Combination Regimens May Expand Options for HR+ Breast Cancer Post-CDK4/6 Inhibitors

Shipra Gandhi, MD

Patients with hormone receptor (HR)–positive breast cancer who have experienced disease progression on a frontline CDK4/6 inhibitor in the metastatic setting may benefit from continuing CDK4/6 inhibition or switching to a different class of agents in the presence of targetable mutations, according to Shipra Gandhi, MD. She emphasized that the introduction of combination strategies may further complicate this arena.

In an interview with OncLive®, Gandhi, an assistant professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York, discussed factors influencing treatment decision-making for patients with advanced HR-positive breast cancer who have progressed on CDK4/6 inhibitors, including the role of capivasertib (Truqap) in this setting. She also stressed ways that clinical trial designs should be improved to more accurately determine the efficacy of standard-of-care therapies alone or in combination regimens.

Gandhi shared research updates regarding the use of oral selective estrogen receptor degraders and PARP inhibitors in patients with HR-positive breast cancer in another article.

OncLive: How do you decide which patients with HR-positive advanced breast cancer should continue a CDK4/6 inhibitor and which should switch to a different therapy?

Gandhi: There are several strategies we could adopt in the setting after progression on frontline CDK4/6 inhibitors. We could either continue the CDK4/6 inhibitor or we could switch therapy based on the presence or absence of targetable mutations. We’ve seen data from 2 phase 2 trials, PALMIRA [NCT03809988] and PACE [NCT03147287], which explored continuing palbociclib [Ibrance] after progression on palbociclib. We have data from the phase 2 MAINTAIN trial [NCT02632045], which investigated switching the CDK4/6 inhibitor to ribociclib [(Kisqali) after progression on palbociclib], and we have data from the phase 3 postMONARCH trial [NCT05169567], which evaluated switching the CDK4/6 inhibitor to abemaciclib [(Verzenio) after progression on palbociclib or ribociclib].

For the approaches where palbociclib was continued after palbociclib no improvement was seen in progression-free survival [PFS]. However, in the other 2 trials, MAINTAIN and postMONARCH, where the CDK4/6 inhibitor was [switched to] ribociclib and abemaciclib, respectively, we saw modest PFS benefits. Subgroup analyses from these trials found that most of the benefit was seen in patients who had endocrine-sensitive disease, meaning they had been on a prior CDK4/6 inhibitor for more than 1 year or did not have visceral disease.

I would use the approach of continuing a CDK4/6 inhibitor in patients with endocrine-sensitive disease, specifically patients who don’t have targetable mutations. In the other patients, where there is [evidence of] a targetable mutation or endocrine-resistant disease, I would possibly consider switching therapy.

How did the combination of capivasertib and fulvestrant (Faslodex) perform in patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer in the phase 3 CAPItello-291 trial (NCT04305496)?

CAPItello-291 was a randomized clinical trial that enrolled patients with metastatic HR-positive breast cancer. Approximately 51% of these patients had already received prior CDK4/6 inhibitors. These patients were randomly assigned to either receive capivasertib with fulvestrant or fulvestrant alone. Capivasertib was given on a schedule of 400 mg twice a day for 4 days on and 3 days off.

A PFS benefit was seen [with the addition of capivasertib to fulvestrant]. [The median PFS] was 3.6 months [with fulvestrant alone vs] 7.2 months [with the addition of capivasertib] in all-comers.1 However, when the investigators evaluated patients who had PIK3CA mutations, AKT1 mutations, or PTEN loss, the median PFS was 3.1 [months with fulvestrant alone] vs 7.3 months [with the addition of capivasertib], with an HR of 0.50. These are the patients for whom the use of capivasertib was FDA approved.² Based on this, for patients who have PIK3CA/AKT1 mutations or PTEN loss, we consider giving capivasertib plus fulvestrant after progression on CDK4/6 inhibitors.

What might the future look like for clinical research in the post–CDK4/6 inhibitor setting?

Many clinical trials have used fulvestrant monotherapy as the comparator arm. The median PFS with fulvestrant monotherapy is 2 months, which means by the time patients have their first scan, they may have already progressed. However, with all these novel approaches, either continuing CDK4/6 inhibitors or switching therapy based on targetable mutations, we are seeing a median PFS of approximately 5 to 8 months. As more clinical trials are being designed in the post–CDK4/6 inhibitor setting, investigators need to consider not using fulvestrant monotherapy as the comparator arm. [Instead], we should be using the combination strategies that are now approved in this area.

[Additionally, for] patients who have both ESR1 mutations and PIK3CA mutations, we are always in a dilemma about sequencing therapy. Will elacestrant [Orserdu] come first, or will capivasertib or alpelisib [Piqray] come first? These are unanswered questions, but in my practice, I have seen that elacestrant is a bit better tolerated compared with capivasertib or alpelisib.

If I’m seeing a patient who has both mutations present and their disease is relatively indolent and endocrine sensitive, I would probably choose elacestrant first and then capivasertib or alpelisib after that. However, ongoing clinical trials are studying combinations of agents targeting both ESR1 mutations and PIK3CA mutations. Those will be important clinical trials to watch out for.

References

1. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
2. FDA approves capivasertib with fulvestrant for breast cancer. FDA. November 16, 2023. Accessed August 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer