The HR-Positive Breast Cancer Treatment Paradigm Sits on the Cusp of Significant Shifts

Ongoing research may solidify the roles of oral selective estrogen receptor degraders (SERDs), PARP inhibitors, and additional targeted therapies, particularly after progression in CDK4/6 inhibitors, in the management of hormone receptor (HR)–positive breast cancer, according to Shipra Gandhi, MD. 

“We are living in an interesting era where we have multiple options available for patients [with HR-positive breast cancer],” Gandhi said in an interview with OncLive^® following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Gandhi highlighted key points that she shared at the meeting, touching on data unfolding in the realm of oral SERDs for patients with HR-positive breast cancer and emerging treatment options for patients who have progressed on CDK4/6 inhibitors. She also expanded on the importance of conducting research exploring the efficacy and tolerability of novel regimens combining standard-of-care targeted agents in this population.

Ongoing research with oral SERDs includes the phase 1/2 MORPHEUS BC trial (NCT03280563), which is investigating giredestrant (GDC-9545) plus everolimus (Afinitor) in patients with estrogen receptor–positive, HER2-negative, locally advanced or metastatic breast cancer. Findings from an interim analysis this study, which were presented at the 2024 ASCO Annual Meeting, showed an overall response rate (ORR) of 40.0% (95% CI, 16.34%-67.71%) with giredestrant plus everolimus (n = 15) vs 5.6% (95% CI, 0.14%-27.29%) with giredestrant alone (n = 18).1 All responses were partial responses.

Gandhi also explained how data from the phase 2 TBCRC 048 trial (NCT03344965) may broaden the use of PARP inhibitors across patients with various genetic alterations. In expansion cohorts of the TBCRC 048 trial, patients with metastatic breast cancer and germline PALB2 mutations who received olaparib (Lynparza) monotherapy (n = 24) achieved an ORR of 75% (80% CI, 60%-86%).2 Furthermore, those with somatic BRCA1/2 mutations (n = 30) achieved an ORR of 37% (80% CI, 25%-50%).

Gandhi is an assistant professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

OncLive: What are the current and potential roles for oral SERDs in HR-positive breast cancer?

Gandhi: The only oral SERD approved right now for metastatic HR-positive breast cancer is elacestrant, and that is based on data from the phase 3 EMERALD study [NCT03778931]. The randomized clinical trial enrolled patients with advanced HR-positive breast cancer, all of whom had received prior CDK4/6 inhibitors, and patients were assigned to receive elacestrant or endocrine therapy of physician’s choice. In patients who had ESR1 mutations and endocrine-sensitive disease, which was defined as those who had been on CDK4/6 inhibitors for 12 months or longer, there was a median progression-free survival [PFS] benefit [seen with elacestrant], at 8.6 months vs 1.9 months [with endocrine therapy, translating to] a delta of 6.7 months.

There have also been data presented from the SERENA-2 trial [NCT04214288], which was a phase 2 trial that investigated oral camizestrant [AZD9833], and there was PFS benefit seen [with this agent vs fulvestrant (Faslodex)] in patients with ESR1 mutations. Based on this study, there is a larger phase 3 study occurring, SERENA-6 [NCT04964934], that is investigating camizestrant as the oral SERD, and it is enrolling patients with metastatic HR-positive breast cancer. Circulating tumor DNA [ctDNA] is being used to test for ESR1 mutations, so patients who are ctDNA positive for ESR1 mutations who are on an aromatase inhibitor [AI] and a CDK4/6 inhibitor are being randomly assigned to receive oral camizestrant with a switch of CDK4/6 inhibitor or continue the same CDK4/6 inhibitor with an AI.

Importantly, in this trial, even based on the presence of the ESR1 mutation in ctDNA without any radiological disease progression, patients are receiving camizestrant. This will be an exciting trial; we have to watch to see the data. Additionally, oral imlunestrant [LY3484356] is being studied in the phase 3 EMBER-3 trial [NCT04975308]. That is another [trial] to watch for.

We also have the FDA approval of oral elacestrant [Orserdu] for patients with ESR1 mutations, and we are using capivasertib [Truqap] or alpelisib [Piqray] for those with PIK3CA mutations, but right now, we cannot use the 2 [classes of agents] together. Trials are studying these [agents in] combination, such as the phase 1/2 ELEVATE trial [NCT05563220] that is investigating the combination of oral elacestrant with alpelisib or everolimus [among other combinations as well]. Furthermore, the MORPHEUS BC trial is investigating [combinations of] other oral SERDs. These are interesting combination trials we want to watch out for.

What ongoing research may inform treatment decisions following progression on CDK4/6 inhibitors?

If there are no targetable mutations [in patients who have progressed] on CDK4/6 inhibitors, one choice is that we could continue the CDK4/6 inhibitor. The other choice, if there’s no targetable mutation, is that we could use everolimus with endocrine therapy, which is a regimen we have been using for a long time.

If there are targetable mutations present, we have capivasertib for PIK3CA/AKT mutations or PTEN alterations. We have elacestrant for ESR1 mutations. The other treatment we have is for patients who have germline BRCA mutations, where we have approvals of PARP inhibitors based on the phase 3 EMBRACA [NCT01945775] and OlympiAD [NCT02000622] trials.

Data from expansion cohorts of the TBCRC 048 trial presented at the 2024 ASCO Annual Meeting showed that we can potentially extend the use of PARP inhibitors, even for tumors with somatic BRCA mutations or germline PALB2 mutations. The ORR was 75% in patients with germline PALB2 mutations [who received olaparib monotherapy]. That’s another setting where we can use PARP inhibitors.

Lastly, for patients with PIK3CA mutations, we also have seen data from the phase 3 SOLAR-1 trial [NCT02437318], a trial that evaluated alpelisib. However, alpelisib is associated with a lot of adverse effects, so more of us are moving away from that approach and using capivasertib for patients with PIK3CA mutations.

What does the future look like for neoadjuvant and adjuvant HR-positive breast cancer management?

We are using newer agents in the metastatic setting, but we have also started using them in the neoadjuvant and adjuvant settings. For example, CDK4/6 inhibitors have now moved into the adjuvant setting, and antibody-drug conjugates are being increasingly tested in the neoadjuvant and adjuvant settings, [although they are] not yet approved [for that indication]. One question is: If a patient recurs after these regimens, what is the correct regimen to use in the metastatic setting? That is a big question that ongoing or upcoming trials will be designed to investigate.

In the second line after progression on CDK4/6 inhibitors we have 2 mutations. Are we going to target both the mutations together or are we going to still go with sequencing agents? If we are going to use targeted agents for both the mutations together, then what toxicities will patients experience? What are the pros and cons of combining these agents vs giving them sequentially? Those are some of the unanswered questions that we’ll have to watch out for [answers to].

References

1. Wander SA, Stemmer SM, Rugo HS, et al. Interim analysis (IA) of the giredestrant (G) + everolimus (EVERO) arm in MORPHEUS Breast Cancer (BC): a phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative, locally advanced/metastatic BC (LA/mBC). J Clin Oncol. 2024;42(suppl 16):1059. doi:10.1200/JCO.2024.42.16_suppl.1059
2. Tung NM, Robson ME, Nanda R, et al. TBCRC 048 (olaparib expanded) expansion cohorts: phase 2 study of olaparib monotherapy in patients (pts) with metastatic breast cancer (MBC) with germline (g) mutations in PALB2 or somatic (s) mutations in BRCA1 or BRCA2. J Clin Oncol. 2024;42(suppl 16):1021. doi:10.1200/JCO.2024.42.16_suppl.1021