Evolving Post–CDK4/6 Inhibitor Strategies Reflect Need for Precision Approaches in HR+ Breast Cancer

The treatment paradigm for hormone receptor–positive breast cancer post-CDK4/6 inhibition is entering a rapid state of evolution, reflecting the need for novel endocrine therapies and targeted agents that improve historically low survival outcomes for patients in the second-line setting and beyond, according to Kevin Kalinsky, MD, MS, FASCO.

“How we're treating patients in 2025 is going to be different in subsequent years, because we're [developing] additional agents like more selective PI3K and AKT inhibitors,” Kalinsky stated in an interview with OncLive®.“What's going on now is only going to continue to evolve.”

In the interview, Kalinsky discussed the need for additional endocrine-based treatments and targeted therapies in the post–CDK4/6 inhibitor setting; spotlighted key data from the 2025 ESMO Congress that could support potential FDA approvals in this space, including data from the phase 3 VIKTORIA-1 (NCT05501886) and evERA (NCT05306340) trials; and underscored the importance of personalizing approaches based on patient-specific factors and mutational profiles.

Kalinsky is a professor and director in the Division of Medical Oncology of the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as director of the Glenn Family Breast Center at Winship Cancer Institute in Atlanta, Georgia.

OncLive: In recent years, we’ve seen a plethora of trials and agents evaluated in the post–CDK4/6 inhibitor setting in HR-positive breast cancer. What has driven the need to improve strategies in this setting?

Kalinsky: There has been a need for us to have additional endocrine-based treatments, along with targeted therapies, that could really improve how patients do post–CDK4/6 inhibition with endocrine therapy, which we commonly give as frontline therapy. This need is demonstrated by the fact that for some time, including recent studies like [the phase 3] postMONARCH study [NCT05169567] and others, we've had a challenging time with that second line of therapy going beyond 6 months. What's been exciting is that we've seen some recent data where we can exceed that, often with combinations. That's been the real need: having agents that do better than what we've historically [seen].

With several agents receiving FDA approval in recent years in the post–CDK4/6 inhibitor setting, what are some of the factors that inform treatment selection for this patient population?

When we're giving agents after frontline CDK4/6 inhibitor plus endocrine therapy, these decisions are based upon a few things. What's the cadence of disease? Was that patient on that frontline therapy for 6 months? Were they on it for 3 years? [For] patients who are on [CDK 4/6 inhibitor therapy] for a short period of time…how endocrine-sensitive is their tumor, really? Do we need to pivot with a different sort of approach, like capecitabine [Xeloda] or an antibody-drug conjugate, depending upon what's going on? Does the patient have bone-only disease or visceral disease? Is that visceral disease really starting to take off? Those are all important considerations.

[We should also be asking about] the [tumor] genomics, [namely whether] patients have ESR1 mutations, because we have the approval of 2 single-agent, oral selective estrogen receptor degraders [SERDs]—[elacestrant (Orserdu) and imlunestrant (Inluriyo)]. [I also want to know whether] patients have a PI3K/AKT pathway alteration, [because] we have approval for fulvestrant [Faslodex] plus capivasertib [Truqap]. Those sort of considerations influence what we give.

At what point in the disease stage are you testing for these alterations?

The most important time when one is thinking about doing testing at the time [a patient is] diagnosed with metastatic disease, is really when you have a patient who is a candidate for alpelisib [Piqray]. They have endocrine therapy that they received in the early-stage setting, and they recurred on or within 12 months of said endocrine therapy. If they have a PIK3CA mutation, then I would argue that the standard of care [SOC] at this point is fulvestrant plus palbociclib [Ibrance] plus alpelisib, which is a PI3K inhibitor, as we've now seen an overall survival benefit [with this agent]. Otherwise, it is very important that we've at least performed genomic testing at the time of progression on that frontline endocrine therapy plus a CDK4/6 inhibitor, because we have targeted therapies based upon patients’ mutational profiles.

What data from ESMO 2025 could help further shape the post-CDK4/6 inhibitor treatment paradigm?

ESMO 2025 was a very good meeting that had data across all of our subtypes of breast cancer. In the metastatic estrogen receptor–positive setting, we saw some interesting data with gedatolisib [PF-05212384], which is a PI3K/mTORC1/2 inhibitor, from [VIKTORIA-1].1 [This study included] patients with PIK3CA wild-type disease, where we saw that giving gedatolisib along with endocrine-based therapy was better than giving endocrine-based therapy—in this case, fulvestrant—by itself.

[Outcomes with] the triplet of gedatolisib along with palbociclib [and fulvestrant] were numerically even better [than the doublet].Those data were quite interesting. We saw a really nice median PFS in both arms, although [it was] slightly better with the triplet compared to the doublet, [at 9.3 months (95% CI, 7.2-16.6) and 7.4 months (95% CI, 5.5-9.9), respectively]. This comes with the understanding that the adverse effects of that drug include stomatitis, and we do need to monitor for blood sugar. Also, the drug is given intravenously for 3 weeks on and 1 week off.

Then the other interesting study that we saw was the evERA study, which was for patients who were randomly assigned to fulvestrant plus endocrine-based treatment, of which a good proportion of them had fulvestrant plus everolimus [Afinitor] vs giredestrant, which is an oral SERD, along with everolimus.2 In that study, we saw a very nice median PFS favoring the giredestrant arm [vs the SOC]. There was a benefit in the intention-to-treat [ITT] population [HR, 0.56; 95% CI, 0.44-0.71; P <.0001], as well as those who have ESR1 mutations [HR, 0.38; 95% CI, 0.27-0.54; P <.0001]. In a smaller exploratory analysis, they did not see benefit for those who are ESR1 wild-type [HR, 0.84; 95% CI, 0.59-1.18], though I did mention that the ITT population was positive. We'll see if the drug ultimately gets approved and what the indication will be.

The other thing just to note is that there were really no added toxicities with giredestrant. A lot of the toxicities were due to everolimus, like stomatitis. Those were the larger randomized studies that will likely lead to approvals for our patients in terms of therapeutics and clinic.

How do these data underscore the need for a personalized approach to treatment within this setting?

What's been clear is that after frontline therapy, it's complicated. We have different options available. Do you switch the endocrine therapy and give a CDK4/6 inhibitor? Do you use fulvestrant plus capivasertib? Do you give an oral SERD? Will we have access to giving, for instance, elacestrant plus abemaciclib [Verzenio]?

Ultimately, this is going to be an ever-evolving field. We always need to do what's best for our patients, and that includes [asking]: how long were they on their prior therapy? Is the disease endocrine-sensitive? How aggressive is it? Where are the sites? What are the patient's comorbidities? Does the patient have significant diabetes? Are they going to be able to tolerate something like capivasertib?

How we're treating patients in 2025 is going to be different in subsequent years, because we're [developing] additional agents like more selective PI3K and AKT mutation inhibitors; we're also having specific CDK inhibitors. What's going on now is only going to continue to evolve.

References

1. Hurvitz SA, Layman RM, Curigliano G, et al. Gedatolisib plus fulvestrant, with & without palbociclib, vs fulvestrant in patients with HR+/HER2-/PIK3CA wild-type advanced breast cancer: first results from VIKTORIA-1. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA17.
2. Mayer E, Tolaney SM, Martin M, et al. Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i): Primary results of the phase III evERA BC trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA16.