How to cite this article: Bruyniks N, Del Pup L, Biglia N. Safety and Efficacy of Ospemifene in Women with A History of Breast Cancer. J Gynecol Women’s Health. 2019: 13(5): 555871. DOI: 10.19080/JGWH.2018.13.555871
Background: This post-hoc analysis compares the efficacy and safety data from women with or without a history of breast cancer who had been enrolled in the ospemifene clinical trial program.
Methods: Efficacy was assessed by the co-primary endpoints of most bothersome symptom (MBS; pooled data from two studies) and mean baseline to Week 12 change in vaginal pH and maturation index (pooled data from three studies). Safety was assessed using pooled data from all three studies. Comparisons were made between ospemifene-treated women with a history of breast cancer (≥10 years prior to enrolment; n=11) versus those without (n=1091).
Result: There were no differences in ospemifene-related improvements in symptoms of vulvar and vaginal atrophy (percentage whose MBS severity improved by ≥1 point on the 4-point severity scale) and in physiological parameters (vaginal pH, parabasal cells, and superficial cells) in women with versus without a history of breast cancer. Treatment-emergent adverse events and adverse drug reactions were comparable in the women using ospemifene who had a previous history of breast cancer (64% and 36%, respectively) compared with those that who did not (69% and 47%, respectively).
Conclusion: In this small post-hoc analysis, previous history of breast cancer did not appear to affect the efficacy or safety of ospemifene. Trial registration numbers NCT01585558, NCT01586364, NCT00729469 and NCT00566982.
Keywords: Breast cancer; Dyspareunia; Estrogen agonist/antagonist; Ospemifene; Postmenopausal; Safety; Selective estrogen receptor modulator; Vulvar and vaginal atrophy
Abbreviatations: ADR: Adverse Drug Reaction; ER: Estrogen Receptor; EU: European Union; FDA: Food and Drug Administration; MBS: Most Bothersome Symptom; SD: Standard Deviation; SERM: Selective Estrogen Receptor Modulator; TEAE: Treatment-Emergent Adverse Event; VVA: Vulvar and Vaginal Atrophy
Vulvar and vaginal atrophy (VVA) is a chronic, progressive postmenopausal condition characterized by dyspareunia, vaginal dryness and vaginal irritation, which are a consequence of a decline in endogenous estrogen production . It has previously been shown that women with a history of breast cancer are more likely to have moderate or severe symptoms and signs of VVA than women without breast cancer, particularly if treated with aromatase inhibitors  or tamoxifen after high-dose chemotherapy . Due to the risk of breast cancer recurrence if exposed to estrogen , all estrogens (even low-dose vaginal estrogens) are contra-indicated in women with known, past, or suspected breast cancer .
Ospemifene is an oral non-estrogen treatment that has been approved for the treatment of moderate to severe symptomatic VVA in post-menopausal women who are not candidates for local vaginal estrogen therapy [5,6]. It belongs to the selective estrogen receptor modulator (SERM) class, which also includes treatments indicated for the treatment and/or prevention of certain breast cancers [7-10]. Ospemifene binds selectively to estrogen receptors to exert a tissue-specific effect . In the breast, there are two estrogen receptors (ERα and ERβ), which can bind estrogen or a SERM [12,13]. Preclinical animal data suggest that ospemifene inhibits malignant breast tissue growth [14-18]. In addition, data from the ospemifene clinical trial program in women with VVA (including long-term safety
analyses) show that it is well tolerated with neutral/minimal
effects in breast tissue as assessed using breast palpation,
mammography and breast-related treatment-emergent adverse
events (TEAEs) [6,19-21]. Use of ospemifene is indicated in
women with a history of breast cancer once treatment of the
cancer has been completed .
The efficacy and safety of ospemifene was established in
three pivotal Phase 3 trials: two 12-week, double-blind placebocontrolled
trials [22-24] one of which had a blinded 40-week
safety extension in women with an intact uterus  and a 52-
week open-label extension in women without a uterus , and
one 52-week, double-blind placebo-controlled safety trial that
included a primary efficacy assessment at 12 weeks . This
short report focuses on efficacy and safety data from the 19
women with a history of breast cancer who had been included in
these pivotal Phase 3 trials.
Three pivotal Phase 3 studies included 19 women with
a history of breast cancer (diagnosis ≥10 years prior to
enrolment)-11 who had been randomized to 60 mg ospemifene
and 8 women to placebo:
a) In a 12-week, double-blind, placebo-controlled study
(15-50310), there were 2 women in the 60 mg ospemifene
group and 4 in the placebo group who had a prior history of
breast cancer . One woman in each group continued into
the 40-week extension period .
b) In a second 12-week, double-blind, placebo-controlled
study (15-50821), 7 women in the 60mg ospemifene group
and 4 in the placebo group had a prior history of breast
c) In a 52-week, double-blind, placebo-controlled safety
study (15-50718), 2 women in the 60mg ospemifene group
had a prior history of breast cancer .
Based on the FDA ‘Guidance for Products to Treat Vasomotor
Symptoms and Vulvar and Vaginal Atrophy Symptoms , the
following endpoints were assessed as co-primary endpoints in
the two efficacy studies and used in this analysis:
1. Mean change from baseline to Week 12 in the moderate
to severe symptom that has been identified by the patient as
the most bothersome symptom (MBS), based on the following
symptoms (pooled data from studies 15-50310 and 15-50821)
a. Vaginal dryness (none, mild, moderate, or severe)
b. Vaginal and/or vulvar irritation/itching (none, mild,
moderate, or severe)
c. Dysuria (none, mild, moderate, or severe)
d. Vaginal pain associated with sexual activity (none, mild,
moderate, or severe)
e. Vaginal bleeding associated with sexual activity
(presence vs absence)
2. Mean change from baseline to Week 12 in vaginal pH
(pooled data from all three studies) [16,19, 21-23]
3. Mean change from baseline to Week 12 in vaginal
maturation index (parabasal and superficial cells; pooled data
from all three studies) [16,19,21-23].
Due to the small number of women with a history of breast
cancer in each of the MBS categories, it was not attempted to
identify the effect on each MBS individually, but to analyse if
there was a difference in effect on MBS between the women
who did and those who did not have a history of breast cancer.
Responders were identified as those whose severity of MBS
improved by at least one point on the 4-point severity scale.
Safety data from all three studies were pooled for analysis
[19,21-23]. No formal statistical testing was carried out, but
where possible statistics have been included. Data are mean±SD
unless otherwise specified.
With the exception of a difference in age (those with a
history of breast cancer were older at 65.4±6.9 years (range
54-79) vs 59.4±6.5 years (range 40-80); p=0.0014), there
were no other differences between the group with (n=19) and
without (n=1870) a history of breast cancer in terms of baseline
demographics (data not shown).
Of the 9 subjects in the ospemifene 60mg group in studies
15-50831 and 15-50310, three identified dyspareunia as their
MBS and six identified vaginal dryness. The percentage of
women showing a reduction in severity of MBS (improvement by
at least one point on the 4-point severity scale) was higher in the
ospemifene 60 mg groups versus the placebo groups in the total
population (74.9% vs 61.8%, respectively), women with a history
of breast cancer (66.7% vs 50.0%, respectively) and women
with no history of breast cancer (75.0% vs 61.9%, respectively).
There were comparable improvements from baseline to Week
12 in the severity of the MBS (vaginal dryness or dyspareunia)
for those in the ospemifene groups with (n=9) versus without
(n=692) a history of breast cancer (Welch’s T-test, p=0.5492;
data not shown).
The data from all three studies were combined for the
change from baseline to Week 12 for vaginal pH, parabasal cells,
and superficial cells. With the exception of a higher percentage
of parabasal cells in the group of women with a history of breast
cancer, there were no significant differences in physiological
parameters at baseline between women with or without a history
of breast cancer in the ospemifene groups (Table 1). Ospemifene
improved post-menopausal physiological changes in women
with a history of breast cancer, with statistically significant mean decreases from baseline in the percentage of parabasal
cells and vaginal pH and a statistically significant mean increase
from baseline in the percentage of superficial cells (p<0.001 for
each; Table 1). Although the decrease in percentage of parabasal
cells and the increase in percentage of superficial cells in the
women with a history of breast cancer was somewhat larger, and
the decrease in vaginal pH somewhat smaller, than in women
without a history of breast cancer, the differences were not
statistically significant (Table 1).
In the clinical database of all Phase 2 and 3 studies of
ospemifene (5-90mg, 6-64 weeks’ treatment duration; n=1,892),
1291 women (68.2%) reported a TEAE . This was considered
by the investigator to be related to the study drug (adverse drug
reaction [ADR]) in 604 women (31.9%). There was no clear dose
relationship for any TEAE or ADR.
For studies 15-50310, 15-50821 and 15-50718, the incidence
of TEAEs and ADRs reported by ospemifene-treated women who
had a history of breast cancer was compared with those who did
not have history of breast cancer (Table 2). No differences were
found between groups. The proportion of women with a history
of breast cancer reporting a TEAE was similar to the number
of women on ospemifene in the Phase 2 and 3 double-blind,
placebo-controlled studies (63.6% and 67.6%, respectively).
No adverse event was reported more than once in the
ospemifene-treated women with a history of breast cancer.
Three unique TEAEs were reported in this population (mild nasal
dryness and sinus operation in one subject and abnormal weight
gain in a second subject). All other TEAEs were also reported in
the ospemifene population without a previous history of breast
cancer and in the placebo population. Interestingly, whilst hot
flushes were the most commonly reported TEAE (N=106, 8.5%)
and ADR (N=93, 7.5%) in women randomized to ospemifene
in the Phase 2 and 3 double-blind, placebo-controlled studies,
they were not reported by ospemifene-treated women with a
previous history of breast cancer.
There are long-term safety concerns (particularly with
respect to recurrent breast cancer risk) with systemic and
vaginal estrogen therapies that limit their use in postmenopausal
women with symptomatic VVA and previous breast cancer. In
fact, ospemifene is the only treatment approved in the EU for
this patient population, although it should be noted that it is
indicated in women who have completed breast cancer therapies
and is contraindicated in women who have breast cancer or are
undergoing current treatment for breast cancer .
It has previously been shown in the ospemifene development
program that ospemifene was effective and well tolerated in the
management of postmenopausal women with VVA [19,20-24].
Importantly, enrolment of women with a history of breast cancer
>10 years previously was permitted in two pivotal efficacy
studies (15-50310 and 15-50821) and a 1-year endometrial
safety study (15-50718). Here, we provided details of a post-hoc
analysis of data from ospemifene-treated women with versus
without a history of breast cancer from the three studies.
At baseline, the population of women with a history of
breast cancer was not significantly different from the population
that did not have such history, with the exception of age (mean
difference in age was 8.4 years older in the population with a
history of breast cancer). Unsurprisingly, the mean percentage
of parabasal cells at baseline was also significantly higher in this
population (71.4% vs 47.8% in those without breast cancer).
Despite these differences, efficacy as assessed by vaginal dryness
or dyspareunia (identified by the women as their MBS) and
the improvement in physiology (vaginal pH and percentage of
parabasal and superficial vaginal epithelial cells) was comparable
between women with and without a history of breast cancer.
Likewise, there was no difference in the safety profile of
ospemifene, regardless of whether women had a previous history
of breast cancer or not. Three unique TEAEs were reported in
women with a history of breast cancer: mild nasal dryness, sinus
operation and abnormal weight gain. It is difficult to see how
the first two could be related to ospemifene use. The abnormal
weight gain was reported from the first day of tablet intake (from
82 to 87.7kg) and is the only increase in weight gain reported as
a TEAE among 2471 subjects receiving ospemifene in the clinical
trial program. There was no change in median weight in the
placebo or 60mg ospemifene population in the 12-month safety
study 15-50718 . Interestingly, hot flushes were not reported
in the ospemifene-treated women with a history of breast cancer.
The data from this analysis add to previous reports of
neutral/beneficial effects of ospemifene in breast tissue from
preclinical animal studies [14-18] and long-term safety analyses
from clinical trials, which found no significant differences in
breast-related adverse events between ospemifene and placebo
The data do not show any differences in efficacy and safety
between ospemifene-treated women with versus without a
history of breast cancer. However, this analysis is limited due
to its post-hoc nature and the small number of patients with a
previous history of breast cancer and will require confirmation
in a larger number of patients before firm conclusions can be
The three parent studies were performed in accordance with
the Declaration of Helsinki current Good Clinical Practice, and
local regulatory requirements. All participants provided written
informed consent. The protocol for study 15-50821 [22,23] was
reviewed and approved by the Copernicus Group Institutional
Review Board (Durham, NC, USA) for most clinical sites; local
institutional review boards were used for the remaining sites.
The protocol, amendments and informed consent forms for
study 15-50718  were reviewed and approved by the
Independent Ethics Committee (IEC) before study initiation. For
study 15-50310, the protocol was reviewed and approved by the
institutional review board of each study center.
NBr is a consultant to Shionogi Ltd. LDP acted as a consultant
and advisory board member for TEVA and Shionogi Ltd. NBi is
a member of advisory boards and/or consultant with Gedeon
Richter, Italfarmaco, and Shionogi Ltd.
All authors were involved in analysing the data, drafting and/
or critically revising the manuscript, have given final approval
for publication, and agreed to be accountable for the content of