Kirollos S. Hanna, PharmD, BCPS, BCOP, FACCC: I think we set the stage here for our audience around this patient population. Let’s pivot and go into treatment approaches and focus on the CDK4/6 space, that early patient, high-risk, hormone receptor positivity, HER2 negativity. Sam, we’ve mentioned a lot of exciting things that have happened, but maybe walk me through how that treatment paradigm has shifted. Obviously, with our CDK4/6s, most of them are utilized in the advanced setting. We have abemaciclib [Verzenio] with an FDA approval in earlier lines of setting or the earlier patient minus ribociclib [Kisqali] or palbociclib [Ibrance], for example. How does that look or how has that landscape changed over time?

Samyukta Mullangi, MD, MBA: I would say that the early breast cancer treatment landscape has really been about deploying the promise and potential of precision medicine. Once upon a time, we subjected every woman with early breast cancer to a radical mastectomy. Over the years, we’ve been able to pare back. Surgeons not only don’t do that anymore, but they do less and less I think every year. So now we don’t do completion axillary lymph node dissections for many women with limited nodes and nodal involvement. We don’t do re-excision for close margins after a partial mastectomy. And for older women, we’re not even doing sentinel lymph node biopsies anymore, and I think there’s a similar story in radiation. In medical oncology too, with TAILORx [NCT00310180] and RxPONDER [NCT01272037], I think we’ve been able to show using genomic data that there are many, many women with early breast cancer who don’t need adjuvant chemotherapy and can do just fine with hormone therapy alone. So the takeaway of those 2 trials was that postmenopausal women with an Oncotype DX score of less than 25 even with N1 nodal involvement did not need adjuvant chemotherapy, and many premenopausal women with an Oncotype DX score of less than 16. I would say that trials like monarchE [NCT03155997], which we’ll get into today and OlympiA [NCT02032823] have done the opposite, trying to figure out those subsets of women where we can actually intensify our treatment regimens. Where can we use CDK4/6 inhibitors or PARP inhibitors in the adjuvant setting? And you’ve brought up ctDNA [circulating tumor DNA], so there’s been studies that are looking at if we can use ctDNA as a signal to try and predict folks who are at higher risk for disease relapse. And those have been negative so far. But in general, I think breast cancer, early breast cancer, has just been all about where can we avoid overtreatment, where can we avoid undertreatment.

Kirollos S. Hanna, PharmD, BCPS, BCOP, FACCC: That’s very, very helpful. And obviously, we’re here at ASCO [the American Society of Clinical Oncology annual meeting]. We’re waiting for some really exciting readouts actually later today and into tomorrow, so looking forward to it. Sarah, I’ll turn it over to you. Looking at these clinical trials, give us an overview of some of the key clinical trials with these therapeutics in that adjuvant setting, monarchE, NATALEE [NCT03701334]. All of those have looked at different maybe sub-subsets of patients. There were some variabilities there. How are things looking in terms of the clinical trial space?

Sarah Sammons, MD: In the metastatic setting we have 3 approvals of CDK4/6 inhibitors. We have palbociclib, ribociclib, and abemaciclib. And naturally given their success in the metastatic space, they’ve now gone into phase 3 registrational adjuvant clinical trials to see if women with high-risk hormone receptor-positive breast cancer can derive benefit from them. Palbociclib is really the new kid, the first kid on the block. We’ve seen the results of the 2 adjuvant palbociclib clinical trials first. PALLAS [NCT02513394] was the phase 3 clinical trial that looked at 24 months of adjuvant palbociclib added to endocrine therapy versus endocrine therapy alone, and that resulted, 18 to 24 months ago. And it did not show a benefit in terms of invasive disease-free survival or breast cancer really coming back in the metastatic or local regional areas. Then we saw another palbociclib trial with a different patient selection, PENELOPE-B [NCT01864746]. Patients for PENELOPE-B were those who received neoadjuvant chemotherapy and did not have a pathologic complete response. And those patients were randomized to palbociclib with endocrine therapy for 13 months versus endocrine therapy alone, and again there was no benefit. The PALLAS trial that I mentioned that was negative had some nuances. All of these trials have different patient populations, which we can talk about. PALLAS had a bit of a lower-risk population. About a third of patients were node-negative. And then the only FDA-approved adjuvant CDK4/6 inhibitor in June 2023, is abemaciclib. And that’s based on the results of monarchE. MonarchE randomized women to receive 2 years of adjuvant abemaciclib with endocrine therapy versus endocrine therapy alone, and there was a statistically significant early and sustained invasive disease-free survival benefit. The latest data that I saw was a median follow-up of about 4 years with a 6% benefit. And this was a really high-risk population. When I think of monarchE, I think of cohort 1 which was 90% of the population. Those women or men had to have 4 or more positive lymph nodes, or they had to have 1 to 3 positive lymph nodes, but a high-risk pathologic feature such as grade 3 disease or a T3 tumor, which is over 5 centimeters. So that is the space that we can prescribe adjuvant CDK4/6 inhibitors right now, and that’s the only approval we have. And then NATALEE will be presented this afternoon, which is the adjuvant ribociclib clinical trial. It’s been reported positive in a press release, but we have not seen the data. It is highly anticipated. In this trial, they gave adjuvant ribociclib 400 milligrams, which is lower than the metastatic dose, for 3 years added to endocrine therapy. And I know we’re all very excited to see those results.

Kirollos S. Hanna, PharmD, BCPS, BCOP, FACCC:Yes. Well, that’s exciting. It’s, I think, in the grand scheme of things, the duration of therapy or the dosing of therapy also goes back to the quality-of-life aspect and how it’s going to look from NATALEE.

Sarah Sammons, MD: I think so. I think what’s been puzzling, and I’d love to see what the group thinks about this. Why are we seeing these different results in the metastatic and adjuvant settings in terms of end points with the different CDK4/6 inhibitors? Particularly focused on the adjuvant trials, Heather, what are your thoughts on the different populations?

Heather McArthur, MD: I think it’s been interesting how this whole story has played out because, in the metastatic setting, the PFS [progression-free survival] hazard ratios were exactly the same for every single study, every single CDK inhibitor no matter what the hormone therapy backbone was, no matter whether it was pre- or postmenopausal populations being studied. It was very, very consistent. So it was very interesting at this meeting last year to see a difference in the first-line PALOMA [NCT01740427] palbociclib study in which there was no overall survival [OS] advantage, which they attributed to some degree to loss of patient follow-up and attrition of patient data, versus the ribociclib data which showed a clear improvement in overall survival, and at least in my practice changed my standard of care the next day after ASCO. So it’s hard to know from the metastatic setting, especially given the tremendous consistency in the PFS data across studies, why it’s not translating into that OS advantage consistently. It could be attrition of data. It could be that there are actually meaningful differences between these drugs. I think the adjuvant setting struggles have been a little bit different, and you’ve alluded to those. I think that the duration of treatment with the adjuvant palbociclib study, perhaps the 1-year duration of treatment was not sufficient. It was not an enriched population for high-risk, so there were a lot of patients who had node-negative disease who might not be conventionally considered high risk. And a lot of those patients didn’t get chemotherapy, so there was some innate bias by their practitioner that they didn’t require chemotherapy, and therefore maybe they weren’t so high-risk after all. Whereas, in the monarchE study, almost all the patients participating in that study had received prior chemotherapy. So there are probably some important patient enrichment differences, and as you point out, the duration. Adjuvant palbociclib for 1 year, abemaciclib for 2 years, and then ribociclib for 3 years. And we’ll see that data. And then there are important toxicity issues too which we should probably touch on. Diarrhea with abemaciclib is very potentially manageable, especially if you’re aggressive upfront for those first couple of months. Whereas with the adjuvant palbociclib data, they were somewhat limited because of the neutropenia issue that required interruptions and discontinuations probably more than were expected.

Transcript edited for clarity.