lhrh agonist
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2021 ◽  
Vol 17 (2) ◽  
pp. 83-92
Author(s):  
V. B. Matveev ◽  
B. Ya. Alekseev ◽  
B. Sh. Kamolov ◽  
A. S. Markova

Background. Despite the recent amendments to the guidelines for the treatment of metastatic hormone-sensitive prostate cancer (PCa) implying standard use of luteinizing hormone-releasing hormone (LHRH) agonists in combination with chemotherapy or androgen inhibitors, androgen deprivation therapy (ADT) remains an essential component of treatment for advanced PCa. Testosterone target castration level of 20 ng/dL implies routine measurement of testosterone levels along with prostate-specific antigen (PSA) levels during ADT. It is particularly interesting to evaluate the frequency of achieving castration testosterone level in routine clinical practice. Objective: to assess the frequency of achieving castration testosterone level (20 ng/dL) and maintaining it after 6 months of therapy in patients with hormone-sensitive PCa receiving an LHRH agonist for the first time. Materials and methods. In 2019-2020, Russian Society of Cancer Urologists conducted a non-interventional prospective multicenter study (observational program) aimed to evaluate the efficacy of LHRH agonist (including buserelin, goserelin, leuprorelin or triptorelin) in routine clinical practice in Russia. This study involved 39 cancer urologists and 479 patients aged 18 years and older diagnosed with hormone-sensitive PCa, who started their ADT with LHRH agonists for the first time regardless of the disease stage and previous treatment. Patients received hormone therapy with an LHRH agonist for at least 6 months, visiting their doctor every 3 months (visit 1; visit 2: after 3 months; visit 3: after 6 months). Results. Patients received one of the following drugs: leuprorelin (3.75 mg; 7.5 mg; 22.5 mg; 45 mg; n = 225; 47,0 %), goserelin (3.6 mg; 10.8 mg; n = 132; 27.5 %), buserelin (3.75 mg; n = 67; 14.0 %), and triptorelin (3.75 mg; 11.25 mg; n = 55; 11.5 %). Of 479 patients, 186 (38.8 %) received combination treatment with bicalutamide, 12 (2.5 %) with fluta-mide, 54 (11.3 %) with zoledronic acid, and 11 (2.3 %) with denosumab. Among 146 patients with metastatic PCa, a combination of ADT plus docetaxel was administered to 30 participants (20.6 %), ADT plus abiraterone to 8 participants (5.5 %), and ADT plus enzalutamide to 2 participants (1.4 %). After 6 months of therapy, mean PSA level decreased by 94.2 % (from baseline 118.12 ng/mL to 6.87 ng/mL). Mean testosterone level was 19.0 ng/dL (range: 0.029-100 ng/dL). Among 430 patients, the targeted testosterone level <20 ng/dL was achieved in 257 individuals (59.8 %); the level of 20-50 ng/dL was achieved in 158 individuals (36.7 %); and fifteen patients (3.5 %) had their testosterone level >50 ng/dL. The incidence of adverse events was low; most of them were mild. Conclusion. Our findings suggest that not all patients achieve targeted testosterone level of <20 ng/dL, which corroborates the need for routine monitoring of testosterone levels during therapy to ensure its timely correction. We observed frequent administration of ADT with maximum androgen blockade. In patients with metastatic PCa, the use of standards for combination treatment with docetaxel and androgen inhibitors is limited.


2020 ◽  
Vol 12 (3) ◽  
pp. 43-49
Author(s):  
E.Yu. Gritskevich ◽  
◽  
T.Yu. Demidova ◽  
M.R. Maturov ◽  
A.A. Bystrov ◽  
...  

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1023-1023
Author(s):  
Elgene Lim ◽  
Komal L. Jhaveri ◽  
Jose Alejandro Perez-Fidalgo ◽  
Meritxell Bellet ◽  
Valentina Boni ◽  
...  

1023 Background: GDC-9545 is a potent, orally available, selective estrogen receptor degrader developed for the treatment of ER-positive (ER+) breast cancer alone or combined with CDK4/6 inhibitors. A first-in-human study evaluated 10-250 mg GDC-9545; tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical results support expansion cohorts at ≥30 mg (Jhaveri et al., 2019). Methods: This study evaluated PK, PD, and efficacy of GDC-9545 alone and combined with palbociclib, ± LHRH agonist. Eligible patients (pts) had ER+ (HER2-) metastatic breast cancer (MBC) with ≤ 2 prior therapies in the advanced or metastatic setting. No prior treatment with CDK4/6 inhibitor was allowed in pts receiving palbociclib. Results: Eight-five pts were enrolled in 2 cohorts: GDC-9545 100 mg given once daily ± LHRH agonist (Cohort A), and GDC-9545 100 mg +125 mg palbociclib on a 21 day on/7 day off schedule ± LHRH agonist (Cohort B). Of the 39 pts in Cohort A, adverse events (AE) occurring in ≥10% of pts were fatigue, cough, back pain, pain in extremity, and arthralgia. Related AEs were generally Grade (G) 1-2; there were 3 related G3 AEs of fatigue, transaminase increased, and diarrhea. Two pts had GDC-9545 reduced, one due to G3 diarrhea and another due to G3 transaminitis. Of the 46 pts in Cohort B, AEs in ≥10% of pts were neutropenia, fatigue, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, pruritus, and visual impairment. Twenty-six (57%) pts had G≥3 AEs. G≥3 neutropenia was reported in 23 (50%) pts. One pt had palbociclib reduced due to G3 febrile neutropenia. Eleven (13%) of 85 pts had G1 asymptomatic bradycardia considered related to GDC-9545. No pts in either cohort discontinued study treatment due to AEs. PK analysis and clinical data demonstrate no clinically relevant drug-drug interactions between GDC-9545 and palbociclib. Reduced ER, PR, and Ki67 levels, and an ER activity signature, were observed in paired pre- and on-treatment biopsies (n = 12). Eighteen of 33 pts in Cohort A had either confirmed partial responses or were on study 24 weeks (clinical benefit rate 55%). Clinical benefit was observed in pts with prior fulvestrant treatment and with detectable ESR1 mutations at enrollment. Clinical benefit data for both cohorts are anticipated to be mature in April 2020. Conclusions: GDC-9545 was well-tolerated as a single agent and in combination with palbociclib with encouraging PK, PD, and anti-tumor activity in ER+ MBC to support Phase III development. Clinical trial information: NCT03332797 .


2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 31-31
Author(s):  
Przemyslaw Twardowski ◽  
Stuart Atkinson ◽  
Deborah Boldt-Houle ◽  
A. Oliver Sartor

31 Background: LHRH agonists are the most frequently used drugs for the delivery of androgen deprivation therapy (ADT) for PCa. Evidence suggests achieving and sustaining T levels ≤20 ng/dL with ADT is desirable and correlates with improved disease-specific survival in advanced PCa patients. However, T levels may rise above castration level (50 ng/dL) between injections, especially if a subsequent dose is delayed. Increase in prostate-specific antigen (PSA) level on ADT may represent true disease progression to castration resistant PCa, or may be a result of late ADT dosing and inadequate T suppression. Current study evaluated timeliness of LHRH agonist dosing, subsequent rate of T breakthroughs and frequency of T/PSA testing prior to dosing in PCa patients. Methods: A retrospective review of electronic medical records and associated claims data (1/1/07-6/30/16) of LHRH agonist injections (n=85,030) evaluated the frequency of late dosing (defined as occurring after day 32, 97, 128, 194 for 1-, 3-, 4-, 6-month formulations, respectively), T tests >20 ng/dL and frequency of T/PSA tests prior to dosing. Results: 26.9% of injections were late: 14.4% were ≤1 week late, 3.1% were between 1-2 weeks late and 9.4% were >2 weeks late. 43% of T values exceeded 20 ng/dL for late injections; while only 21% exceeded this level for early/on-time injections. 83% of LHRH injections had a PSA value drawn prior to dosing; however, only 13% had a similarly timed T assessment. Conclusions: Overall, >25% of injections were late. For late injections, the proportion of T tests with T >20 ng/dL was higher compared to when the dosing was early/on-time. Late injections correlated with ineffective T suppression (>20 ng/dL) over 40% of the time. For all injections, T levels were not monitored as frequently as PSA levels. Considering the potential clinical benefits of maintaining effective T suppression throughout the course of ADT, clinicians should ensure treatments are delivered within approved dosing instructions, routinely monitor T levels and consider prescribing treatments with proven efficacy through the dosing interval to maintain T ≤20 ng/dL.


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