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The next-generation oral selective estrogen receptor degrader (SERD) camizestrant improved progression-free survival (PFS) compared with fulvestrant in patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, the phase II randomized SERENA-2 trial showed.

Compared with a median PFS of 3.7 months for patients receiving fulvestrant, median PFS was 7.2 months for those receiving camizestrant 75 mg (adjusted HR 0.58, 95% CI 0.41-0.81, P=0.0124) and 7.7 months for those taking camizestrant 150 mg (aHR 0.67, 95% CI 0.48-0.92, P=0.0161).

"The results of SERENA-2 support the continued development of camizestrant in ER-positive breast cancer," said presenter Mafalda Oliveira, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, during the San Antonio Breast Cancer Symposium. Two phase III studies of camizestrant at the 75-mg dose in advanced breast cancer -- SERENA-4 and SERENA-6 -- are ongoing.

For patients with a detectable ESR1 mutation, the two doses of camizestrant also led to clinically meaningful improvements compared with fulvestrant (6.3 and 9.2 months vs 2.2 months, respectively; aHR 0.33, 95% CI 0.18-0.58 and aHR 0.55, 95% CI 0.33-0.89).

"Treatment with camizestrant 75 and 150 mg reduced the level of ESR1 mutation ctDNA to undetectable or near undetectable levels by cycle two, day 1, and maintained this to cycle seven, day 1," Oliveira said.

Press conference moderator Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center in Dallas, noted that "there's a clear suggestion that [camizestrant] might be better. In looking at the effect on the ESR1 mutations, it also appears to be better at reducing that titer in the plasma. That is based on basic science that supports that this mutation may respond better to SERDs. Obviously, this is a small study, but the direction seems to be consistent with what the science has told us."

In an email to 口袋女优, Douglas Marks, MD, of the Perlmutter Cancer Center at NYU Langone Hospital-Long Island, said that "while our understanding of acquired endocrine resistance is still limited, it was very encouraging to see that camizestrant demonstrated efficacy, specifically in patients with ESR1 mutations, a patient group for which improved endocrine therapies are certainly needed."

Patients who had been previously treated with CDK4/6 inhibitors and endocrine therapy also experienced a significant reduction in the risk of disease progression or death with the 75-mg dose compared with fulvestrant (aHR 0.49, 95% CI 0.31-0.75), and a nonsignificant reduction with the 150-mg dose (aHR 0.68, 95% CI 0.44-1.04).

Furthermore, patients with lung and/or liver metastases saw a reduction in the risk of disease progression or death with the 75-mg dose (aHR 0.43, 95% CI 0.28-0.65) and the 150-mg dose (aHR 0.55, 95% CI 0.37-0.82) compared with fulvestrant.

Of note, in a small subgroup analysis of patients defined as "without evidence of endocrine disease" or refractory to current endocrine therapies, both agents appeared to have minimal impact on PFS, Marks said. "This subgroup underscores the heterogeneity within ER-positive/HER2-negative disease, and the importance of further investigation into understanding the different resistance mechanisms which impact benefit from endocrine therapies."

SERENA-2 included 240 postmenopausal patients with ER-positive, HER2-negative advanced breast cancer who were candidates to receive fulvestrant monotherapy and who had recurrence or progression on at least one line of endocrine therapy, and had received no prior fulvestrant, oral SERD therapy, or more than one line of endocrine therapy or chemotherapy in the advanced setting.

They were randomized 1:1:1 to 75 mg camizestrant, 150 mg camizestrant, or fulvestrant. There was also a 300-mg camizestrant arm that was discontinued because of a "relatively flat exposure-efficacy relationship from 75 to 300 mg" found in this trial and a previous dose-escalation trial, said Oliveira.

About half of patients had received prior CDK4/6 inhibitor therapy, as planned during the trial's design. Lung or liver metastases were present in 58.3%. Over one-third had a detectable ESR1 mutation at baseline, and all patients had received and progressed on prior endocrine therapy.

Grade ≥3 treatment-emergent adverse events occurred in 12.2% of the 75-mg arm, 21.9% of the 150-mg arm, and 13.7% of the fulvestrant arm. The most common adverse events of any grade with camizestrant were photopsia, sinus bradycardia, fatigue, anemia, asthenia, and arthralgia.

Photopsia occurred more frequently at the higher dose of camizestrant, said Oliveira, "but it is extremely important to note that these are grade 1 events." The mechanism is unclear at this time, but thorough ophthalmologic evaluation did not find structural alterations in the eye.

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