Earlier Introduction of ADCs, PARP and CDK4/6 Inhibitors Improve Outcomes in Breast Cancer

Joanne Mortimer, MD

The evaluation of olaparib (Lynparza) and abemaciclib (Verzenio), as well as trastuzumab deruxtecan, in earlier lines of therapy has demonstrated an improvement in invasive disease-free survival (iDFS) and progression-free survival (PFS), respectively, for patients with breast cancer, creating 3 new treatment paradigms within the past 2 years, explained Joanne Mortimer, MD.

“The pace of change in how we manage breast cancer is so rapid, it’s hard to keep up in a subpopulation of breast cancer, let alone all of breast cancer or all of oncology. We are making great strides and, increasingly, targeted therapies such as the PARP inhibitors and HER2-directed therapies are really revolutionizing the outcomes of patients with metastatic breast cancer and early-stage disease,” Mortimer said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on breast cancer.

In the interview, Mortimer discussed current applications for HER2-directed antibody-drug conjugates (ADCs), CDK4/6 inhibitors, PARP inhibitors, and checkpoint inhibitors in early-stage and metastatic breast cancer. She is a medical oncologist; the Baum Family Professor in Women’s Cancers; associate director, Education and Training, Comprehensive Cancer Center; vice chair and professor, Department of Medical Oncology and Therapeutics Research; and director, Women’s Cancer Programs, at City of Hope.

OncLive^®: What have been some of the most importance changes in the management of HER2-positive breast cancer?

Mortimer: One of the most important in the past 12 to 18 months has been the use of the subcutaneous fixed dose of trastuzumab [Herceptin] and pertuzumab [Perjeta], which allows patients to get a subcutaneous injection over 10 minutes every 3 weeks instead of getting infusional therapy. That [regimen] has been proven to be comparable with infusional trastuzumab and pertuzumab in the neoadjuvant setting.

Another important study was DESTINY-Breast03 [NCT03529110], which compared fam-trastuzumab deruxtecan-nxki (Enhertu) with TDM-1 [ado-trastuzumab emtansine (Kadcyla)]—2 antibody-drug conjugates—as secondline therapy in patients whose disease has progressed after first-line therapy. The results showed that trastuzumab deruxtecan had a significantly higher response rate, duration of response [DOR], and [overall] outcome compared with T-DM1. In fact, the median PFS had yet to be achieved [with trastuzumab deruxtecan at data cutoff]. The [National Comprehensive Cancer Network] guidelines have [since] changed: They don’t completely exclude T-DM1 as second-line therapy, but [they list trastuzumab deruxtecan as a favored agent in this setting because] the data from DESTINY-Breast03 suggest that trastuzumab deruxtecan is superior to T-DM1.

Where else has trastuzumab deruxtecan shown benefit?

Trastuzumab deruxtecan is really an amazing drug. [In addition to an updated analysis of the DESTINY-Breast03 trial, we also saw very compelling efficacy data with trastuzumab deruxtecan] from the 2021 San Antonio Breast Cancer Symposium in patients with HER2-low disease. We also saw data that the drug worked in HER2 0+ patients, which [theoretically] makes no sense since it’s an ADC, so if there’s no HER2, what is this drug doing? Also interesting were the [data we saw with the agent in the] management of brain metastases.

Compared with T-DM1, trastuzumab deruxtecan had a better PFS in the [central nervous system]. This is really a very important drug and one that will receive more indications. The fact that the drug isn’t purely [targeting] HER2 and the fact that it crosses the blood-brain barrier really opens a lot of avenues for other indications for the drug.

What trials will be important to watch in the HER2-positive setting?

Many ongoing trials are evaluating combinations, including those adding trastuzumab deruxtecan to tucatinib [Tukysa]. It will be interesting to see those results, because tucatinib and trastuzumab deruxtecan have impressive responses and DOR, but they also have toxicity. In contrast, we’ve gotten used to T-DM1 not having much in the way of systemic toxicity, such that you can have patients on it for years. It’s hard for patients to stay on trastuzumab deruxtecan for a very long period.

Similarly, with tucatinib, the diarrhea that patients get with tucatinib and trastuzumab and capecitabine can be significant. Keeping patients on therapy long term is a bit of a challenge sometimes. It will be interesting to see how these [data] play out long term in terms of whether there’s an advantage to putting patients on 2 of these newer agents at the same time.

Your colleague, Niki Patel, MD, of City of Hope, presented on updates in hormone receptor (HR)–positive breast cancer. How has the utility of CDK4/6 inhibitors broadened in scope?

Dr Patel talked about the three CDK4/6 inhibitors and how we have survival data for all of them. The most important advance in the past year with the CDK4/6 inhibitors is the approval of abemaciclib [Verzenio] in the setting of high-risk, HR-positive breast cancer. iDFS was statistically improved by taking 2 years of abemaciclib after completion of neoadjuvant chemotherapy. Many of the women included in that trial were patients receiving neoadjuvant therapy, and it’s rare that a patient with HR-positive disease has a complete pathologic response [pCR]. It’s critical that we pay attention to these patients and give them the opportunity to be on a CDK4/6 inhibitor like abemaciclib that decreases relapse.

Yuan Yuan, MD, PhD, of City of Hope, gave a presentation on the use of immunotherapy in triple-negative breast cancer (TNBC). How have treatment recommendations changed since the withdrawal of atezolizumab (Tecentriq) in the metastatic setting?

In the triple-negative arena, Dr Yuan reviewed the current data [with immunotherapy]. Initially, the checkpoint inhibitor atezolizumab was used in advanced disease and had a positive outcome in combination with nab-paclitaxel [Abraxane], but then when combined with paclitaxel, there was no advantage. It appears that the drug is likely to be abandoned and surpassed by pembrolizumab [Keytruda] at this point.

Pembrolizumab has been used in the neoadjuvant setting, which seems to be associated with an increased pCR regardless of PD-L1 status. In patients with metastatic disease, PD-L1 positivity should be looked for; the addition of pembrolizumab does improve breast cancer outcomes in metastatic disease when combined with drugs like taxanes.

In the final presentation, Daphne B. Stewart, MD, MS, of City of Hope, shared insight on the use of PARP inhibitors throughout breast cancer. In what settings have they had the greatest impact?

Dr Stewart reviewed the importance of PARP inhibitors in breast cancer. We already had data that showed that that PARP inhibitors may be somewhat advantageous to chemotherapy in women who have BRCA1/2 deleterious mutations and metastatic disease. [Then there’s] the OlympiA trial [NCT02032823], the most recent adjuvant trial, which showed that the addition of 1 year of olaparib [Lynparza] to chemotherapy and endocrine therapy in this high-risk population of patients with TNBC or HR-positive breast cancer who had BRCA mutations was associated with an improvement in disease-free and overall survival [OS].

Notably, OS looked to be better, but it did not meet the prespecified statistical end point, so more data will be forthcoming. However, the data are convincing enough that olaparib should be considered in this high-risk population of patients.