Novel evidence demonstrates the clinical utility of circulating tumour DNA in patients with HR+/HER2- cancers harbouring ESR1 and PIK3CA mutations
For many years now, endocrine therapy in combination with a CDK4/6 inhibitor has been the mainstay of first-line therapy for Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-metastatic breast cancer after the results of several pivotal phase III trials that showed an improvement in patient outcomes versus endocrine therapy alone. Aromatase inhibitors are the combinatorial endocrine therapy of choice for patients with de novo metastatic disease or a metastatic relapse after 12 months or more since the end of adjuvant endocrine therapy.
Positive pivotal randomised trials presented at the 2025 ASCO Annual Meeting confirm the important role of molecular profiling to guide therapy and the emerging role of circulating tumour DNA (ctDNA) in the detection and targeting of resistance mechanisms.
The SERENA-6 study, a phase III switching trial of the next generation oral selective endocrine receptor degrader (SERD) camizestrant in ESR1-mutant breast cancer during first-line treatment, leveraged both novel endocrine therapies and the clinical use of ctDNA-based liquid biopsies (N Engl J Med. 2025 Jun 1).
ESR1 mutations occur in the ligand-binding domain of the estrogen receptor and activate the pathway in the absence of estrogen. They are an acquired mechanism of resistance to aromatase inhibitors and their prevalence increases with a longer duration of endocrine therapy (NPJ Breast Cancer. 2024 Feb 22;10(1):15). They are usually absent from untreated primary tumors and can be detected on biopsies of metastatic lesions and/or ctDNA-based liquid biopsies. SERDs retain anti-tumour activity in the presence of ESR1 mutations.
In the previously reported PADA-1 randomised phase III study, switching from an aromatase inhibitor to fulvestrant upon the detection of an ESR1 mutation while continuing palbociclib led to an improvement of progression-free survival (PFS) (Lancet Oncol. 2022 Nov;23(11):1367-1377). Camizestrant was found to be more active than fulvestrant in the SERENA-2 phase 2 trial (Lancet Oncol. 2024 Nov;25(11):1424-1439). In SERENA-6, 3,325 patients who had received at least 6 months of an aromatase inhibitor plus a CDK4/6 inhibitor were screened, and 3,256 underwent at least one ESR1 mutation test. Of those, 548 patients had a positive test during serial surveillance, and 315 patients without overt metastatic disease were randomised to camizestrant or to continuing treatment with an aromatase inhibitor. Patients in both treatment arms continued the treatment with a CDK4/6 inhibitor.
The study met its primary endpoint of improved median investigator-assessed PFS in the camizestrant arm: 16.0 months (95% confidence interval [CI], 12.7 to 18.2) versus 9.2 months (95% CI, 7.2 to 9.5) with a hazard ratio (HR) for disease progression or death of 0.44 (95% CI, 0.31 to 0.60; P<0.0001). This result was maintained in all specified subgroups. With 27% maturity, the PFS2 hazard ratio was 0.52 (95% CI 0.33 – 0.81) and overall survival (OS) was immature at data cutoff. The results were presented as potentially influencing clinical practice, but questions still remain about the sustainability of such a strategy in terms of patients attrition and related costs, the definition of PFS2 – in the study, after 2 lines of therapy in the experimental arm versus 1 line in the control arm - and the OS benefit. Nevertheless, patients in the camizestrant group experienced a longer time to deterioration of quality of life as measured by the 30-item EORTC quality-of-life questionnaire: 23.0 months versus 6.4 months (HR 0.53; 95% CI, 0.33 to 0.82).
At ASCO 2025, updated results from the INAVO120 study were also presented. The randomised phase III study was conducted in patients with HR+/HER2- tumors harbouring PIK3CA mutations - who represent 40% of all cases of the metastatic population (J Clin Oncol 42, 2024, suppl 16; abstr 1003) -, the more endocrine-resistant population as defined by relapse on or within 12 months of adjuvant endocrine therapy. In the study, 325 patients were randomised to fulvestrant plus palbociclib and inavolisib or fulvestrant plus palboclib and placebo (N Engl J Med. 2024 Oct 31;391(17):1584-1596). The study met its primary endpoint of improved PFS and the PIK3CA inhibitor inavolisib received regulatory approval in this setting. Updated data showed that the addition of inavolisib to placebo led to an improvement in OS compared to standar treatment (34 versus 27 months; HR 0.67). Updated PFS analyses confirmed previously reported results (17.2 vs 7.3 months). Time to chemotherapy was significantly delayed with the addition of inavolisib, and no new safety signals were observed. The rate of all-grade hyperglycemia in the inavolisib arm was 63.4% (6.8% G3/4). The lack of crossover and the low rate of post-progression use of PI3K inhibitors (only 14 patients in the placebo arm) were discussed at the end of the session.
Finally, the primary endpoint results of the phase III VERITAC-2 trial investigating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) targeting and breaking down the estrogen receptors found on cancer cells, were discussed (J Clin Oncol 43, 2025, suppl 17; abstr LBA1000). In the study, 624 patients were randomised to either receive vepdegestrant or fulvestrant after progression on prior CDK4/6 inhibition treatment. Stratification factors were the detection of ESR1 mutations and the presence of visceral disease. In the ESR1-mutant population, median PFS by blinded indipendent central review (BICR) was 5 months in the vepdegestrant arm compared to 2.1 months in the fulvestrant arm (HR 0.58). The most frequent adverse events were fatigue, liver function tests increase and nausea, with 20% of grade 3 or grade 4 treatment-emergent adverse events (TEAEs), the more frequent being neutropenia. Following these results, vepdegestrant becomes the third novel endocrine therapy after elacestrant (J Clin Oncol. 2022 Oct 1;40(28):3246-3256) and imlunestrant (N Engl J Med. 2025 Mar 27;392(12):1189-1202) to improve outcomes in a phase III study in HR+/HER2- metastatic breast cancer with ESR1 mutations.
