Dataset Information

Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study.

ABSTRACT:

Background

Androgen deprivation therapy (ADT) for prostate cancer (PCa) is accompanied by side effects affecting health-related quality of life (HRQL).

Objective

To assess the effects of the fetal estrogen estetrol (E4) on symptoms related to estrogen and androgen deficiency, and on HRQL measured using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.

Design setting and participants

This was a phase 2, double-blind, randomized, placebo-controlled study in patients with advanced PCa.

Intervention

Patients receiving ADT were randomly assigned at a 2:1 ratio to daily treatment with a high dose of E4 (HDE4; n = 41) or placebo (n = 21) for 24 wk.

Outcome measurements and statistical analysis

The primary outcome was the effect of HDE4 cotreatment on hot flushes (HFs). Secondary outcomes were the Q-Man questionnaire for evaluation of the effect on estrogen and androgen deficiency symptoms, and the FACT-P questionnaire for evaluating HRQL.

Results and limitations

At 24 wk, the number of patients experiencing HFs was significantly lower in the HDE4 group than in the placebo group (14.3% vs 60.0%; p < 0.001). HDE4 treatment was associated with lower incidence of night sweats, arthralgia, and fatigue, but more nipple tenderness and gynecomastia. At 24 wk, the mean HRQL score favored HDE4 over placebo for the FACT-P total score (122.2 ± 12.3 vs 118.7 ± 19.7) and for several other FACT subscales.

Conclusions

Daily HDE4 coadministration almost completely prevented HFs in patients with advanced PCa treated with ADT. HDE4 also had positive effects on HRQL and counteracted other estrogen deficiency symptoms caused by ADT. These data support the dual efficacy concept of ADT and HDE4 to improve HRQL and increase the antitumor effect of ADT.

Patient summary

For patients on androgen deprivation therapy for advanced prostate cancer, cotreatment with a high dose of estetrol almost completely prevents the occurrence of hot flushes and improves quality of life and well-being, but nipple sensitivity and an increase in breast size may occur.

SUBMITTER: Zimmerman Y

PROVIDER: S-EPMC9637725 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study.

Zimmerman Yvette Y Frydenberg Mark M van Poppel Hendrik H van Moorselaar R Jeroen A RJA Roos Erik P M EPM Somford Diederik M DM Roeleveld Ton A TA de Haan Tjard D TD van Melick Harm H E HHE Reisman Yacov Y Krijgh Jan J Debruyne Frans M J FMJ Coelingh Bennink Herjan J T HJT

European urology open science 20221003

<h4>Background</h4>Androgen deprivation therapy (ADT) for prostate cancer (PCa) is accompanied by side effects affecting health-related quality of life (HRQL).<h4>Objective</h4>To assess the effects of the fetal estrogen estetrol (E4) on symptoms related to estrogen and androgen deficiency, and on HRQL measured using the validated Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire.<h4>Design setting and participants</h4>This was a phase 2, double-blind, randomized, placebo-c ...[more]

PMID: 36353657

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Project description:BackgroundAndrogen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2-3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.ObjectiveTo undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC.Design, setting, and participantsRNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes.Outcome measurements and statistical analysisWe searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model.Results and limitationsWe identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches.ConclusionsRNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.

Project description:BackgroundAndrogen deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved.ObjectiveTo assess safety, the frequency and severity of hot flushes (HFs), bone health, and antitumor effects of high-dose estetrol (HDE4) when combined with ADT.Design setting and participantsA phase II, double-blind, randomized, placebo-controlled study was conducted in advanced prostate cancer patients requiring ADT (the PCombi study).InterventionPatients receiving LHRH agonist treatment were randomized 2:1 to 40 mg HDE4 (n = 41) or placebo (n = 21) cotreatment for 24 wk.Outcome measurements and statistical analysisCoprimary endpoints were frequency/severity of HFs and levels of total and free testosterone (T). Secondary endpoints included assessments of bone metabolism (osteocalcin and type I collagen telopeptide [CTX1]), prostate-specific antigen (PSA), and follicle-stimulating hormone (FSH). Efficacy analysis was based on the selected per-protocol (PP) population.Results and limitationsOf 62 patients included in the study, 57 were suitable for a PP analysis (37 HDE4; 20 placebo). No E4-related serious cardiovascular adverse events occurred at 24 wk. Weekly HFs were reported by 13.5% of patients with HDE4 and 60.0% with placebo (p < 0.001). Daily HFs occurred in 5.9% versus 55%. Bone turnover parameters decreased significantly with HDE4 (p < 0.0001). Total and free T decreased earlier (p < 0.05), and free T was suppressed further (p < 0.05). PSA suppression was more profound and earlier (p < 0.005). FSH levels were suppressed by 98% versus 57% (p < 0.0001). Estrogenic side effects were nipple sensitivity (34%) and gynecomastia (17%).ConclusionsHDE4 cotreatment of ADT patients with advanced prostate cancer was well tolerated, and no treatment-related cardiovascular adverse events were observed at 24 wk. HFs and bone turnover were substantially reduced. Suppression of free T, PSA, and FSH was more rapid and profound, suggesting enhanced disease control by HDE4 cotreatment. Larger and longer-lasting studies are needed to confirm the results of the study reported here.Patient summaryCotreatment of androgen deprivation therapy with high-dose estetrol in advanced prostate cancer patients results in fewer occurrences of hot flushes, bone protection, and other antitumor benefits. Nipple sensitivity and gynecomastia may occur as side effects.

Dataset Information

Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study.

Background

Objective

Design setting and participants

Intervention

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Publications

Estetrol Prevents Hot Flushes and Improves Quality of Life in Patients with Advanced Prostate Cancer Treated with Androgen Deprivation Therapy: The PCombi Study.

Similar Datasets

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