Adjuvant CDK4/6 Inhibitors Lay a Solid Treatment Foundation in HR+, HER2– Breast Cancer

Updated data from the phase 3 monarchE (NCT03155997), NATALEE (NCT03701334), and OlympiA (NCT02032823) trials have further established the treatment paradigm for patients with hormone receptor (HR)–positive, HER2-negative breast cancer, particularly with adjuvant therapies, according to Tanya Gupta, MD.

Additional analyses from the trials, which were predominately presented at the 2024 ESMO Congress and the 2024 San Antonio Breast Cancer Symposium, continued to demonstrate the efficacy of CDK4/6 inhibitors abemaciclib (Verzenio) and ribociclib (Kisqali) and PARP inhibitor olaparib (Lynparza) as adjuvant therapies for patients with HR-positive, HER2-negative breast cancer.

“If a patient is completely open to either [abemaciclib or ribociclib], in my practice, I currently [give] abemaciclib, just because we have longer follow-up data,” said Gupta, of the Palo Alto Medical Foundation in Mountain View, California. “That being said, either therapy is completely appropriate to choose for patients with high-risk disease, given that both studies included patients with high-risk disease, and we have FDA approval for both.”

In an interview with OncLive® following a State of the Science Summit™ on breast cancer, Gupta highlighted data from the 3 pivotal trials, the FDA approval of ribociclib following positive data from the NATALEE trial, and the role of PARP inhibitors as adjuvant therapy.

OncLive: Could you discuss the evaluation of adjuvant abemaciclib in the monarchE study?

Gupta: The monarchE study enrolled patients with high-risk, early-stage HR-positive, HER2-negative, node-positive breast cancer, and they needed to be [randomly assigned] within 16 months of their surgery to participate in this study.1,2 Patients needed to either have 4 or more positive axillary lymph nodes or 1 to 3 lymph nodes with an additional risk factor, and that could be grade 3 disease, a tumor greater than or equal to 5 cm, or a Ki-67 proliferative index greater than or equal to 20%. These patients were randomly assigned to receive standard endocrine therapy, which could be an aromatase inhibitor or tamoxifen, or standard endocrine therapy in conjunction with abemaciclib, which was given for 2 years.1

We now have 5-year invasive disease-free survival [iDFS] data from monarchE that shows an absolute difference of 7.6% in favor of patients receiving abemaciclib. This clearly shows, at 5 years, a very real benefit for these high-risk patients receiving abemaciclib.

What were some of the findings regarding adjuvant ribociclib in the NATALEE study?

The NATALEE study evaluated the use of adjuvant ribociclib.3 In this case, it was for patients with intermediate- and high-risk HR-positive, HER2-negative early breast cancer. This was a little bit different than the monarchE study, which only enrolled patients we would conventionally consider high risk, whereas the NATALEE study enrolled patients who also had intermediate-risk disease in addition to high-risk disease. Intermediate risk, based on the NATALEE study, for example, included some patients who had N0 disease, or anatomical stage IIA, [stage IIB, and stage III] disease, so patients who wouldn’t have been eligible for the monarchE study. In NATALEE, patients received a nonsteroidal aromatase inhibitor vs a nonsteroidal aromatase inhibitor in conjunction with ribociclib. As of ESMO 2024, we now have 4-year follow-up data from this study, and we see an absolute iDFS benefit of 4.9% in favor of ribociclib. Based on this trial, ribociclib is now also FDA approved for patients with intermediate- and high-risk disease.

How has the September 2024 FDA approval of adjuvant ribociclib in HR-positive, HER2-negative breast cancer affected the treatment paradigm for this subtype?

We now have 2 adjuvant CDK4/6 inhibitors that are FDA approved: abemaciclib and now ribociclib. In my practice, if patients are only eligible for ribociclib because they had just intermediate-risk disease, then I talk with patients about adjuvant ribociclib. This is to maintain the way the [monarchE and NATALEE trials] were conducted with their [respective] eligibility criteria. If I have a patient who’s eligible for either therapy, specifically a patient with high-risk disease, where they could receive either abemaciclib or ribociclib, and they would have been eligible for both studies, I usually have an extended conversation with these patients about the data that we have currently from monarchE and NATALEE, along with the safety profile of each drug, because they do differ for some patients. Sometimes hearing those data will make patients favor one therapy vs another, and usually, throughout the conversation, we’re able to arrive at the CDK4/6 inhibitor they would prefer to try.

What were some findings from the OlympiA trial evaluating adjuvant olaparib, especially with updated 6-year follow-up data?

The OlympiA study enrolled patients who had high-risk early breast cancer with germline BRCA 1/2 mutations, and these patients were randomly assigned to receive adjuvant olaparib or placebo for 1 year.4 This study enrolled patients who had both triple-negative breast cancer and HR-positive, HER2-negative breast cancer. Patients with HR-positive, HER2-negative breast cancer had to have quite high-risk disease to be eligible. If they were treated adjuvantly with chemotherapy, they needed to have at least 4 lymph nodes involved, and if they were treated neoadjuvantly, then at the time of surgery, they needed to have a clinical and pathological stage and estrogen receptor status [CPS+EG] score that was greater than or equal to 3 to be eligible.

Now, we have 6-year follow-up data from the OlympiA study, and we see that there is a 6-year overall survival [OS] benefit in favor of olaparib in the intention-to-treat [ITT] population, with the absolute difference being 4.3%.5 When it comes to iDFS at 6 years in the ITT population we also see a sizable benefit with an absolute difference of 9.3% in favor of olaparib. This is an important reminder that for patients who do have a germline BRCA1/2 mutation and are at heightened risk of recurrence, adjuvant olaparib can make a very important difference in helping reduce that risk of recurrence.

Following the OlympiA study, how have PARP inhibitors like olaparib further improved the treatment paradigm?

The data that we have from the OlympiA trial is incredibly compelling, and as we now see at 6-year follow up, receiving adjuvant olaparib for patients who have a BRCA1/2 germline mutation who have high-risk disease does make a substantial difference in reducing the risk of recurrence and in improving OS. Any patient who has high-risk disease who has a germline BRCA1/2 mutation should be considered for an adjuvant PARP inhibitor, namely olaparib, [because of] the OlympiA trial. In my practice and the practice of many of my colleagues, we’ve extrapolated this further than the OlympiA trial. For example, patients who were eligible for the OlympiA trial with HR-positive, HER2-negative disease had to have very high-risk disease. If they were treated with adjuvant chemotherapy, they needed to have 4 or more lymph nodes involved. Therefore, my colleagues and I have extrapolated this data to now sometimes apply adjuvant olaparib to patients who don’t quite meet the eligibility criteria, just because that is particularly high-risk disease.

I certainly would talk to a patient who has 2 or 3 lymph nodes involved about the possibility of adjuvant olaparib if they otherwise met the criteria but note that this wasn’t part of the eligibility criteria of this study. The other practice incorporation that’s happened among myself and many medical oncologists around the United States is that olaparib is sometimes now being considered adjuvantly for patients who carry a PALB2 mutation, which, behaviorally and biologically, is essentially the same as BRCA2. As of ASCO 2024, data showed that using olaparib in patients with a PALB2 mutation and metastatic breast cancer in the Olaparib Extended trial was incredibly effective. Therefore, this and the OlympiA study showed a great benefit [with PARP inhibition] in adjuvant breast cancer treatment, and many of us have begun to consider the use of adjuvant olaparib in patients with PALB2 early-stage, high-risk breast cancer.

References

1. Rastogi P, O’Shaughnessy J, Martin M, et al. Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. J Clin Oncol. 2024;42(9):987-993. doi:10.1200/JCO.23.01994
2. Endocrine therapy with or without abemaciclib (LY2835219) following surgery in participants with breast cancer (monarchE). ClinicalTrials.gov. Updated March 3, 2025. Accessed March 14, 2025. https://www.clinicaltrials.gov/study/NCT03155997
3. Fasching PA, Stroyakovskiy D, Yardley D, et al. Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2– early breast cancer (EBC): 4-year outcomes from the NATALEE trial. Ann Oncol. 2024;35(suppl 2):S1207. doi:10.1016/j.annonc.2024.08.2251
4. Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215
5. Lynparza demonstrated clinically meaningful prolonged survival benefit in early breast cancer in OlympiA phase III trial. News release. AstraZeneca. December 11, 2024.