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DRUG:

camizestrant (AZD9833)

i
Other names: AZD9833, AZD-9833, AZD 9833
Company:
AstraZeneca
Drug class:
Selective estrogen receptor degrader
3ms
SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer. (clinicaltrials.gov)
P1, N=305, Recruiting, AstraZeneca | Trial primary completion date: Dec 2022 --> Oct 2023
Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)
5ms
Serena-1: Updated analyses from a phase 1 study (parts C/D) of the next-generation oral SERD camizestrant (AZD9833) in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer. (ASCO 2022)
There was no limit on the number of lines of prior endocrine treatment in the advanced setting; prior treatment with CDK4/6 inhibitors and fulvestrant (F) was permitted. The PK and safety profile of camizestrant 75 mg QD in combination with palbociclib is favorable in this mature Phase 1 dataset. Despite extensive pre-treatment - including chemotherapies, CDK4/6i, and F - camizestrant 75 mg QD in combination with palbociclib exhibits encouraging clinical activity. The results from the ongoing Phase 3 studies, SERENA-4 and SERENA-6, will further elucidate the role of this combination in the treatment of patients with HR+/HER2− ABC.
Clinical • P1 data • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative
|
Ibrance (palbociclib) • fulvestrant • camizestrant (AZD9833)
9ms
SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer. (clinicaltrials.gov)
P1, N=340, Recruiting, AstraZeneca | Trial completion date: Sep 2023 --> Dec 2023
Trial completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)
9ms
A Phase 1 Study of AZD9833 in Japanese Women With ER Positive, HER2 Negative Advanced Breast Cancer (clinicaltrials.gov)
P1, N=10, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | N=18 --> 10
Clinical • Enrollment closed • Enrollment change
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative
|
camizestrant (AZD9833)
9ms
AZD9833 China PK Study (clinicaltrials.gov)
P1, N=42, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting
Enrollment open • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • camizestrant (AZD9833)
10ms
SERENA-2: A Comparative Study of AZD9833 Versus Fulvestrant in Women With Advanced ER-Positive HER2-Negative Breast Cancer (clinicaltrials.gov)
P2, N=240, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2022 --> Jun 2023 | Trial primary completion date: Nov 2021 --> Sep 2022
Clinical • Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 positive • ER positive • HER-2 negative • ER positive + HER-2 negative • PGR expression
|
fulvestrant • camizestrant (AZD9833)
11ms
Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer. (PubMed, Expert Opin Investig Drugs)
Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties...Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant...Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.
Journal
|
ER (Estrogen receptor)
|
HR positive
|
tamoxifen • fulvestrant • amcenestrant (SAR439859) • elacestrant (RAD1901) • giredestrant (GDC-9545) • camizestrant (AZD9833) • rintodestrant (G1T48)
12ms
SERENA-4: A Phase III comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive/HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease (SABCS 2021)
In most countries, current standard-of-care first-line treatments include an aromatase inhibitor or fulvestrant, a selective ER degrader, combined with cyclin-dependent kinase 4/6 inhibitors...Patients with recurrent disease must have received adjuvant aromatase inhibitor or tamoxifen therapy for at least 24 months without relapse...Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting.
Clinical • P3 data
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 positive • ER positive • HER-2 negative • ER positive + HER-2 negative
|
Ibrance (palbociclib) • tamoxifen • fulvestrant • anastrozole • camizestrant (AZD9833)
12ms
SERENA-6: A Phase III study to assess the efficacy and safety of AZD9833 (camizestrant) compared with aromatase inhibitors when given in combination with palbociclib or abemaciclib in patients with HR+/HER2- metastatic breast cancer with detectable ESR1 m who have not experienced disease progression on first-line therapy (SABCS 2021)
Patients with HR+/HER2− mBC who have received at least 6 months of 1L AI (letrozole or anastrozole) + CDK4/6i (palbociclib or abemaciclib) and do not have clinical or radiological disease progression will be enrolled into Step 1, the ESR1 m detection phase. Acknowledgments: We thank Julia Mawer, PhD, of Oxford PharmaGenesis, UK, for medical writing assistance, which was funded by AstraZeneca. Funding: The SERENA-6 trial is funded and overseen by AstraZeneca.
Clinical • P3 data • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HR positive • HER-2 negative • ER Y537S • ER D538G
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • letrozole • anastrozole • camizestrant (AZD9833)
1year
Clinical • Enrollment closed
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 positive • ER positive • HER-2 negative • ER positive + HER-2 negative • PGR expression
|
fulvestrant • camizestrant (AZD9833)
1year
Clinical • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 positive • ER positive • HER-2 negative • ER positive + HER-2 negative • PGR expression
|
fulvestrant • camizestrant (AZD9833)
1year
SERENA-3: A Study to Investigate the Biological Effects of AZD9833 in Women With ER-positive, HER2 Negative Primary Breast Cancer (clinicaltrials.gov)
P2, N=92, Recruiting, AstraZeneca | Trial completion date: Jun 2022 --> Jan 2023 | Trial primary completion date: Jun 2021 --> Jan 2023
Clinical • Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER positive • HER-2 negative • PGR expression • ER expression
|
fulvestrant • camizestrant (AZD9833)
1year
Clinical • New P3 trial • Circulating tumor DNA
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative
|
Ibrance (palbociclib) • Verzenio (abemaciclib) • letrozole • anastrozole • camizestrant (AZD9833)
over1year
[VIRTUAL] SERENA-4: A phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease. (ASCO 2021)
Current standard-of-care first-line treatments include an aromatase inhibitor (AI) or fulvestrant, a selective ER degrader (SERD), combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors...Patients with recurrent disease must have received adjuvant AI or tamoxifen therapy for at least 24 months without relapse...Secondary endpoints will include overall survival (up to 8 years), length of second PFS period, objective response, time to chemotherapy, and changes in QoL measures . Enrollment began in January 2021.
Clinical • P3 data
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative
|
Ibrance (palbociclib) • tamoxifen • fulvestrant • anastrozole • camizestrant (AZD9833)
over1year
SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer (clinicaltrials.gov)
P1, N=276, Recruiting, AstraZeneca | Trial completion date: Mar 2023 --> Sep 2023 | Trial primary completion date: May 2022 --> Oct 2022
Clinical • Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)
over1year
Clinical • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER positive • HER-2 negative • ER expression
|
fulvestrant • camizestrant (AZD9833)
over1year
AZD9833 China PK Study (clinicaltrials.gov)
P1, N=42, Not yet recruiting, AstraZeneca
Clinical • New P1 trial • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • camizestrant (AZD9833)
over1year
SERENA-3: A Study to Investigate the Biological Effects of AZD9833 in Women With ER-positive, HER2 Negative Primary Breast Cancer (clinicaltrials.gov)
P2, N=92, Recruiting, AstraZeneca | Trial completion date: Oct 2022 --> Jun 2022 | Trial primary completion date: Oct 2022 --> Jun 2022
Clinical • Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER positive • HER-2 negative • ER expression
|
fulvestrant • camizestrant (AZD9833)
over1year
Clinical • Enrollment open
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • anastrozole • camizestrant (AZD9833)
over1year
SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer (clinicaltrials.gov)
P1, N=276, Recruiting, AstraZeneca | Trial primary completion date: Jan 2022 --> May 2022
Clinical • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)
over1year
Clinical • New P3 trial
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • anastrozole • camizestrant (AZD9833)
almost2years
Clinical • New P2 trial
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative
|
fulvestrant • camizestrant (AZD9833)
almost2years
Clinical • Enrollment open
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER positive • HER-2 negative • ER expression
|
fulvestrant • camizestrant (AZD9833)
almost2years
A Phase 1 Study of AZD9833 in Japanese Women With ER Positive, HER2 Negative Advanced Breast Cancer (clinicaltrials.gov)
P1, N=18, Recruiting, AstraZeneca | Trial completion date: Oct 2023 --> Nov 2022 | Trial primary completion date: Oct 2023 --> Nov 2022
Clinical • Trial completion date • Trial primary completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative
|
camizestrant (AZD9833)
almost2years
Clinical • Enrollment change
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)
almost2years
Clinical • New P2 trial
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER positive • HER-2 negative • ER expression
|
fulvestrant • camizestrant (AZD9833)
almost2years
Clinical • Enrollment open
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative
|
camizestrant (AZD9833)
2years
[VIRTUAL] A randomized, open-label, parallel-group, multicenter phase 2 study comparing the efficacy and safety of oral AZD9833 versus fulvestrant in women with advanced ER-positive HER2-negative breast cancer (SERENA-2) (SABCS 2020)
The first-in-human study, assessing AZD9833 as a monotherapy and in combination with palbociclib (SERENA-1; NCT03616587), established a dose-dependent safety profile with clinical benefit and target engagement in pre- and postmenopausal women at all dose levels. The primary analysis will use a Cox proportional hazards model stratified by prior use of CDK4/6 inhibitors and presence of lung and/or liver metastases to compare progression-free survival in each dose of AZD9833 versus fulvestrant. Another randomized, open-label, parallel-group, pre-surgical study investigating the biological effects of AZD9833 in ER+, HER2˗ primary breast cancer (SERENA-3) is also ongoing.
Clinical • P2 data
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 positive • ER positive • HER-2 negative • ER positive + HER-2 negative
|
Ibrance (palbociclib) • camizestrant (AZD9833)
2years
[VIRTUAL] Updated data from SERENA-1: A Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer (SABCS 2020)
AZD9833 continues to show an encouraging efficacy and dose-dependent safety profile as a monotherapy or in combination with palbociclib. A Phase 2 study comparing the efficacy and safety of three doses of AZD9833 versus fulvestrant (NCT04214288), and a Phase 2 pre-surgical ‘window of opportunity’ study (EUDRA-CT; 2019-003706-2) are ongoing.
Clinical • P1 data • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
ER positive • HER-2 negative • ER mutation • ER Y537S
|
Ibrance (palbociclib) • fulvestrant • camizestrant (AZD9833)
2years
Discovery of AZD9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist. (PubMed, J Med Chem)
This compound was demonstrated to be a highly potent SERD which showed a comparable pharmacological profile to fulvestrant in its ability to degrade ER in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favourable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.
Journal
|
ER (Estrogen receptor)
|
fulvestrant • camizestrant (AZD9833)
2years
Clinical • New P1 trial
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor)
|
HER-2 negative
|
camizestrant (AZD9833)
2years
SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer (clinicaltrials.gov)
P1, N=168, Recruiting, AstraZeneca | Trial completion date: Apr 2022 --> Mar 2023
Clinical • Trial completion date
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)
2years
SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer (clinicaltrials.gov)
P1, N=182, Recruiting, AstraZeneca | Trial primary completion date: Mar 2021 --> Jan 2022
Clinical • Trial primary completion date • Combination therapy
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative
|
Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)
over2years
[VIRTUAL] Not all selective estrogen receptor degraders are equal - Preclinical comparison of AZD9833, AZD9496 and fulvestrant (AACR-II 2020)
The selective ER degrader (SERD) fulvestrant has demonstrated clinical benefit over aromatase inhibitors and the selective ER modulator tamoxifen. AZD9496, on the other hand, demonstrated inferior ERα degradation in several ER+ breast cancer cell lines and partial agonism. This may explain the result of the clinical window of opportunity study, comparing AZD9496 to fulvestrant, in which AZD9496 failed to demonstrate superior degradation of ERα, downregulation of PR expression and reduction in Ki67 positivity.
Preclinical
|
ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER D538G
|
tamoxifen • fulvestrant • AZD9496 • camizestrant (AZD9833)
over2years
[VIRTUAL] Preclinical mechanistic PK/PD-efficacy modeling for AZD9833, a novel next generation oral SERD, to support dose selection during early clinical development (AACR-II 2020)
Objectives: The estrogen receptor alpha (ERα) is highly expressed in breast cancers and is a clinically validated target in oncology. This study provides quantitative mechanistic insights into the links between key biomarker modulation (ER and PR) and anti-tumor responses, supporting our understanding of the required high target modulation needed (>70% modulation of PR in MCF-7 and >85% modulation of ER in CTC-174) for maximal anti-tumor effects in these two animal tumor models. This basic mechanistic understanding is valuable to contextualize compound-induced PD modulation in patients, for given doses and schedules and helps to support dose selection decisions.
PK/PD data
|
ER (Estrogen receptor) • PGR (Progesterone receptor)
|
ER D538G
|
fulvestrant • camizestrant (AZD9833)
over2years
Clinical • P2 data
|
HER-2 (Human epidermal growth factor receptor 2)
|
ER positive
|
fulvestrant • camizestrant (AZD9833)
over2years
[VIRTUAL] A phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast cancer. (ASCO 2020)
At 20 January 2020: 60 patients were treated (median prior therapies 5 (1–9); prior fulvestrant (Fv) 82%; prior CDK4/6i 68%) across five doses; 25 mg QD n=12, 75 mg QD n=12, 150 mg QD n=13, 300 mg QD n=13, 450 mg QD n=10. AZD9833 exposure was dose proportional after multiple doses, with a median terminal t1/2 of 12h. Treatment-related AEs experienced by ≥10% of patients were visual disturbances (53%; 91% G1, 6% G2, 3% G3), bradycardia/sinus bradycardia (45%; 93% G1, 7% G2), nausea (18%; 46% G1, 55% G2), fatigue (13%; 38% G1, 63% G2), dizziness (10%; 83% G1, 17% G3) vomiting (10%; 50% G1, 33% G2, 17% G3), and asthenia (10%; 67% G1, 33% G2).
Clinical • P1 data
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • CDK4 (Cyclin-dependent kinase 4)
|
ER positive • HER-2 negative • ER positive + HER-2 negative
|
fulvestrant • camizestrant (AZD9833)
over2years
[VIRTUAL] Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833 (AACR-I 2020)
Modeling also allowed us to assess the potential for drug-drug interactions with likely co-medications such as CDK 4/6 inhibitors. The PBPK predictions of good human exposure and long t ½ are being explored in the ongoing clinical trial.
PK/PD data • Preclinical
|
ER (Estrogen receptor)
|
camizestrant (AZD9833)