Post-CDK4/6i wars in HR⁺/HER2⁻ breast cancer: is elacestrant a solid contender through the lens of precision oncology

Adding a CDK4/6 inhibitor (CDK4/6i) to endocrine therapy (ET) could improve survival outcomes in HR⁺/HER2⁻ advanced or metastatic breast cancer (1,2). However, recent trials challenged its place in the first-line treatment since the first-line endocrine monotherapy followed on progression by the second-line ET + CDK4/6i yielded similar quality of life, progression-free survival (PFS) or overall survival (OS) compared to the first-line combination followed on progression by the second-line endocrine monotherapy (3). Nevertheless, current standard-of-care (SOC) in the first- or second-line treatment of HR⁺/HER2⁻ advanced breast cancer includes a CDK4/6i. Therefore, mandatory CDK4/6i as an inclusion criterion in the randomized phase III EMERALD trial was a rational decision. However, the optimal treatment or treatment sequencing in the post-CDK4/6i setting is still not well-established since it is a rapidly evolving area considering multiple Food and Drug Administration (FDA)-approved options (mostly biomarker-driven) and/or various ongoing trials assessing new generations of endocrine therapies.

Elacestrant was approved in 2023 by FDA for postmenopausal women or adult men with ER⁺/HER2⁻, ESR1-mutated advanced breast cancer with disease progression following at least one line of ET based on the results from the EMERALD trial (Bidard et al. NCT03778931) (4). It reported a median PFS of 3.8 and 1.9 months in the ESR1-mutated cohorts while they were 2.8 and 1.9 months in the overall cohort for the elacestrant and SOC (fulvestrant or AI) arms, respectively. Bardia et al. performed subgroup analyses of the EMERALD trial by prior ET + CDK4/6i duration as well as clinically relevant parameters and alterations, revealing the best candidates for maximum benefit from elacestrant monotherapy in the post-CDK4/6i setting (5). This study is valuable for several reasons: first, it focuses on a clinically relevant population of patients that progressed after a previous ET + CDK4/6i combination as recommended by clinical guidelines, and patients harboring ESR1 mutations, which are among the most frequently observed resistance mechanisms to the ET. Second, while comprehensive subgroup analyses reveal that the clinical benefit from elacestrant was consistent across subgroups, some parameters (such as PIK3CA H1047X) could diminish it, broadening our understanding of which patients elacestrant is best suited for and thus its clinical utility. Third, the study not only provides clinical efficacy analysis by these subgroups but also a detailed toxicity and safety profile of elacestrant monotherapy. Elacestrant as an oral medication could compare favorably with parenteral fulvestrant in terms of patient preference and comfort, assuming a similar or better safety profile. This study proves that across all subgroups, the majority of adverse events were grade 1/2 and manageable in both arms.

The study has some limitations. First, as acknowledged by the authors, the subgroup analyses were post hoc and exploratory, limiting the strength of the conclusions due to the lack of adjustment for multiple testing. The findings thus should be interpreted cautiously and ideally confirmed in prospective studies. Second, the analyses were performed for only ESR1-mutated cohort. While the ESR1 mutations are frequently observed after ET ± CDK4/6i treatment, the impact of the other key alterations such as PIK3CA and TP53 could be separately studied. Third, the primary endpoint in the EMERALD was PFS but the secondary endpoints included OS. While PFS is an important endpoint, OS data are eventually more clinically meaningful. Mature OS data are needed to fully assess the impact of elacestrant on long-term outcomes and by the subgroups defined by the authors. Finally, the authors highlighted that elacestrant monotherapy had a much lower discontinuation rate compared to CDK4/6i- or PI3K/AKT/mTOR inhibitor-containing regimens. Although endocrine monotherapy could be a valuable alternative for certain patients, especially the elderly, fulvestrant-based combinations are more commonly utilized in the clinic and elacestrant has a potential to replace it as the backbone of these combinations. In the EMERALD trial, it was discontinued for a treatment-related adverse event in 3.4% of the patients while the SOC in the 0.9% (for an adverse event 6.3% vs. 4.4%), signaling that a higher rate of the patients could discontinue the elacestrant-based combination regimens. Nevertheless, elacestrant could hold a significant place in our arsenal against HR⁺/HER2⁻ breast cancer, and we could position it better through the subgroup analyses performed by the authors and additional considerations we summarized below.

The majority of the ESR1-mutated patients enrolled in the EMERALD had a prolonged response to prior ET plus CDK4/6i combination: 71.6% had received a prior ET + CDK4/6i ≥12 months, 20.7% received ≥6 but <12 months, and those receiving <6 months were not specified (5). As highlighted by the authors, the survival curves show a separation of the elacestrant vs. SOC arms in the patients with more prolonged response to prior ET + CDK4/6i after a rapid drop in the first 2 months. Accordingly, while the median PFS for the patients with prior ET + CDK4/6i ≥12 months was 8.61 months, it more than halved (4.14 months) when analyzed for prior ET + CDK4/6i ≥6 months in the elacestrant arm, which remained almost unchanged in the SOC arm. This potentially implies that the elacestrant as monotherapy could be preserved for the former subgroup of patients.

ESR1 mutations are prevalent (up to 60% after AI) but not universal among patients with endocrine resistance. Furthermore, not all ESR1 alterations are equal, and Y537S could hinder not only AI but also fulvestrant activity unlike other ESR1 and Y537X mutations. Consequently, the subgroup analyses for the Y537S mutation should be conducted separately rather than combining it with Y537N. Moreover, some patients in the EMERALD seem to have multiple ESR1 mutations, which was associated with poorer responses to ET-based regimens (6). The efficacy of the elacestrant could have been examined for single versus multiple ESR1 mutations. Although elacestrant is more efficacious in and indicated for ESR1-mutated patients, it could also be a therapeutic option in combination with a CDK4/6i and other targeted therapies in the ESR1 WT patients. Recently, pooled results from the phase 1b ELECTRA (NCT05386108) and phase 2 ELEVATE (NCT05563220) demonstrated that elacestrant + abemaciclib yielded similar PFS outcomes for both ESR1-mutated vs. WT patients (8.7 vs. 7.2 months, SABCS 2024 Poster PS7-07). More importantly, the PFS was almost doubled (16.6 months) in patients who received a prior ET + CDK4/6i ≥12 months. The randomized phase 3 EMBER-3 trial similarly found that imlunestrant + abemaciclib significantly extended PFS independent of ESR1 status while imlunestrant was only effective in the ESR1-mutated cohort, not in the overall cohort (7). Likewise, fulvestrant + abemaciclib in the phase III postMONARCH trial (NCT05169567) demonstrated a statistically significant improvement in PFS after progression on prior ET + CDK4/6i across key clinical and genomic subgroups, irrespective of ESR1 or PIK3CA mutation status (8). Notably, vepdegestrant (ARV-471) monotherapy in the phase 1/2 VERITAC trial (NCT04072952, prior ET and CT plus mandatory CDK4/6i) provided a PFS of 3.7 and 5.7 months in the overall and ESR1-mutated cohorts (SABCS 2022, GS3-03), potentially surpassing the efficacy of elacestrant. Even vepdegestrant, however, is being evaluated in the phase 2/3 trials in combination with CDK4/6i or mTOR inhibitor. Lastly, a recent systematic review and meta-analysis concluded that maintaining treatment with an ET + CDK4/6i in the post-CDK4/6i setting was associated with longer PFS and OS in ESR1 WT patients compared with ET monotherapy, even though prior CDK4/6i duration was not taken into account (9). Thus, it could have been valuable if the same subgroup analyses were provided for the ESR1 WT cohorts, which comprise more than half of all the patients in the EMERALD.

PIK3CA mutations could cause resistance to the endocrine monotherapy in HR⁺/HER2⁻ advanced breast cancer while this was not clearly defined for ET + CDK4/6i. In line, Bardia et al. documented that patients with the worst PFS in the elacestrant arm (vs. SOC) had ESR1 and PIK3CA co-mutations (PFS: 5.5 vs. 1.9 months), especially H1047X (PFS: 4.6 vs. 3.3 months). Importantly, there are multiple therapeutic approaches approved for HR⁺/HER2⁻, PIK3CA-mutated metastatic breast cancer following progression on endocrine-based regimen. The randomized phase III SOLAR-1 trial (NCT02437318) included 20 patients that received a previous CDK4/6i treatment (10). Although the number is low, it demonstrated a survival benefit trend towards the fulvestrant + alpelisib arm (5.5 vs. 1.8 months, HR: 0.48) (10,11). The phase II BYLieve trial (NCT03056755), which allowed 2 previous anticancer therapies and 1 previous chemotherapy in the advanced breast cancer setting, explored this combination in the post-CDK4/6i setting (11,12). It reported a median PFS of 8.0 and 5.6 months for the fulvestrant + alpelisib (cohort A) and letrozole + alpelisib (cohort B), respectively. The randomized phase III CAPItello-291 trial (NCT04305496) has a similar set of criteria to the EMERALD for patient enrollment, except for mandatory CDK4/6i but more than 80% of the patients had previously used it (13). Fulvestrant + capivasertib provided a PFS benefit (5.5 vs. 2.6 months, HR: 0.62) in the overall patient population with prior CDK4/6i exposure, while the HR was 0.49 for patients with AKT pathway alterations and prior CDK4/6i exposure (PFS not provided). Considering that approximately 40% of all ESR1-mutated patients also harbored at least one PIK3CA mutation in the EMERALD (5) and ESR1 WT patients similarly harbor high rates of PIK3CA mutation, the efficacy of the elacestrant could have been assessed in the whole cohort by PIK3CA status. While head-to-head comparison is challenging due to differences in trial designs and patient populations, this could help better positioning of elacestrant in the growing landscape of available options for PIK3CA-mutated breast cancer outlined above. Importantly, elacestrant + alpelisib is currently under investigation in the ELEVATE trial (14), and we reported this combination as a clinically active and tolerable regimen in a heavily pretreated metastatic breast cancer patient (15). Moreover, mutant-selective PIK3CA inhibitors (such as OKI-219 for H1047R) are currently being investigated in clinical trials. It would be interesting to see if such agents could improve benefit from elacestrant for ESR1 and PIK3CA H1047R patients, who need it the most. As PIK3CA mutations could lead to a numerically shorter OS by 10–20% in the PALOMA-3 (NCT01942135) and MONARCH-2 (NCT02107703) trials of fulvestrant + a CDK4/6i, elacestrant could be tested within triplet combinations, similar to fulvestrant + inavolisib + palbociclib in the phase III INAVO120 trial (NCT04191499) (16).

There are other subgroups worth mentioning, such as TP53 and BRCA1/2-mutated patients. TP53 mutations could result in worse PFS and OS after fulvestrant ± CDK4/6i treatment (17). Elacestrant, however, resulted in the PFS benefit compared to the SOC for both ESR1-mutated/TP53 WT (7.39 vs. 1.91 months) and ESR1/TP53 co-mutated (8.61 vs. 1.87 months) patients. Still, the impact of TP53 mutations on the efficacy of elacestrant could be analyzed in the overall cohort to find out if elacestrant could substitute for fulvestrant in this population. Unlike patients with TP53 mutations, patients with ESR1 and BRCA1/2 co-mutations seem to derive less benefit from the elacestrant versus SOC (5.5 vs. 2.1 months) compared to all patients with ESR1 mutations (8.6 vs. 1.9 months). In both randomized phase III EMBRACA (talazoparib, NCT01945775) and OlympiAD (olaparib, NCT02000622) trials, approximately half of the patients in both treatment arms were HR-positive (18,19). HR⁺ patients received a median of 2 lines and at least one endocrine therapy in the EMBRACA and the OlympiAD, respectively. Of all patients, 60–80% also received prior chemotherapy. The median PFS was 8.6 months for talazoparib (vs. 5.6 for standard therapy), and 7.6 months for olaparib (vs. 3.8 for standard therapy) in the whole cohort. Talazoparib resulted in a better PFS for the HR⁺ compared with the triple-negative breast cancer (TNBC) (9.4 vs. 5.8 months) (20). The hazard ratios (HRs) for talazoparib and olaparib were 0.47 and 0.80 for the HR⁺ patients (0.60 and 0.43 for TNBC). Although CDK4/6i was not mandatory and ESR1 status was not considered, talazoparib could still be a better option than elacestrant monotherapy for BRCA1/2-mutated patients, especially if they have not previously received a platinum chemotherapy. However, the ongoing ET + PARP inhibitor (± immunotherapy) trials could provide better alternatives, at least for some patient populations. This could be another setting where elacestrant could form the backbone of the combination regimens. Finally, ESR1-mutated patients with HER2-low status (IHC 1+ or IHC 2+/ISH−) seem to be good candidates for the elacestrant monotherapy compared with the SOC (median PFS: 9.0 vs. 1.9 months). The randomized, phase 3 DESTINY-Breast04 trial of trastuzumab deruxtecan (T-DXd, a HER2 ADC – NCT03734029) versus the physician’s choice (TPC) enrolled HER2-low advanced breast cancer patients, all of whom received a prior chemotherapy and at least one line of ET (if HR⁺) and 70% also received a prior CDK4/6i. It reported a median PFS of 10.0 months (vs. 5.4 months in the TPC arm, HR: 0.55) for patients who previously received a CDK4/6i (without a prior CDK4/6i: 11.7 vs. 5.9 months), albeit not accounting for ESR1 mutations and CDK4/6i duration (21). A more recent exploratory biomarker analysis in the overall cohort demonstrated that T-DXd efficacy was not dependent on the ESR1 status (mPFS for mutant vs. WT: 9.8 vs. 10 months with overall response rates of 54.2% vs. 51.1%) (22). The DESTINY-Breast06 and DESTINY-Breast08 trials in the HER2-low advanced breast cancer, although not allowed prior chemotherapy in the metastatic setting, reported remarkable PFSs with T-DXd monotherapy (13.2 months) and T-DXd + ET (13.4 months with anastrozole and not evaluable with fulvestrant), respectively (23,24). Approximately 90% of all the patients in the DESTINY-Breast06 had received a prior ET + CDK4/6i. These data potentially indicate that elacestrant and T-DXd as monotherapy could have comparable efficacy in the ESR1-mutant, HER2-low subgroup, while T-DXd could be more preferable in the ESR1 WT, HER2-low setting. Still, it should be decided upon the analysis of the EMERALD data for the ESR1 WT, HER2-low subgroup. On the other hand, T-DXd + elacestrant combination could be a viable option in the second or later lines for the HR⁺, HER2-low patients.

In conclusion, we appreciate the detailed subgroup analyses performed by the authors and hope that it could be a routine and preplanned practice in the future clinical trials to better reflect the investigated drug’s clinical efficacy and better match the treatment with the “better candidates”. However, we strongly believe that future clinical trials should be designed based on precision oncology principles to test and enable patient-tailored therapeutic approaches in the era of personalized medicine.

Acknowledgments

We are grateful to all the authors of the original study (Bardia et al.), and all the patients made that study possible.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-13/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-13/coif). The authors have no conflicts of interest to declare.

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