CDK4/6 Inhibitors, Other Treatment Advances Show Hope for Patients With Breast Cancer

Stephanie L. Graff, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Stephanie L. Graff, MD

The rise of CDK4/6 inhibitors, PARP inhibitors, and other targeted therapies has allowed for patients with metastatic breast cancer to be treated on an individualized basis, explained Stephanie L. Graff, MD. Nevertheless, much work remains in the coming years for breast oncologists.

Graff said that in estrogen receptor (ER)-positive disease, the CDK4/6 inhibitors abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali) should be utilized across the board in an early-line setting.

All 3 agents have been approved by the FDA in the frontline setting, most recently with ribociclib receiving approval for use in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)—positive/HER2-negative advanced or metastatic disease. The agency also approved ribociclib for use in combination with fulvestrant (Faslodex) for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy. Both decisions were made in July 2018.

Furthermore, the TOPACIO trial showed efficacy and tolerability for the addition of a PARP inhibitor to immunotherapy—in this case niraparib (Zejula) in combination with pembrolizumab (Keytruda)—for the treatment of patients with BRCA-positive triple-negative breast cancer. The overall response rate (ORR) was 25%.

“I left the 2018 ASCO Annual Meeting feeling very invigorated and excited and that’s what I shared with the audience here,” said Graff, director of the Breast Program at the Sarah Cannon Cancer Institute HCA Midwest Health, and associate director of the Breast Cancer Research Program at Sarah Cannon Research Institute. “I’m very excited for what’s coming in the treatment of breast cancer.”

OncLive: Please provide background on your presentation on metastatic breast cancer.

In an interview during the 2018 OncLive^® State of the Science Summit™ on A Summer of Progress: Updates from ASCO 2018, Graff discussed the current and evolving landscape of breast oncology and what this means for patients.Graff: One highlight of my presentation was the role of CDK4/6 inhibitors. They are clearly now a mainstay in the treatment of patients with HR-positive metastatic breast cancer. At the 2018 ASCO Annual Meeting, we saw updates looking at both frontline and second-line CDK4/6 inhibitors for a premenopausal population. Interestingly, there was an FDA-pooled analysis from Dr Jennifer Gao that took women with metastatic ER-positive breast cancer across all the CDK4/6 inhibitors and looked to see if all the patient populations equally benefitted. The answer was a resounding “Yes.”

It is clear that CDK4/6 inhibitors need to be used early and used virtually across the board in ER-positive metastatic breast cancer.

Another big topic from the 2018 ASCO Annual Meeting was novel therapy in the HER2-positive metastatic breast cancer space. We also saw updates on medicines like niraparib (Zejula). We are all very comfortable with docetaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) in the frontline setting followed by ado-trastuzumab emtansine (T-DM1; Kadcyla) in the second-line setting. Now, filling that back end of these HER2- positive patients, who are really doing so great, becomes crucial. This year’s meeting finally gave us some of those updates and hope for the future.

Another emerging area of interest at this year’s meeting was more on the PI3K pathway. We saw several different novel compounds in that space and good markers that genomic sequencing can better select patients who will respond to treatment targeting that pathway. It is a time for breast oncologists to break into this world of exploring genomic sequencing to drive treatment. I’m really excited to see these data mature and head into the phase III stage.

Along with CDK4/6 inhibitors, there were some exciting data presented about abemaciclib. Could you speak to that?

We also have dipped our toes into the field of PARP inhibitors, as well as the TOPACIO study, which looked at PARP inhibitors paired with immunotherapy. We saw a really good response there.For the CDK4/6 inhibitors, we saw that there is clear evidence that they’re effective in premenopausal women. We now have premenopausal data for the big 3: ribociclib, abemaciclib, and palbociclib. All of those agents have been used in combination with aromatase inhibitors plus a medicine for ovarian suppression. The fact that premenopausal women are getting the same hazard ratio and same ORR tells us that this is still a very positive, meaningful treatment. This is definitely something I’m doing in my clinic.

What is the design of the TOPACIO trial?

Also, some trials are in progress looking at combining CDK4/6 inhibitors with trastuzumab. They are looking to move these combinations over from the HR-positive space to the HER2- positive space. These are just really exciting opportunities for patients to get therapy that is less toxic.The TOPACIO study took an anti—PD-1 drug and combined it with a PARP inhibitor. It was an early-phase study and took patients with germline BRCA mutations and randomized them. We always suspected that patients with germline BRCA mutations are going to be those who respond well to immunotherapy. Combining that with a PARP inhibitor took 2 novel approaches together.

What updates were presented with sacituzumab govitecan?

Based on all of these data, what does a diagnosis of metastatic breast cancer mean today versus 5 years ago?

Although it was a small trial of fewer than 50 women we saw that of the patients who responded, the vast majority could stay on that treatment for more 1 year. It was nontoxic, safe, and efficacious for a long period of time in combination with a PARP inhibitor. It would be interesting to better understand who the better-selected group is. If we can show good signal in the metastatic setting, we can get this moved down the pike.At the 2018 ASCO Annual Meeting, we got an update about this agent in the metastatic HR-positive setting. Honestly, this agent is showing tremendous ORR across the board. The data presented showed that the HR-positive patients are getting a significant response. It’s clear this drug might break through across many different subtypes of breast cancer.The diagnosis in 2018 is still scary and still very real. About 113 women die every day from this disease. There is nothing that we’ve seen to dramatically change that. However, I continue to feel hope for those patients. There are constantly new medicines, new strategies, and new genomic pathways and signals to help women with this disease.

Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/KEYNOTE-162 (NCT02657889): a phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)— results from ROC cohort. J Clin Oncol. 2018;36 (suppl; abstr 106).