Questions and Controversies in Treating Breast Cancer - Episode 21

Evolving Therapies in HR+ Metastatic Breast Cancer


Aditya Bardia, MD, MPH: We saw the results of the MONARCH 2 trial at ASCO. This was a clinical trial that looked at fulvestrant in combination with abemaciclib as opposed to fulvestrant alone. And essentially, it was a second-line therapeutic trial. So, the trial included patients with postmenopausal breast cancer who had progressed on adjuvant or neoadjuvant AI and within 12 months had metastatic disease or patients who had progressed on first-line endocrine therapy.

So, essentially, this was a second-line trial and in this trial, the combination of fulvestrant/abemaciclib was associated with a major improvement in progression-free survival as opposed to fulvestrant alone. The median progression-free survival was about 16 months as compared to fulvestrant alone, which was around 9 months. I think there are 3 things that should be noted from this trial. The first is that it also validates that the addition of the CDK4/6 inhibitor can potentially reverse endocrine resistance. Even in a second-line setting and beyond, CDK4/6 inhibitors have a role.

The second is that the control arm in this trial did much better as opposed to the control arm in, say, the PALOMA-3 trial. And the reason could be that this was a second-line trial while PALOMA-3 was more of a second-line plus trial. So, PALOMA-3 was a more heavily pretreated patient population as opposed to MONARCH 2, and that’s why the control arm did better, and the addition of abemaciclib did better as well. And there’s no question that fulvestrant/abemaciclib was superior as opposed to fulvestrant alone.

And the third thing to be noted is that abemaciclib appears to be a bit different as opposed to palbociclib or ribociclib. It is given on a continuous schedule as opposed to the 3-week on/1-week off schedule that we use with ribociclib or palbociclib. And also, the most common side effect that is observed with abemaciclib is diarrhea as opposed to neutropenia, which is the most common side effect that we see with palbociclib or ribociclib.

So, we’ve clearly seen that CDK4/6 inhibitors have changed the landscape of ER-positive breast cancer first-line, second-line, and potentially second-line plus. The question is, what to do in a patient who has disease progression and CDK4/6 inhibitors? Should we continue the CDK4/6 backbone like we do for anti-HER2 therapy? For someone with metastatic HER2-positive breast cancer, we always continue the anti-HER2 therapy—be it Herceptin (trastuzumab) or lapatinib, an anti-HER2 therapy backbone is always maintained. Do the same principles apply in ER-positive metastatic breast cancer where we should continue the CDK4/6 backbone? That’s an open question at this time.

There are ongoing trials that are looking at the CDK4/6 backbone question. And an example would be the TRINITI-1 trial. That is a trial specifically for patients who have disease progression on a CDK4/6 inhibitor. Patients continue the same CDK4/6 inhibitor but you add everolimus along with exemestane to see whether the CDK4/6 backbone should be maintained or not. And I think we need more and more of studies like that to essentially look at the CDK4/6 backbone question.

In addition, we need biomarkers that can help us choose specific targeted therapies. And an excellent example would be PI3 kinase mutations. PI3 kinase mutations are the most common mutations that we see in ER-positive breast cancer. And there are PI3 kinase inhibitors that can potentially target those mutations and work very well in that subset.

The first generation of PI3 kinase inhibitors were pan-PI3 kinase inhibitors, which were associated with toxicity, rash, diarrhea, and change in mood. And there is now interest in looking at alpha-selective PI3 kinase. Similar principle to CDK4/6 where we started with pan-CDK inhibitors and then narrowed down to CDK4/6 with alpha-specific PI3 kinase inhibitors. The principle is the same in that we hit the target hard while reducing the off-target effects as well as the side effects.

So, there are 2 ongoing trials: the Sandpiper trial looking at taselisib, which is a beta sparing PI3 kinase inhibitor, as well as the SOLAR-1 trial looking at alpelisib, which is an alpha-specific PI3 kinase inhibitor. Both were in combination with fulvestrant, and fulvestrant alone is the control arm. The results of these trials are positive and would establish the role of PI3 kinase inhibitors in ER-positive metastatic breast cancer, and this would be a genotype-directed therapy because the trial has specific arms for patients who have PI3 kinase mutations.

It’s an exciting time to be in breast oncology, the landscape of ER-positive metastatic breast cancer has changed with CDK4/6 inhibitors. There’s excitement with PI3 kinase inhibitors, excitement with oral selective ER-degraders in the HER2-positive space. There is excitement with novel HER2 TKIs like neratinib. In metastatic triple-negative breast cancer, there is excitement with PARP inhibitors, immunotherapy, and antibody drug conjugates like IMMU-132. So, this is a very exciting time to be in breast oncology. We have a number of agents that would result in improvement in progression-free survival, and essentially make metastatic breast cancer a chronic disease.

Transcript Edited for Clarity