TY - JOUR
T1 - Estetrol Cotreatment of Androgen Deprivation Therapy in Infiltrating or Metastatic, Castration-sensitive Prostate Cancer
T2 - A Randomized, Double-blind, Phase II Trial (PCombi)
AU - Coelingh Bennink, Herjan J.T.
AU - van Moorselaar, Jeroen A.
AU - Crawford, E. David
AU - Roos, Erik P.M.
AU - Somford, Diederik M.
AU - Roeleveld, Ton A.
AU - de Haan, Tjard D.
AU - van Melick, Harm H.E.
AU - Reisman, Yacov
AU - Zimmerman, Yvette
AU - van Osta, Gonnie
AU - Krijgh, Jan
AU - Shore, Neal D.
AU - Saad, Fred
AU - Schally, Andrew V.
AU - Debruyne, Frans M.J.
N1 - Funding Information: Financial disclosures: Herjan J.T. Coelingh Bennink certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr. Debruyne is a paid consultant for Pantarhei Oncology BV. Dr. van Moorselaar received grants and fees from Astellas, Ipsen, Astra Zeneca, Bayer, and Janssen. Dr. Crawford was consultant for Astellas, Bayer, Dendreon, Ferring, Janssen, Pfizer, Sanofi, Tolmar, and MDxHealth. Dr. Shore is conducting research/consulting at Amgen, Astellas, AstraZeneca, Bayer, BMS, Dendreon, Ferring, Janssen, Merck, Myovant, Nymox, Pfizer, Sanofi‐Genzyme, and Tolmar. Dr. Saad has served as a consultant for, and received funding from, Amgen, Astellas, AstraZeneca, Bayer, BMS, Janssen, and Sanofi. Dr. Somford is a member of advisory boards of Astellas and Janssen, and research grant from Astellas. Dr. Coelingh Bennink is the president and a shareholder of Pantarhei Oncology, an affiliate of Pantarhei Bioscience BV. Dr. Zimmerman is the chief executive officer and a shareholder of Pantarhei Oncology. Dr. Krijgh is the chief medical officer of Pantarhei Oncology. The other authors declare no conflict of interest. Publisher Copyright: © 2021 The Authors
PY - 2021/6
Y1 - 2021/6
N2 - Background: Androgen deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved. Objective: To 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 participants: A phase II, double-blind, randomized, placebo-controlled study was conducted in advanced prostate cancer patients requiring ADT (the PCombi study). Intervention: Patients 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 analysis: Coprimary 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 limitations: Of 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%). Conclusions: HDE4 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 summary: Cotreatment 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.
AB - Background: Androgen deprivation therapy (ADT) for prostate cancer with luteinizing hormone-releasing hormone (LHRH) agonists can be improved. Objective: To 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 participants: A phase II, double-blind, randomized, placebo-controlled study was conducted in advanced prostate cancer patients requiring ADT (the PCombi study). Intervention: Patients 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 analysis: Coprimary 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 limitations: Of 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%). Conclusions: HDE4 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 summary: Cotreatment 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.
KW - Androgen deprivation therapy
KW - Antitumor efficacy
KW - Bone
KW - Cardiovascular safety
KW - Estetrol
KW - Hot flushes
KW - Luteinizing hormone-releasing hormone agonists
KW - PCombi
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85105293393&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.euros.2021.04.005
DO - https://doi.org/10.1016/j.euros.2021.04.005
M3 - Article
C2 - 34337526
SN - 2666-1691
VL - 28
SP - 52
EP - 61
JO - European urology open science
JF - European urology open science
ER -