Camizestrant in combination with capivasertib for women with ER-positive, HER2-negative advanced breast cancer: results from SERENA-1.

Introduction
Breast cancer remains the second most common cancer globally and the leading cause of cancer death in women. Despite recent advances in the management of breast cancer, there remains a major unmet need to improve outcomes for patients.1,2
The most prevalent subtype of breast cancer, which also accounts for the majority of those with metastatic disease, is hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative.1,3 HR-positive cancers are characterized by expression of the estrogen receptor (ER) and/or progesterone receptor, and are therefore generally sensitive to treatments targeting these receptor pathways.4
Endocrine therapy (ET) is designed to reduce ER signaling through direct or indirect mechanisms, and is a key component of the treatment of those with both early and advanced-stage HR-positive breast cancer.4,5 Many HR-positive breast cancers are controlled for some time by first-line ET but subsequently become resistant, highlighting the need for novel ET and combination therapy approaches to address these mechanisms.6
Selective estrogen receptor degraders (SERDs) are a type of ET that antagonize and degrade ER from cells.4,7,8 Fulvestrant was the first approved SERD and is commonly used as an intramuscular monotherapy or in combination with oral cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for patients with HR-positive, HER2-negative breast cancer.7 Fulvestrant has poor oral bioavailability, however, and fulvestrant 500 mg may not result in maximal ER degradation, suggesting greater clinical efficacy could be achieved with more complete antagonism and degradation.9
Camizestrant, the next-generation oral SERD and complete ER antagonist, is currently in phase III development for the treatment of ER-positive, HER2-negative breast cancer in early and advanced settings as a 75 mg daily dose.10 In preclinical studies, camizestrant demonstrated strong antitumor activity in both estrogen receptor 1 (ESR1) wild type and fulvestrant-resistant ESR1 mutated (ESR1m) patient-derived xenograft models, and was active in combination with CDK4/6i and with PI3K/AKT/mTOR inhibitors.8 SERENA-1 is a multi-part, open-label phase I trial (NCT03616587) designed to investigate the safety and tolerability of camizestrant as a monotherapy and in combination with other anticancer agents in women with ER-positive, HER2-negative advanced breast cancer.
In previously reported parts of the SERENA-1 trial, camizestrant demonstrated a tolerable safety profile, antitumor activity, and clinical benefit, both as monotherapy10 and when combined with all three Food and Drug Administration-approved CDK4/6i (abemaciclib, palbociclib, and ribociclib) in women with ER-positive, HER2-negative advanced breast cancer.11 In the randomized SERENA-2 trial, camizestrant monotherapy was well tolerated and demonstrated clinically meaningful and statistically significant improvement in progression-free survival (PFS) compared with fulvestrant.12 Recently, the pivotal phase III SERENA-6 trial showed that in patients with ER-positive, HER2-negative advanced breast cancer whose tumors have an emergent ESR1m during first-line therapy, switching to camizestrant from an aromatase inhibitor while continuing CDK4/6i resulted in significant and clinically meaningful improvement in PFS compared with remaining on aromatase inhibitor plus CDK4/6i until disease progression.13 In SERENA-6, camizestrant in combination with CDK4/6i was well tolerated, with safety data consistent with known safety profiles of each drug individually, and low discontinuation rates throughout.13
Camizestrant is also being investigated in other patient populations in several ongoing trials, including SERENA-4 (NCT04711252) and the EvoPAR-BR01 trial (NCT06380751), evaluating camizestrant in patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment of advanced disease; and CAMBRIA-1 (NCT05774951) and CAMBRIA-2 (NCT05952557), evaluating camizestrant in early-stage ER-positive, HER2-negative breast cancer in the adjuvant setting.
Approximately 50% of HR-positive, HER2-negative advanced breast cancers harbor PIK3CA/AKT1/PTEN alterations,14 components of the PI3K/AKT signaling pathway whose downstream effects contribute to proliferation, invasion, and metastasis of tumor cells.15,16 Capivasertib is a potent, selective inhibitor of all three AKT isoforms (AKT1/2/3), indicated in combination with fulvestrant for the treatment of patients with HR-positive, HER2-negative advanced breast cancer with PIK3CA/AKT1/PTEN alterations after disease progression or recurrence following one or more previous lines of ET.14,17 In the phase III pivotal trial CAPItello-291, capivasertib 400 mg [twice daily (b.i.d.) for 4 days on/3 days off (4d on/3d off)] combined with fulvestrant demonstrated a manageable safety profile and improved PFS in patients with HR-positive, HER2-negative advanced breast cancer compared with fulvestrant alone.14 Capivasertib is approved for use in combination with fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer with PIK3CA/AKT1/PTEN alterations; however it can be hypothesized that a combination of camizestrant (rather than fulvestrant) with capivasertib may show superior clinical efficacy. With this in mind, the safety and tolerability of such a combination would need to be addressed.
Here, we report results from parts I and J of the SERENA-1 trial, which investigated the safety and tolerability, pharmacokinetics (PK), and efficacy of camizestrant in combination with capivasertib.

Patients and methods

Trial compliance
All participants consented to participate in this trial and gave their written informed consent before enrolment. The trial was carried out according to the principles of the Declaration of Helsinki, Council for International Conference on Harmonization Guidelines for Good Clinical Practice, and applicable national and local laws. The protocol was approved by the respective regulatory authorities and the research ethics committee of each participating site and was subject to Ethics Committee and Institutional Review Board approvals.

Objectives
The primary objective was to investigate the safety and tolerability of camizestrant in combination with capivasertib in women with ER-positive, HER2-negative advanced breast cancer. The secondary objectives were to assess the antitumor activity, efficacy, and PK of this combination.

Participants
Participants were enrolled from eight centers across Spain (4), the UK (3), and the USA (1). Eligible participants were pre- or postmenopausal women aged ≥18 years with endocrine-resistant, ER-positive, HER2-negative advanced breast cancer (n = 29) that was refractory or intolerant to existing therapy known to provide clinical benefit. Participants were to have received no more than two lines of chemotherapy for advanced disease but have had recurrence or progression on at least one line of ET in the advanced/metastatic disease setting. Previous treatment with CDK4/6i and PIK3/AKT/PTEN pathway inhibitors was permitted, unless participants had a history of hypersensitivity or intolerance to capivasertib or drugs with a similar chemical structure or class. Presence of PIK3CA/AKT1/PTEN alterations or ESR1m in tumors was not a criterion for inclusion in this trial.
Premenopausal participants were to have commenced treatment with luteinizing hormone-releasing hormone agonist at least 4 weeks before their first treatment with camizestrant and capivasertib.

Trial design
In the dose escalation phase (part I), 16 participants were allocated to receive camizestrant in combination with capivasertib. Each participant underwent a 28-day evaluation period to determine any dose-limiting toxicities (DLTs). In the dose-expansion phase (part J), another 13 participants received camizestrant in combination with capivasertib for further exploration of the safety and tolerability of this dose regimen. This trial reports on all participants from part I (n = 16) and part J (n = 13) combined.
Once-daily camizestrant 75 mg was the selected dose based on previous results from camizestrant monotherapy10 and combination therapy studies.11 Capivasertib 400 mg was administered in accordance with its current label (b.i.d.) with a schedule of 4d on/3d off.18 Participants continued treatment until disease progression or trial withdrawal. Patient reports of diarrhea and rash were expected to be evaluated and treated by investigators according to local practice. If treatment was unsuccessful, dose interruptions of capivasertib were permitted.

ctDNA analysis
Details of ctDNA analysis and the definition of ESR1m have been described previously.10 A participant was considered to have a PIK3CA/AKT1/PTEN alteration using the definition applied in the CAPItello-291 trial14 (PTEN loss is not detected by either of the assays used in this study). Mutations could be detected in either the screening and/or the cycle 1 day 1 sample, with no minimum variant allele frequency (VAF) cut-off.

Clinical outcomes
Safety and tolerability were analyzed by observing DLTs, adverse events (AEs), vital signs, clinical parameters, and electrocardiogram data. AE severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
Details of efficacy measurements have been published previously.10 Efficacy was assessed by objective response rate (ORR), duration of response, clinical benefit rate at 24 weeks (CBR24), percentage change in tumor size, and PFS.
Triplicate, centrally-read digital electrocardiograms were obtained at screening, during cycle 1 (day 1 pre-dose, day 8, day 18 pre-dose), during cycles 2, 3, and 4 (pre-dose), on day 1 of any subsequent cycle, on occurrence of any cardiac-related AE, at discontinuation visit, at 7-day and 14-day follow-up visits from discontinuation, and at 28-day follow-up.
Following continuous multiple doses of camizestrant in combination with intermittent doses of capivasertib, PK blood sampling was carried out on cycle 1 day 18 (C1D18; on the last day of the 4d on/3d off capivasertib schedule) for camizestrant and capivasertib. Camizestrant PK samples were also taken on cycle 2 day 1 (C2D1; on the first of 4d on/3d off capivasertib following 3 days of washout). Based on previous data, steady state concentrations were expected to be achieved after 5 (camizestrant)19 and 3 (capivasertib)20 days of continuous dosing. Plasma concentrations of camizestrant and capivasertib were compared with population PK model stimulations. A within-participant comparison was carried out at C2D1 and C1D18 to investigate any difference in camizestrant PK between the first and fourth dose of capivasertib on the 4d on/3d off schedule.

Statistical analysis
All participants across both parts I and J received the same dose combination and schedule; therefore, the cohorts were combined into a single analysis and reported here together.
Descriptive statistics are presented for all variables. Percentages were calculated for the total population unless otherwise stated. Continuous variables are summarized by the number of observations, mean, standard deviation (SD), median, minimum, and maximum. Categorical variables are summarized by frequency counts and percentages for each.
For ORR, confidence intervals (CIs) were calculated by the exact Clopper–Pearson method. PFS parameters were calculated using the Kaplan–Meier technique.
All participants were included in the safety and evaluable-for-response analysis sets, which analyzed safety and efficacy. PK was assessed in the PK analysis set, which included all participants with at least one quantifiable post-dose PK sample (n = 26).
SAS® System version 9.2 or higher (SAS Institute Inc., Cary, NC) software was used to conduct all statistical analysis.

Results
The first participant was screened on 9 August 2021, and the final participant was screened on 22 June 2022.
At data cut-off (29 September 2023), 29 participants had received trial treatment, and 6 were continuing trial treatment (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.106049). The median (min, max) duration of follow-up in censored participants was 14.9 (0.03, 19.4) months. Participant disposition is described in Table 1.

Baseline characteristics
Participant demographics, characteristics, and medical/surgical histories are shown in Table 1 and Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.106049. Overall, 72.4% (21/29) of participants had visceral disease and 93.1% (27/29) had measurable disease at baseline.
The population in these cohorts had received a median of two previous regimens in the advanced setting, including two previous endocrine regimens. Previous treatment with fulvestrant had been received by 55.2% (16/29) of participants, and 89.7% (26/29) had received previous treatment with a CDK4/6i.

Safety and tolerability
The mean (±SD) treatment duration was 8.6 ± 6.7 months for camizestrant and 7.3 ± 6.7 months for capivasertib.
Collectively, the most common treatment-emergent AEs of any grade were diarrhea (75.9%) and nausea (44.8%; Table 2). All reported AEs of nausea, and the majority of diarrhea, were grade 1 or 2. The most common grade ≥3 treatment-emergent AE was diarrhea (10.3%).
The most common AEs possibly causally related to camizestrant were sinus bradycardia (37.9%), photopsia (20.7%), and visual impairment (20.7%; Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.106049). All of these AEs were CTCAE grade 1 (not interfering with activities of daily living). For sinus bradycardia, camizestrant in combination with capivasertib was associated with a time-dependent, reversible reduction in resting heart rate, with a gradual decrease to a stable nadir over ∼14 days. In terms of visual effects, ophthalmological examination, including assessment of visual fields, visual acuity, intraocular pressure, and fundoscopy, revealed no evidence of functional or structural changes in the eye associated with camizestrant treatment.
The most common AEs possibly causally related to capivasertib were diarrhea (65.5%), nausea (34.5%), and rash (grouped term, 31.0%; Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.106049). Most AEs were grade ≤2; however, three participants (10.3%) reported grade ≥3 diarrhea, and two participants reported grade ≥3 rash (grouped term, 6.9%). Two participants experienced hyperglycemia [grade 1 (n = 1, 3.4%) and grade 3 (n = 1, 3.4%)].
Dose modifications due to an AE were required for camizestrant in 8/29 participants (27.6%); specifically, 8 participants reported an AE that led to a dose interruption with 1 (3.4%) participant requiring a dose reduction to 25 mg. No participants reported an AE that led to discontinuation of camizestrant. For capivasertib, 12/29 participants (41.4%) reported an AE that led to a dose modification; all 12 participants required a dose interruption, and 3 (10.3%) of these participants ultimately required a dose reduction (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.106049). Four participants reported AEs that led to discontinuation of capivasertib; one due to acute kidney injury (grade 3), hyperglycemia (grade 3), palpitations (grade 1), and mucosal inflammation (grade 3); one due to maculopapular rash (grade 2); one due to hypersensitivity (grade 2); and one due to increased hepatic enzymes (grade 4).
Two (6.9%) participants experienced a DLT related to capivasertib 400 mg of grade 3 maculopapular rash. This was resolved by interruption of both camizestrant and capivasertib.
No deaths were reported by investigators as related to either camizestrant or capivasertib. There was one (7.7%) death attributed to septic shock in the follow-up period of the dose-expansion phase (24 days after the last dose of camizestrant and 26 days after the last dose of capivasertib), considered by the investigator to be unrelated to either drug.

Pharmacokinetics
Dosing and PK sampling schedules are shown in Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.106049.
Following multiple doses of camizestrant in combination with capivasertib, camizestrant 75 mg was steadily absorbed, and the median tmax was achieved ∼4 hours post dose (Figure 1A and B) on both C1D18 (3.7 hours) and C2D1 (3.8 hours).
The exposure of camizestrant in combination with capivasertib on C2D1 was 70.1 ng/ml (44%) based on geomean (CV%) Cmax and 907.9 ng/ml (37%) based on geomean (CV%) area under the curve of the dosing interval (AUCtau; Figure 1B). Camizestrant geometric mean Cmax and AUCtau in combination with capivasertib on the last day of the 4 day on/3 day off schedule [C1D18: 89.8 ng/ml (45%)] and area under the curve [AUC; 1139 ng/ml (52%)] were increased by 28.1% and 25.5% respectively, compared with C2D1 (Figure 1A).
The PK profile for capivasertib 400 mg showed rapid absorption, with tmax achieved in a median of ∼2 hours post dose after 4 days of continuous dosing (Figure 1C).
The PK of capivasertib in this trial was compared with the population PK (popPK) derived parameters from capivasertib in combination with fulvestrant in the CAPItello-291 pivotal trial, which had a larger pool of participants (n = 340).14 In the current trial, the exposure of capivasertib in combination with camizestrant on C1D18 was 2016 ng/ml (78%) based on geomean (CV%) Cmax and 10 080 ng/ml (61%) based on geomean (CV%) AUC. This was 47% and 25% higher, respectively, than the geomean (CV%) Cmax [1371 ng/ml (37%)] and AUC [8069 ng/ml (30%)] observed in the CAPItello-291 trials, however, was determined to be within the same range, suggesting that PK exposures were similar between the two studies.

Clinical efficacy
Despite the pretreated nature of these participants including previous fulvestrant, previous CDK4/6i treatment, and/or previous chemotherapies, encouraging antitumor activity was observed (Figure 2A and B).
ORR, CBR24, and median PFS are presented in Figure 2B. Of those with measurable disease at baseline, the ORR was 37.0% (10/27; 95% CI 19.4%, 57.6%). In participants with measurable disease at baseline, ORR was 37.5% (6/16; 95% CI 15.2%, 64.6%) for those with detected ESR1m in tumors, and 36.4% (4/11; 95% CI 10.9%, 69.2%) for those without. In participants with tumors with at least one PIK3CA/AKT1/PTEN alteration, ORR was 46.2% (6/13; 95% CI 19.2%, 74.9%), and for those without was 28.6% (4/14; 95% CI 8.4%, 58.1%).
The percentage of participants who showed CBR24 was 51.7% (15/29; 95% CI 32.5%, 70.6%). The CBR24 was 56.3% (9/16; 95% CI 29.9%, 80.2%) in participants with previous fulvestrant treatment in the advanced disease setting and 50.0% (13/26; 95% CI 29.9%, 70.1%) in those with previous CDK4/6i treatment only in the advanced setting. For participants with tumors containing at least one ESR1m, CBR24 was 52.9% (9/17; 95% CI 27.8%, 77.0%), and for those without was 50.0% (6/12; 95% CI 21.1%, 78.9%). For participants with PIK3CA/AKT1/PTEN-altered tumors, CBR24 was 66.7% (10/15; 95% CI 38.4%, 88.2%), and for those without was 35.7% (5/14; 95% CI 12.8%, 64.9%).
Overall, median PFS was 8.3 months (95% CI 3.5, 11.5 months). In participants with tumors with ESR1m, median PFS was 10.9 months (95% CI 4.7 months, not calculated), and in those without was 5.8 months (95% CI 1.7, 10.9 months). In participants with PIK3CA/AKT1/PTEN-altered tumors, median PFS was 9.6 months (95% CI 3.5 months, not calculated), and in those without was 5.3 months (95% CI 2.9, 11.5 months).

ESR1m ctDNA dynamics
The effect of camizestrant in combination with capivasertib on ESR1m ctDNA was assessed in participants with ESR1m detected at baseline (cycle 1 day 1) and with follow-up (cycle 2 day 1) samples collected and successfully analyzed. A ≥50% reduction from baseline in summed ESR1m VAF was observed in 92% (11/12) of participants treated with camizestrant plus capivasertib, including clearance to undetectable levels in 67% (8/12) of patients (Figure 3).

Discussion
Camizestrant (75 mg daily) in combination with capivasertib (400 mg b.i.d., 4d on/3d off) was generally well tolerated in participants with ER-positive, HER2-negative advanced breast cancer, with clinically relevant efficacy for this pretreated group of participants and a safety profile consistent with both drugs as monotherapy.10,14,21,22
Participant demographics were as expected for this population (Table 1, Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.106049).
Gastrointestinal symptoms, diarrhea, and nausea were the most commonly reported AEs; the majority of instances were grade 1 or 2. AEs reported to be related to camizestrant in this trial were in line with those previously reported for camizestrant monotherapy, namely bradycardia and visual effects; all of which were grade 1.10 The incidence of these AEs did not appear to be exacerbated by combination with capivasertib. No AEs led to the discontinuation of camizestrant.
Similarly, the safety profile of capivasertib was consistent with previous reports,14,21,22 with diarrhea, nausea, and rash reported as the most common treatment related AEs, the majority of which were grade 1. Skin reactions, including rash, have been previously reported with capivasertib and can be managed using severity-based dose modifications and treatment such as oral antihistamines.23 Similarly, diarrhea is a frequent clinical observation with some anticancer agents, including capivasertib, and can be effectively managed with anti-diarrheal treatment and dose modifications.23 Interestingly, transient and manageable hyperglycemia, which constitutes a common side effect of PI3K/AKT pathway inhibitors, was rarely observed in this trial, including only one case of grade 3.16
PK data for camizestrant 75 mg in combination with capivasertib were mostly consistent with that observed in monotherapy studies.10 Specifically, camizestrant steady state Cmax and AUC on C2D1 and geomean plasma concentrations were consistent with previously reported camizestrant monotherapy values on cycle 1 day 15.10 Additionally, popPK stimulations for camizestrant monotherapy supported these findings.19 Relatively small increases in exposure for camizestrant, detected on C1D18 compared with C2D1, and in exposures for capivasertib, detected on C1D18 compared with popPK derived values from CAPItello-291,14 were observed. Considering the safety profile observed in this trial was consistent with camizestrant as a monotherapy and capivasertib in combination with fulvestrant,10,14,22 these data suggest that any increase in exposure is not clinically significant and does not represent a clinically relevant drug–drug interaction.
In this pretreated population, including previous CDK4/6i, fulvestrant, and/or chemotherapies, camizestrant in combination with capivasertib exhibited encouraging clinical activity, in addition to evidence of ESR1m clearance.10 Furthermore, this encouraging efficacy was seen in participants with and without tumors with ESR1m and in participants with and without PIK3CA/AKT1/PTEN-altered tumors. Capivasertib is now approved in combination with fulvestrant for patients with PIK3CA/AKT1/PTEN-altered tumors in many countries. As camizestrant has demonstrated clinical superiority to fulvestrant as a monotherapy in SERENA-2,12 and has recently reported meeting its primary endpoint (clinical superiority to aromatase inhibitors when administered in combination with CDK4/6i in patients with an emergent ESR1m) in SERENA-6,13 these data support further investigation of camizestrant in combination with capivasertib in the treatment of patients with ER-positive, HER2-negative advanced breast cancer.
This trial has some limitations. As parts I and J of SERENA-1 formed a non-randomized, open-label trial, both participants and investigators were aware that all participants were receiving active treatment, introducing potential assessment biases that could skew results. The trial population was small; however, the number of participants was selected on the basis of obtaining adequate tolerability, safety, PK, and efficacy data for a phase I trial. Finally, it should be noted that the GuardantOMNI™ and Resolution Bioscience custom 10 gene next-generation sequencing assays used in this trial to determine PIK3CA/AKT1/PTEN alterations are not able to detect PTEN loss as comprehensively as alternative next-generation sequencing assays used in previous studies on capivasertib.14,22 The current trial’s assessment of participants with tumors including PIK3CA/AKT1/PTEN alterations may therefore be an underestimation of the frequency of this composite of alterations, although PTEN loss is rare in this patient population.

Conclusions
In this pretreated population of participants with advanced breast cancer, camizestrant 75 mg in combination with capivasertib 400 mg was generally well tolerated, with AEs consistent with each of the combination partners as monotherapy and no evidence of clinically relevant drug–drug interactions. The combination showed encouraging evidence of significant clinical benefit and antitumor activity.
Together, these results support further investigation of camizestrant 75 mg (phase III dose) in combination with capivasertib 400 mg (approved dose, b.i.d. for 4d on/3d off) in patients with ER-positive, HER2-negative negative breast cancer.