Alisertib Induces Early Signals of Efficacy in Endocrine-Resistant Breast Cancer

Alisertib (MLN8237) as monotherapy and in combination with fulvestrant (Faslodex) stands at the forefront of the clinical investigation of selective AURKA pathway inhibition in patients with endocrine-resistant advanced breast cancer, according to Tufia C. Haddad, MD.

A phase 2 trial (NCT02860000) evaluated the efficacy and safety of alisertib with or without fulvestrant in patients with endocrine-resistant, HER2-negative metastatic breast cancer who had previously received fulvestrant. In the efficacy-evaluable population, all of whom had received prior CDK4/6 inhibitors, the objective response rate (ORR) was 19.6% (90% CI, 10.6%-31.7%) with alisertib monotherapy and 20.0% (90% CI, 10.9%-32.3%) with the combination. Common grade 3 or higher adverse effects that were associated with alisertib included neutropenia (41.8%) and anemia (13.2%).

“Further evaluation of alisertib in endocrine-resistant breast cancer is warranted,” Haddad said in an interview with OncLive®.

In the interview, Haddad discussed the rationale for inhibiting AURKA in endocrine-resistant advanced breast cancer, the potential role of alisertib in this disease, and how this agent performs in combination with fulvestrant in patients with estrogen receptor (ER)–positive breast cancer.

Haddad is the chair of Practice Innovation in the Department of Oncology (Medical) at Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

OncLive: What is the mechanism of action of alisertib?

Haddad: Alisertib is an AURKA inhibitor. AURKA is an intracellular enzyme and mitotic kinase. Alisertib was initially developed as an anti-mitotic agent to inhibit cell cycle. It had chemotherapy-like properties whereby it was inhibiting cell cycle but doing so through a more targeted approach for this specific mitotic kinase.

My preclinical collaborator in the laboratory, Antonio D’Assoro, MD, PhD, [of Mayo Clinic Comprehensive Cancer Center], discovered a novel non-mitotic action and role for AURKA. He showed in the laboratory that when AURKA is activated, it stimulates the epithelial-mesenchymal transition [EMT] in breast cancer cells. Specifically, when AURKA is activated in luminal ER-positive breast cancer cells that are sensitive to endocrine therapy, these cells undergo that EMT reprogramming and clonal propagation. These cells have stem cell–like features—so they’re more basal, they lose their ER expression, they become resistant to endocrine therapy, and they have enhanced metastatic potential. Alisertib aims to block AURKA potentially in both its mitotic properties as well as its non-mitotic properties with that activation of EMT reprogramming.

What is the rationale for targeting AURKA in the phase 2 trial?

Dr D’Assoro’s laboratory showed that when you target AURKA with alisertib in these cells, you can reverse that phenomenon of EMT. [In] these cells that have become basal-like, lose ER expression, [and] are resistant to endocrine therapy, when you block AURKA with alisertib, you restore that luminal phenotype. The [tumor] cells regain ER expression, they again become sensitive to endocrine therapy, and they have reduced metastatic potential. The rationale for this body of research was to target AURKA in endocrine-resistant advanced breast cancer.

What was the rationale for combining alisertib with fulvestrant in this trial?

In preclinical studies, both in endocrine-resistant cell lines and mouse models, we saw that alisertibalone had excellent antitumor activity, likely because of its anti-mitotic properties. However, in the endocrine-resistant models, [studies] demonstrated that although these cell lines and mouse models were resistant to endocrine therapy [with] drugs such as aromatase inhibitors, letrozole, or selective estrogen receptor degraders [SERDs] like fulvestrant, when you treated them with alisertibcombined with fulvestrant, the tumors were again sensitive to fulvestrant. This combination therapy was additive and synergistic, and appeared to be better than alisertib monotherapy. The rationale to combine these agents was to restore [endocrine] sensitivity. Alisertibwould restore sensitivity to endocrine therapy, then you bring in that endocrine therapy [for treatment].

What early efficacy data were seen with alisertib in this study?

All patients who participated in this clinical trial had advanced metastatic breast cancer that, although ER-positive, had become resistant to endocrine therapy. All patients had received prior fulvestrant and had tumors that had become resistant to fulvestrant. All patients had also received CDK4/6 inhibitors, as those became the standard of care [SOC] during this clinical trial. Additionally, 58.2% of patients had received prior chemotherapy. These patients had seen a lot of prior therapies.

Patients were randomly assigned to receive alisertibmonotherapy or the combination with fulvestrant. We saw a 19.6% ORR and a 24-week clinical benefit rate [CBR] of 41.3% for the patients who received alisertibmonotherapy. The median progression-free survival [PFS] was 5.6 months. For the combination therapy arm, the results were similar [to those in the monotherapy arm]; the ORR in this setting was 20.0%, the 24-week CBR was 28.9%, and the median PFS was 5.4 months.

We didn’t see that the combination therapy outperformed alisertib, however in both arms of the study, these results were encouraging. These types of response rates, CBRs, and median PFS rates were comparable [with those of] some of the other drugs that were being evaluated in this setting of CDK4/6 inhibitor and endocrine therapy resistance. We were encouraged by these early efficacy results.

What safety data were seen so far with alisertib?

Generally, alisertib is a well-tolerated agent. It’s associated with cytopenias—neutropenia and anemia can be observed, and we [observed] low rates of febrile neutropenia. Low-grade gastrointestinal toxicities, particularly nausea, [also occurred], but usually those can be well managed with antiemetic agents. Thankfully, we did not see the high rates of mucositis or mouth sores that had been seen in prior clinical trials with alisertibin other tumor types, where a different schedule for the drug was administered. The drug was well tolerated; approximately one-third of patients required a dose reduction, and [approximately] 10% of patients [in the monotherapy arm] stopped participation in the trial due to toxicities as opposed to progression of their cancer. We saw a favorable safety profile.

What main message would you like your colleagues to know about the trial’s findings?

We have another targeted agent and a novel pathway that has been understudied in breast cancer, the AURKA pathway. We have a drug now that shows significant clinical activity in a clinical setting for which we have no current SOC, which is after progression on a CDK4/6 inhibitor and endocrine therapy.

The toxicity profile was reasonable, and some patients had durable responses to this agent. Although the median PFS was approximately 5.5 months, [approximately] 20% of patients who participated in the study were on treatment for 12 cycles or longer. These are 4-week cycles, so [12 cycles is approximately 1] year or longer of treatment.

Some of the additional work that is ongoing is investigating other approaches with different endocrine agents. Also, now that we have the emergence of oral SERDs, [we are evaluating] other endocrine therapy backbones for alisertib combinations to see if we can improve upon some of the initial results we’ve seen thus far.

How could AURKA inhibitors fill an unmet need for patients with endocrine-resistant metastatic breast cancer?

AURKA is a novel and understudied pathway for targeting [that is] relative to the plethora of drugs that are targeting a different pathway of endocrine resistance, the PI3K/AKT/mTOR pathway. We now have multiple drugs that are approved targeting the PI3K/AKT/mTOR pathway. Although there are multiple treatment options [for patients with advanced breast cancer], we don’t know whether sequential treatment with these agents will be feasible or whether there will be cross-resistance across the pathway more broadly.

Alisertib targeting this novel AURKA pathway could full an unmet need. Because alisertib targets cells with stem cell–like properties, by eradicating the stem cells, [alisertib could have] better therapeutic activity relative to drugs that target other pathways of endocrine resistance. Some of that head-to-head evaluation needs to occur both preclinically and clinically before we can draw conclusions on that. However, we’re excited about that potential.

What are the next steps for this research?

We’re excited that alisertib has now been licensed by Puma Biotechnology and is moving forward for further development in endocrine-resistant metastatic breast cancer. Some of the immediate next steps will be focusing on optimization of the dose and schedule of the drug so we can optimize its efficacy and minimize the toxicities. [We will] focus initially on optimizing the dose and schedule, but then, in anticipation of moving the drug forward for additional efficacy [evaluation], clinical trials [will evaluate alisertib] against some current SOC therapies.

The AURKA pathway is also being evaluated in triple-negative breast cancer. We’re just scratching the surface for how alisertib can have activity in endocrine-resistant breast cancer and across other molecular subtypes.

Reference

Haddad TC, Suman VJ, D’Assoro AB, et al. Evaluation of alisertib alone or combined with fulvestrant in patients with endocrine-resistant advanced breast cancer: the phase 2 TBCRC041 randomized clinical trial. JAMA Oncol. 2023;9(6):815-824. doi:10.1001/jamaoncol.2022.7949