GnRH Research Articles

Lutetium-177-PSMA-617 radioligand therapy in patients with high volume metastatic prostate cancer prior to chemotherapy and new generation androgen deprivation therapy: Clinical Experience.

We aimed to evaluate the efficacy oflutetium-177-prostate-specific membrane antigen-617 (177Lu-PSMA-617) with the luteinizing hormone releasing hormone (LHRH) analogues in the first or in the second-line setting formetastatic castration sensitive patients and metastatic castration resistance after progression with LHRH analogues. Sixteen consecutive patients with high volume metastatic prostate cancer undergone 177Lu-PSMA-617 therapy who were refused chemotherapy and were unable to use new generation anti-androgen drugs because of unavailibility of reimbursement, were included in this retrospective study. Prostate specific antigen (PSA) response (>50% decrease), disease control rate (DCR: complete or partial response), progression-free survival (PFS) and overall survival (OS) were calculated to evaluate according to the clinicopathological features of the patients. Treatment response evaluated by 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT). Mean age was 74,6 (SD±8,36). Among them, 7 (43,8%) patients has castration resistant disease, while the remaining has castration sensitive disease. Lutetium-177-PSMA-617 was administered to 10 (62,5%) patients as one of the first-line treatment and 6 patients received the treatment after progression on LHRH as a second-line treatment. Considering all patients, PSA response rate and DCR were 50% and 62% respectively. The median PFS and OS (with 95% CI) were 11,2 months (11-15) and 29 months (25,6-32,4), respectively in patients treated with 177Lu-PSMA-617 and LHRH analogues. Clinicopathological features and basal PSA level did not have effect on PSA response rates, DCR, OS and PFS. On the other hand, increment in PFS and OS (with 95% CI) was observed in castration resistant disease and in the second-line therapy; for castration resistant disease 16,5 months (12.3-19.7); 30 months (25.3-32.7), for the second-line therapy 14.5 months (12-20.5); 29 months (NR), respectively but statistically not significant. Serious toxicity was observed in a limited number of patients (18,7%), treatment-related death was not observed. Favorable results can be achived with second-line 177Lu-PSMA-617 treatment in terms of OS and PFS, especially in castration-resistant disease, when chemotherapy and new generation ADT's cannot be used.

Triptorelin Peptide Conjugated Alginate Coated Gold Nanoparticles as A New Contrast Media for Targeted Computed Tomography Imaging of Cancer Cells.

Increasing research has been focused on the development of various nanocomplexes as targeted contrast media in diagnostic modalities, mainly in computed tomography (CT) scan imaging. Herein, we report a new method that uses Triptorelin [a luteinizing hormone-releasing hormone (LHRH) agonist]-targeted gold nanoparticles (AuNPs) via alginate for early detection of cancer by molecular CT imaging. In the experimental study, the formed multifunctional AuNPs coated with alginate conjugated with Triptorelin peptide (Triptorelin-Alginate-AuNPs) were synthesized and characterized via different techniques, including transmission electron microscopy (TEM), dynamic light scattering (DLS), and fourier transform infrared (FTIR) spectroscopy. The MTT assay was applied to calculate the toxicity of the NPs. The results indicated that the formed Triptorelin-Alginate-AuNPs with an Au core size of ~18 nm are noncytotoxic at 127-, 254-, 381- and 508-mM concentrations and revealed significant improvement in the attenuation of X-rays intensity and contrast to noise ratio (CNR), compared with non-targeted cells at the highest energies (90, 120, 140 kVp). At 90 kVp, compared to non-targeted cells, targeted cells (Triptorelin-Alginate-AuNPs) enable 1.58, 1.69, 3.7 and 3.43 times greater contrast at a concentration of 127 mM, 254 mM, 381 mM, and 508 mM, respectively. These results suggest that the developed Triptorelin-Alginate-AuNPs may be considered an effective contrast agent for molecular CT imaging of gonadotropin-releasing hormone (GnRH) receptor-expressing cancer cells.

Targeted silencing of the MCL-1 gene using multi-layered dendrimer-based nanoconstructs achieves efficient tumor regression in xenografted mice models

The setback in the practical clinical use of RNA interference (RNAi)-based cancer treatment stems from the lack of targeted small interfering RNA (siRNA) delivery. Here, we show that luteinizing hormone-releasing hormone(LHRH) analog-tethered multi-layered polyamidoamine (PAMAM) nanoconstructs silence the anti-apoptotic MCL-1 gene in LHRH receptor overexpressing human breast (MCF-7) and prostate cancer (LNCaP) cells with 70.91 % and 74.10 % efficiency, respectively. These results were confirmed by RT-PCR. The Acridine orange/Ethidium bromide (AO/EB) dual staining revealed that the silencing of MCL-1 induced apoptosis in both the cell lines. In vivo tumor regression studies performed using MCF-7 and LNCaP xenografted severe combined immunodeficiency(SCID) mice demonstrated highly improved tumor regression in groups treated with targeted nanoconstructs complexed with MCL-1 siRNA (T + siMCL-1) compared to the other treatment groups. The quantitative RT-PCR results of tumor tissues demonstrated significant MCL-1 gene silencing, i.e., 73.76 % and 92.63 % in breast and prostate tumors, respectively, after T + siMCL-1 treatment. Reduction in MCL-1 protein expression as assessed by immunohistochemistry further confirmed these results. Furthermore, the caspase 3/7 assay demonstrated apoptosis in the MCL-1 silenced tissues. The study strongly suggests that targeted delivery of siRNAs using multi-layered dendrimer nanostructures could be an effective therapy for LHRH overexpressing cancers.

Pre-And post-Androgen deprivation lipid profiles of men with prostate cancer A multi-center study

Introduction: Dyslipidemia is the primary cause of hospitalization and death in men with advanced prostate cancer. Our goal was to examine how androgen deprivation therapy (ADT) affects lipid profiles in Indian men with locally progressed or metastatic prostate cancer. Methods: this multi center study was conducted in LRH urology department From jan 2020 to jan 2021 Patients with prostate cancer who received ADT and for whom lipid account data from the first two years of ADT treatment was available were split into two groups for retrospective analysis. Members of Group A had bilateral orchidectomy, whereas those in Group B were given a luteinizing hormone-releasing hormone agonist (LHRHa). The information considered are quality standards, prostate-specific antigen (PSA), and lipid profiles. Results: 69 eligible patients were divided evenly between teams A (29) and B (40). After starting ADT, the median blood PSA level dropped significantly in both groups and remained low until 24 months. At six months, there was a statistically insignificant decline in all lipid profile parameters in team A patients except for high-density lipoprotein cholesterol.

Prognostic significance of nadir PSA value and time to nadir PSA in patients with metastatic castration-naive prostate cancer receiving first-line hormonotherapy.

The current study aimed to evaluate the effect of the time duration to reach the lowest prostate-specific antigen (PSA) from the onset of first-line hormonal treatment (time to nadir PSA, TTNpsa) on survival in castration-naive metastatic prostate cancer (CN-MPC) patients. Eighty patients who had PSA response >80% with first-line hormonal therapy (luteinizing hormone-releasing hormone, LH-RH analog +/- bicalutamide) were included in this study. Under androgen deprivation therapy (ADT), a significant positive correlation was found between TTNpsa, nadir PSA (Npsa) duration, and progression-free survival (PFS) ( p < 0.001) and overall survival (OS) ( p < 0.001). There was no correlation between TTNpsa and Npsa duration. TTNpsa and Npsa durations were independently correlated with PFS and OS. In patients with TTNpsa value ≥19 weeks, the median PFS was 126 (95% CI, 68-184) weeks compared with TTNpsa <19-week group in which the median PFS was 44 (95% CI, 26-62) weeks ( p = 0.033). In patients with TTNpsa value ≥19 weeks, the median OS was 242 (95% CI, 169-315) weeks compared with TTNpsa <19-week group in which the OS was 156 (95% CI, 89-223) weeks ( p = 0.018). The median nadir PSA value was 1 ng/mL. The median PFS was significantly longer in the patient group with ≤1 ng/mL (137 weeks, 95% CI, 50-224) compared with the group with >1 ng/mL (41 weeks, 95% CI, 34-48) ( p < 0.001). The median OS was significantly longer in the patient group with nadir PSA ≤1 ng/mL (296 weeks, 95% CI, 220-272) compared to the group with >1 ng/mL (131 weeks, 95% CI, 84-178) ( p = 0.002). In patients with nadir PSA ≤1 ng/mL ( n = 40), there was no relationship between TTNpsa and Npsa duration with both PFS and OS. However, in patients with nadir PSA >1 ng/mL ( n = 40) subgroup, there was a significant positive correlation between TTNpsa and PFS, and OS ( p < 0.001, P = 0.016, respectively). In CN-MPC who received first-line ADT, especially in the group with the nadir PSA value >1 ng/mL, the duration of TTNpsa was positively correlated with PFS and OS.

ROHHAD Syndrome – Focus on Endocrine Abnormalities and Precocious Puberty

Background: ROHHAD (rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation) syndrome is a rare disease, with around 200 cases described worldwide. Other clinical manifestations may be pulmonary hypertension, cough, recurrent upper respiratory tract infections, metabolic disorders. Objective: The aim of this article was to present a case of ROHHAD syndrome, a very rare disorder with multisystemic involvement and an unknown etiology. Case report: We present the case of an 11-year-old girl with ROHHAD syndrome. The disease was diagnosed at the age of 3.5 years when she was hospitalized due to obesity, adynamia, hyponatremia, and a convulsion. An electroencephalogram (EEG) recording showed epileptic brain activity, and antiepileptic therapy was initiated. Diagnostic tests revealed the presence of a tumor mass in the abdomen, which was surgically removed. Histopathology confirmed malignant ganglioneuroblastoma. The girl received chemotherapy according to the protocol. Genetic analysis of the patient showed no genetic predisposition to the onset of the disease. At the age of 8.5, she was hospitalized again due to vaginal bleeding. Endocrinological evaluation revealed precocious puberty, absolute growth hormone deficiency (although growth was at the 25th percentile), and hypothyroidism. Growth hormone, luteinizing hormone-releasing hormone (LH-RH) analogue, and Levothyroxine were included in therapy. The precocious puberty episodes have been stopped, and she no longer receives LH-RH analog. Levothyroxine, growth hormone, and antiepileptic drugs are continued in the therapy. The girl has no cognitive disorders, achieves good results in school, and her current growth chart values are within the reference values for her age. Conclusion: ROHHAD syndrome is a rare disease, with around 200 cases described worldwide. The disease can lead to severe complications, including intellectual impairment and death. The diagnosis is made on the basis of clinical manifestations, and the therapy requires a multidisciplinary approach.

A Simple and Efficient Method for Generating KO Rats Using In Vitro Fertilized Oocytes.

The development of ZFN, TALEN, and CRISPR/Cas9 systems has simplified the process of generating knockout (KO) and knock-in (KI) rats in addition to mice. However, in rats, an efficient genome editing technique that uses in vitro fertilized oocytes has not been established. Recently, we reported the stable generation of offspring from five standard strains of rats by superovulation and in vitro fertilization (IVF). Furthermore, genome-edited rats can be easily generated by electroporation. First, juvenile female rats are administered LHRH (luteinizing hormone-releasing hormone) to synchronize the estrous cycle and then AIS (Automatic Identification System) with PMSG (pregnant mare serum gonadotropin) before hCG (human chorionic gonadotropin) for superovulation. Sperm collected from a sexually mature male rat the following morning is then pre-cultured. Cumulus cell-oocyte complexes (COCs) are collected from female rats under anesthesia, and COCs are induced into a medium containing concentration-adjusted sperm. Thereafter, oocytes with two pronucleus are selected as fertilized oocytes. Next, fertilized oocytes are transferred into a glass chamber containing CRISPR ribonucleoprotein (RNP) complexes formed from gRNA and Cas9 protein. After electroporation, fertilized oocytes are then immediately transferred to culture medium. The next day, embryos are transferred into the oviduct of pseudopregnant female rats. Using the above method, offspring can be obtained 22days after the day of embryo transfer. In this paper, we outline a method allowing simple and efficient generation of genetically modified rats without the need for technically difficult micromanipulation techniques.

Hormonal Therapies in Cancers.

The hormonal therapy for cancer has become a household name and the series of experiments performed leading to the discovery of hormones use in the treatments of breast cancer. The hormones like antiestrogen, aromatase restrictors, antiandrogens, and use of extremely strong luteinizing hormone-releasing hormone agonists to perform a "medical hypophysectomy" because of their ability of causing desensitization in the pituitary gland have proven their value in the treatment of cancers over the last two decades. Millions of women still use hormonal therapy for menopause symptoms. Estrogen plus progestin or estrogen separately utilized as a menopause hormonal therapy throughout the world. Women receiving different premenopausal and postmenopausal hormonal therapies are on higher risk of having ovarian cancer. The risk of ovarian cancer did not increase with the increase of duration of hormonal therapy. Postmenopausal hormone use was found to be inversely related to major colorectal adenomas.

Effect of different schemes of androgen deprivation therapy on bone mass density in prostate cancer patients

ObjectivesTo evaluate aspects of the basal bone health status in prostate cancer patients. Furthermore, to evaluate in a real-world setting the effect of different schemes (intermittent or continuous) of androgen deprivation therapy (ADT) and the effect of denosumab in bone mass density (BMD). MethodsObservational, retrospective study of a cohort of prostate cancer patients in treatment with luteinizing hormone-releasing hormone (LH-RH) agonists, evaluated in the rheumatology department of a tertiary center. Demographics, FRAX score, LH-RH treatment scheme, osteoporosis treatment, laboratory data and BMD were collected. Mixed effect regression models to analyze the interaction between LH-RH treatment scheme, denosumab and BMD evolution were used. Results83 patients (mean age 71 ± 8 years) were included. At the basal evaluation, 16% of patients presented densitometric osteoporosis and 27% of patients presented high fracture risk. 80% of patients had inadequate vitamin D levels. Vitamin D > 30 ng/mL was correlated with higher T-scores. There was no association between LH-RH treatment scheme and BMD evolution, however there was a positive association with denosumab. ConclusionA high proportion of patients presented elevated fracture risk or inadequate vitamin D levels, not previously recognized. Bone health assessment and fracture risk evaluation are convenient in these patients. In a real-world setting, the effect of denosumab in BMD is detected, however the effect of intermittent LH-RH schema treatment is less evident.

Scheduled simple production method of pseudopregnant female mice for embryo transfer using the luteinizing hormone-releasing hormone agonist

The use of mice as experimental animal models has been a practice since the development of genetically engineered mouse models (GEMMs) in the early 1980s. New technologies, including genome editing, have helped in the time- and cost-efficient generation of GEMMs. However, methods for preparing pseudopregnant females, essential for the generation of GEMMs, remain less advanced. This study proposes a new method to achieve simple production of pseudopregnant female mice using a luteinizing hormone-releasing hormone agonist (LHRHa). A 20 µg LHRHa/mouse was identified as the best dose for inducing estrus synchronization. However, the frequency of copulation was 40% on a single injection. With sequential injections of 20 µg LHRHa/mouse on Days-1 and -2, followed by pairing on Day-5, 74% of LHRHa-treated females copulated with male mice. Moreover, LHRHa treatment did not affect fetal and postnatal development. Eventually, successful generation of offspring via embryo transfer was attained using LHRHa-treated pseudopregnant females. LHRHa administration method is efficient in producing pseudopregnant female mice for the generation of GEMMs, and we expect that it will contribute towards advancing the clinical research.

Persistent Testosterone Suppression After Cessation of Androgen Deprivation Therapy for Prostate Cancer.

Introduction Many men receiving temporary androgen deprivation therapy (ADT) for localized prostate cancer fail to achieve baseline testosterone levels after cessation. Testosterone recovery in men with localized prostate cancer receiving temporary ADT was assessed. Methods A global federated health research network (TriNetX) was used to identify men diagnosed with prostate cancer undergoing temporary ADT. Two cohorts were identified: men receiving luteinizing hormone-releasing hormone (LHRH) antagonists or LHRH agonists, and men receiving combined ADT (LHRH agonist and antiandrogens). Further stratification was based on a treatment duration of six months (short-term) or 18 months (long-term) to compare testosterone (T) recovery profiles five years after ADT cessation. Results A total of 28,583 men received LHRH agonist or antagonist therapy alone, and 20,188 men received combination ADT. A total of 46.7% of men who received short-term LHRH agonists or antagonistsand 40.6% of men who received short-term combined ADT, recovered to mean baseline T levels at five years. Only men who received short-term LHRH agonists/antagonists recovered to eugonadal levels at the five-year follow-up. Around 50% of men who received long-term LHRH agonist/antagonist therapy and 10.7% of men who received combined ADT, recovered to mean baseline T levels at five years. However, neither group recovered to eugonadal T levels. Conclusions At the five-year follow-up after ADT cessation, most patients failed to recover to their mean baseline and eugonadal T levels. Given that testosterone deficiency is associated with metabolically adverse changes in body composition, increased insulin resistance, impaired bone health, and hypogonadal symptoms, serum T levels must be closely monitored in men receiving ADT following treatment cessation.

Adherence With Oral Anticancer Therapies: Clinical Trial versus Real-World Experiences with a Focus on Prostate Cancer.

In this review, we address adherence rates in clinical settings, barriers to compliance with dosing schedules, and potential strategies to overcome challenges in maintaining high levels of adherence. Four studies reporting real-world adherence to prostate cancer medications, 52 studies describing barriers to adherence, and 16 studies on methods to minimize poor adherence were reviewed. Mean nonadherence rates of 25 to 51% have been identified in prostate cancer patients prescribed oral therapies, with higher rates in older patients. An extensive review of prostate cancer patients receiving gonadotropin hormone-releasing hormone agonist injections found an overall nonadherence rate of over 27%. Patients may encounter barriers to complying with dosing instructions related to the medication (eg, complex dosing schedules, the total burden of medication management, fasting or dietary requirements, high medication costs, adverse effects, and drug-drug interactions). Barriers may also be related to patient-specific factors (eg, suboptimal education regarding the importance of adherence, physical limitations and cognitive decline associated with advancing age, living alone without a care partner, high symptom burden, needle phobia, and comorbid mental disorders). Interventions to improve dosing adherence may include automated reminders, treatment diaries, educational materials, and the involvement of patients, family members, care partners, and healthcare teams. Many oral anticancer medications improve survival in men with prostate cancer and therefore it is vital to establish good adherence by understanding the pitfalls that patients may encounter. In situations where both oral and injectable drugs are interchangeable, injections of long-acting drugs lead to fewer opportunities for dosing nonadherence than oral therapies. In contrast, oral medicines do not require scheduling for injections and travel for injection appointments. Therefore, maximizing adherence to all treatment regimens will reduce the chance of efficacy failures and likely lead to improved clinical outcomes.

Maintaining bone health by estrogen therapy in patients with advanced prostate cancer: a narrative review.

The purpose of androgen deprivation therapy (ADT) in prostate cancer (PCa), using luteinizing hormone-releasing hormone agonists (LHRHa) or gonadotrophin-releasing hormone antagonists, is to suppress the levels of testosterone. Since testosterone is the precursor of estradiol (E2), one of the major undesired effects of ADT is the concomitant loss of E2, causing among others an increased bone turnover and bone loss and an increased risk of osteoporosis and fractures. Therefore, the guidelines for ADT indicate to combine ADT routinely with bone-sparing agents such as bisphosphonates, denosumab or selective estrogen receptor modulators. However, these compounds may have side effects and some require inconvenient parenteral administration. Co-treatment with estrogens is an alternative approach to prevent bone loss and at the same time, to avoid other side effects caused by the loss of estrogens, which is the topic explored in the present narrative review. Estrogens investigated in PCa patients include parenteral or transdermal E2, diethylstilbestrol (DES), and ethinylestradiol (EE) as monotherapy, or high-dose estetrol (HDE4) combined with ADT. Cardiovascular adverse events have been reported with parenteral E2, DES and EE. Encouraging effects on bone parameters have been obtained with transdermal E2 (tE2) and HDE4, in the tE2 development program (PATCH study), and in the LHRHa/HDE4 co-treatment study (PCombi), respectively. Confirmation of the beneficial effects of estrogen therapy with tE2 or HDE4 on bone health in patients with advanced PCa is needed, with special emphasis on bone mass and fracture rate.

Serum testosterone measured by liquid chromatography-tandem mass spectrometry is an independent predictor of response to castration in metastatic hormone-sensitive prostate cancer

BackgroundAlthough testosterone levels have been associated with progression-free survival (PFS) in metastatic hormone-sensitive prostate cancer (mHSPC) patients, this has primarily been investigated using inaccurate immunoassays (IA). Here, we investigated whether castrate testosterone levels determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay is an independent risk factor for treatment response in mHSPC. MethodsIn total, 106 mHSPC patients treated with luteinizing-hormone releasing-hormone (LHRH) agonists were retrospectively analyzed between March 2018 and August 2021. Testosterone levels in serum samples were quantitated using an LC-MS/MS assay. In a subset of patients, IA (Roche Cobas Pro) values were compared with LC-MS/MS results. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazard models. ResultsMedian PFS was shorter for high testosterone levels (>0.231 nmol/L, 18.4 v. 42.6 months, HR 1.7, p = 0.018). Low testosterone levels and a PSA response below 4 ng/mL was associated with longer median PFS (46.2 months) than the remaining combinations (13.8–19.3 months, 3.4–5.8, overall p < 0.01). In 67 patients, testosterone levels below the median remained associated with longer PFS, whereas IA measurements did not show a similar difference. ConclusionOur results suggest that high castration testosterone levels measured by LC-MS/MS is an independent response predictor for mHSPC patients.

Evaluation of thumbnail clipping as a specimen for retrospectively assessing average production of testosterone

BackgroundThe chronic abnormal production of testosterone (T) is associated with many disorders in men. Fingernail clippings might be more suited for the diagnosis and medium-to-long term therapeutic monitoring for the T-related chronic disorders than the blood-derived specimens. The objective of this study was to characterize a thumbnail clipping as the specimen for assessing the several months-old T status. MethodsThumbnail clippings from various subjects were analyzed by liquid chromatography/electrospray ionization-tandem mass spectrometry to evaluate the gender difference, and changes caused by aging and androgen deprivation therapy (ADT) in the thumbnail T concentration. ResultsThere was an evident gender difference in the thumbnail T concentrations [male; 2.55 ± 0.85 ng/g and female; 0.48 ± 0.29 ng/g, mean ± SD (n = 25 each), Welch t-test]. The thumbnail T concentrations significantly decreased with age in men (n = 268, Scheffé F-test), which was similar to those of the free or bioavailable T in serum/plasma. The thumbnail T concentrations sharply decreased by a 6-months ADT (especially the effect of the luteinizing hormone-releasing hormone agonist/antagonist) for patients with prostate cancer (n = 10). ConclusionsThe thumbnail clipping can be a specimen to retrospectively assess the average T production.

The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 −) advanced/metastatic breast cancer

PurposeGDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling.MethodsA phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 −) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status.ResultsPatients (N = 152) received GDC-0810 100–800 mg once daily (QD) or 300–400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%).ConclusionGDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs.Clinical Trial and registration date April 4, 2013. NCT01823835 .

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer (EXTEND): A Multicenter, Randomized Phase II Trial

<h3>Purpose/Objective(s)</h3> There has been increased utilization of metastasis directed therapy (MDT) for oligometastatic prostate cancer. Despite data demonstrating the benefit of upfront hormone therapy (HT) and synergy between radiation and HT, there exists no randomized trials testing their combination. As it is accepted by most clinicians and men with prostate cancer that time off HT holds intrinsic value, we evaluated whether the addition of metastasis directed therapy (MDT) to intermittent HT in men with oligometastatic prostate cancer facilities time off HT by improving PFS and eugonad PFS. <h3>Materials/Methods</h3> EXTEND (NCT03599765) is a phase II randomized basket trial for multiple solid tumors testing whether the addition of MDT improves PFS. The primary endpoint was pre-specified to be independently assessed and reported for the prostate intermittent HT basket at 41 events. Men with ≤5 metastases were randomized after ≥2 months of HT to continuing HT with or without MDT. HT consisted of a luteinizing hormone-releasing hormone agonist/antagonist with or without a 2^nd generation androgen-receptor targeting agent (SART). The primary endpoint was progression, defined as death or radiographic, clinical, or biochemical progression. A planned HT break occurred 6 months after enrollment, after which HT was withheld until progression. The study was designed to have 80% power to detect an improvement in median PFS from 18 to 36 months, with a type I error of 0.1. Exploratory analysis included flow cytometry and TCR sequencing from peripheral blood at baseline and 3 months follow up. <h3>Results</h3> Between Sept 2018 to Nov 2020, 87 men were randomized, 43 combined therapy and 44 to HT-only. Arms were well balanced. At a median follow-up of 22.1 months (range 13.0 to 39.3 months), 41 events were observed. PFS was improved by the receipt of MDT (median not reached vs 15.8 months for HT-only, P<0.001; HR=0.25 [95% CI, 0.12 to 0.55]). Among secondary endpoints, time from eugonad testosterone levels (>150 ng/dL) to progression was improved by MDT (median not reached vs 6.1 months, P=0.03), as was time to appearance of new lesions (2-year rate 33% vs 41%, P=0.04). Three grade 3 toxicities were observed in each arm. Subgroup analysis identified PFS improvement with MDT in patients who received (HR=0.24 [95% CI, 0.08 to 0.71]) or did not receive a SART (HR=0.36 [95% CI, 0.15 to 0.83]). Flow cytometry and TCR sequencing demonstrated increases in markers of T cell activation, proliferation, and clonal expansion limited to the combined therapy arm. <h3>Conclusion</h3> EXTEND represents the first randomized study to evaluate MDT with HT in oligometastatic prostate cancer and demonstrated improvement in PFS and eugonad PFS. Combination of MDT with intermittent HT may allow for both excellent disease control while facilitating prolonged eugonad testosterone intervals.

P088 - Medication adherence among patients with prostate cancer prescribed luteinizing hormone-releasing hormone agonists in England: Primary results from a real-world, retrospective cohort study

P088 - Medication adherence among patients with prostate cancer prescribed luteinizing hormone-releasing hormone agonists in England: Primary results from a real-world, retrospective cohort study

Changes in Ovulation-Related Gene Expression during Induced Ovulation in the Amur Sturgeon (Acipenser schrenckii) Ovarian Follicles.

The luteinizing hormone (LH) and maturation-inducing steroids (MIS), such as 17α,20β-dihydroxy-4-pregnen-3-one, regulate the final oocyte maturation in teleosts. Oocyte maturational competence (OMC) and ovulatory competence measure the sensitivity to MIS for oocyte maturation and ovulation, respectively. However, the molecular mechanisms underlying the acquisition of ovulatory competence remain unknown. Sturgeons are an excellent research model for investigating these mechanisms. We examined the seasonal profiles of OMC and ovulatory competence in vitro and the expression of 17 ovulation-related gene candidates using quantitative PCR in Amur sturgeon ovarian follicles. The ovulatory competence was induced by the LH-releasing hormone analog (LHRHa) priming injection after acquiring the OMC, which was spontaneously induced in spring or autumn. Seven genes, including the tissue-type plasminogen activator (plat), were enhanced following the LHRHa priming injection in ovarian follicles sampled from anovulated and ovulated fish. The activin receptor type 1 (acvr1) and prostaglandin G/H synthase 2 (ptgs2) were only upregulated in ovulated fish. Our results suggest that plat/plasmin and prostaglandin (PG)/PG receptor systems are essential for sturgeon ovulation, similar to other vertebrates. Notably, successful ovulation depends on a sufficient PG synthesis, and mediators activating the PG/PG receptor system are essential for acquiring the ovulatory competence. We provide the first report of ovulation-related gene alterations in the ovarian follicles of Amur sturgeons.

Variations in Gonadosomatic Index, Gonadal Development and Spawning Induction of Spotted Scat Scatophagus argus (Linnaeus, 1766)

This study evaluated variations in gonadosomatic index (GSI), gonadal development stages, and hormonal spawning induction of Scatophagus argus in captivity. Male and female fish were cultured separately in net cages in Tam Giang lagoon, Central Vietnam, from January to December 2020. Five fish of each sex were randomly sampled monthly. Gonads were collected, GSI determined, and subsequently prepared for histology. Gamete quality was assessed with a light microscope. Spawning was hormonally induced with different doses of human chorionic gonadotropin (hCG) and luteinizing hormone-release hormone (LHRH-A2). Gonadal development started to increase in March, peaking in July. The peak spawning period of the fish was from June to August, displaying the highest GSI value, sperm motility, and oocyte diameter. Only female GSI fluctuated significantly month-by-month (P&lt;0.05). Histological examination indicated that S. argus is a multiple-spawner. Application of LHRH-A2 (70 µg/kg) stimulated spawning and resulted in better latency periods, fertilization, and hatching rates.