myers Squibb, Eisai Co., Ltd, EUSA Pharma, Ipsen, Janssen, and Merck; being a consultant or advisory board member for Janssen, Merck Sharp & Dohme Oncology, and Pfizer Inc./EMD Serono; and receiving support for travel, accommodation, and expenses from EUSA Pharma, and Ipsen. Arnauld Villers reports receiving research grants from Astellas Pharma Inc., Ferring Pharmaceuticals, Ipsen, and Janssen. Henry H. Woo reports being an advisory board member for Astellas Pharma Inc., Bayer, Boston Scientific Corporation, and Mundipharma International Ltd; and reports receiving speaker honoraria from AbbVie, Astellas Pharma Inc., Boston Scientific Corporation, and Janssen. Stephen J. Freedland reports being a consultant for Astellas Pharma Inc., AstraZeneca, Bayer, Dendreon Pharmaceuticals LLC, Janssen, Merck, Myovant Sciences, Pfizer Inc., and Sanofi. ACKNOWLEDGMENTS: The authors thank all the patients, their families, and the investigators and investigational site members involved in this study.Editorial Acknowledgement:Medical writing and editorial support was provided by Julie B. Stimmel, PhD, Sinead Stewart, and Rosie Henderson, of Onyx (a Prime Global Agency), funded by Pfizer, Inc. and Astellas Pharma Inc., the co-developers of enzalutamide.Submission Category:prostate cancer.Sub-category:Advanced (including drug therapy).

A Clinically-Achievable Injectable and Sprayable in Situ Lyotropic Liquid Crystalline Platform in Treating Hormone-Sensitive and Castration-Resistant Prostate Cancer.

When it comes to long-acting injections, lyotropic liquid crystals (LLCs) are considered as an effective and powerful drug delivery technology due to their low manufacturing and injection difficulty, consistent releasing behaviors with low burst, as well as broadly applicable drug loading capacity. However, monoolein and phytantriol, as two widely used LLC-forming materials, may give rise to tissue cytotoxicity and undesired immunological responses, which may hinder the wide application of this technology. In this study, we opted for two ingredients, phosphatidylcholine and α-tocopherol, as carriers on account of their nature-obtainable and biocompatible qualities. By changing the ratios between them, we conducted research on crystalline types, nanosized structures, viscoelastic differences, characteristics of releasing behaviors, and in vivo safety. To fully exploit this in situ LLC platform with both injectability and sprayability, we focused on the treatment of both hormone-sensitive (HSPC) and castration-resistant prostate cancer (CRPC). For HSPC, we found that spraying leuprolide and a cabazitaxel-loaded LLC platform on the tumor bed after resection greatly reduced tumor metastatic rate and prolonged the survival time. Besides, for CRPC, our results demonstrated that although leuprolide (a kind of drug for castration) alone could hardly limit the progression of CRPC with low MHC-I expression, its combination with cabazitaxel in our LLC platform achieved a significantly better tumor-inhibiting and anti-recurrent efficacy than single cabazitaxel-loaded LLC platform, owing to enhanced CD4+ T cell infiltration in tumors and immune-potentiating cytokines. In conclusion, our dual-functional and clinically achievable strategy might provide a treating solution toward both HSPC and CRPC.

Clinical outcomes of leuprolide acetate in the treatment of recurrent ovarian granulosa cell tumors.

BACKGROUND: The optimal treatment of recurrent ovarian granulosa cell tumors is not known. Preclinical studies and small case series have suggested direct antitumor activity of gonadotropin-releasing hormone agonists in the treatment of this disease, but little is known about the efficacy and safety of this approach. OBJECTIVE: This study aimed to describe patterns of use and clinical outcomes of leuprolide acetate in a cohort of patients with recurrent granulosa cell tumors. STUDY DESIGN: This was a retrospective cohort study of patients enrolled in the Rare Gynecologic Malignancy Registry at a large cancer referral center and affiliated county hospital. Patients meeting inclusion criteria had a diagnosis of recurrent granulosa cell tumor and received either leuprolide acetate or traditional chemotherapy as cancer treatment. Outcomes were separately examined for leuprolide acetate used as adjuvant treatment, maintenance therapy, and the treatment of gross disease. Demographic and clinical data were summarized using descriptive statistics. Progression-free survival was calculated from the initiation of treatment to the date of disease progression or death, and compared between groups with the log-rank test. The 6-month clinical benefit rate was defined as the percentage of patients without disease progression 6 months after starting therapy. RESULTS: Sixty-two patients received a total of 78 leuprolide acetate-containing therapy courses, owing to 16 instances of retreatment. Of these 78 courses, 57 (73%) were for treatment of gross disease, 10 (13%) were adjuvant to tumor reductive surgery, and 11 (14%) were for maintenance therapy. Patients had received a median of 2 (interquartile range, 1-3) systemic therapy regimens before their first leuprolide acetate treatment. Tumor reductive surgery (100% [62/62]) and platinum-based chemotherapy (81% [50/62]) were common before first leuprolide acetate exposure. The median duration of leuprolide acetate therapy was 9.6 months (interquartile range, 4.8-16.5). Nearly half of the therapy courses were single-agent leuprolide acetate (49% [38/78]). Combination regimens most often included an aromatase inhibitor (23% [18/78]). Disease progression was the most common cause of discontinuation (77% [60/78]); only 1 patient (1%) discontinued leuprolide acetate because of adverse events. In the treatment of gross disease, the 6-month clinical benefit rate for first use of leuprolide acetate was 66% (95% confidence interval, 54-82). Median progression-free survival was not statistically different compared with that which followed chemotherapy (10.3 months [95% confidence interval, 8.0-16.0] vs 8.0 months [95% confidence interval, 5.0-15.3]; P=.3). CONCLUSION: In a large cohort of patients with recurrent granulosa cell tumors, the 6-month clinical benefit rate of first-time leuprolide acetate treatment of gross disease was 66% and progression-free survival was comparable to patients treated with chemotherapy. Leuprolide acetate regimens were heterogeneous, but significant toxicity was rare. These results support leuprolide acetate as safe and effective for the treatment of relapsed adult granulosa cell tumors in the second line and beyond.

Leuprolide Protects Ovarian Reserve in Adolescents Undergoing Gonadotoxic Therapy.

Purpose: Treatment sequelae compromising reproductive health are highly prevalent in childhood cancer survivors, and a main determinant of health and quality of life. Follicular reserve determines ovarian function life span; thus, its preservation is important in the care of female survivors. Anti-Müllerian hormone (AMH) is a biomarker to measure functional ovarian reserve. We aimed to evaluate the effect of leuprolide during gonadotoxic therapy on pubertal females' post-treatment functional ovarian reserve using AMH levels. Methods: We conducted a single-center retrospective study including all pubertal females who had undergone gonadotoxic treatments between January 2010 and April 2020, and had an AMH level after completion of therapy. We used multivariable linear regressions to compare AMH-level beta coefficients in patients stratified by gonadotoxic risk, adjusting for leuprolide use. Results: Fifty-two females meeting study eligibility were included, of which 35 received leuprolide. The use of leuprolide was associated with higher post-treatment AMH levels in the lower gonadotoxic risk group (beta 2.74, 95% CI 0.97-4.51; p = 0.004). This association was lost in the higher gonadotoxic risk groups. Conclusions: Leuprolide may have a protective effect on the functional ovarian reserve. However, this is limited by increasing treatment gonadotoxicity. Larger, prospective studies are needed to elucidate the potential benefits of gonadotropin-releasing hormone agonist on preservation of ovarian reserve among children receiving gonadotoxic therapies, as cancer survivors.