Estetrol Inhibits the Prostate Cancer Tumor Stimulators FSH and IGF-1

Abstract

Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 (n = 41) or placebo (n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p < 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p < 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA.

Keywords: PCombi study; androgen deprivation therapy (ADT); estetrol (E4); follicle-stimulating hormone (FSH); insulin-like growth factor-1 (IGF-1).

Figure 1

The mean levels of follicle-stimulating hormone (A) and insulin-like growth factor-1 (B) after 12 and 24 weeks of treatment with 40 mg estetrol or placebo in patients with prostate cancer treated with an GnRH agonist (per-protocol population). FSH: follicle-stimulating hormone; IGF-1: insulin-like growth factor-1; GnRH: gonadotrophin-releasing hormone; NB: No statistical analysis was performed on the 12-week data.

Figure 2

Individual change (%) from baseline follicle-stimulating hormone levels at weeks 12 and 24 of treatment with 40 mg estetrol or placebo ADT co-administration (per-protocol population). ADT androgen deprivation therapy; E4: estetrol; source: Supplementary Table S2.

Figure 3

Individual change (%) from baseline insulin-like growth factor-1 levels at weeks 12 and 24 of treatment with 40 mg estetrol or placebo ADT co-administration (per-protocol population). ADT androgen deprivation therapy; E4: estetrol; source: Supplementary Table S3.