Capivasertib/Fulvestrant Extends PFS With Limited Toxicity in AR-Defiant, HR+/HER2- Advanced Breast Cancer


In an interview with Targeted Oncology, Hope S. Rugo, MD, explained the results of the phase 3 CAPItello-291 trial, and the potential impact of the study on the breast cancer treatment paradigm.

Hope S. Rugo, MD, FASCO

Hope S. Rugo, MD, FASCO

Efficacy results for the combination of capivasertib plus fulvestrant (Faslodex) in patients with aromatase inhibitor (AR)-resistant, hormone receptor (HR)-positive, HER2-negative advanced breast cancer implied that the combination could improve outcomes in this patient population regardless of prior exposure to CDK4/6 inhibitors. The results also confirmed that the combination therapy produces better outcomes than single-agent therapy.1

Results comes from the phase 3 CAPItello-291 trial (NCT04305496), which were published in the New England Journal of Medicine. In the overall population of patients in the study, treatment with the combination of capivasertib and fulvestrant achieved an improved progression-free survival (PFS) compared with placebo (HR 0.60; 95% CI, 0.51-0.71; P < .001). Among those with AKT pathway-altered disease, the hazard ratio for PFS improvement in the capivasertib/fulvestrant arm vs the placebo arm was (HR 0.50; 95% CI, 0.38-0.65; P < .001).

At the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, Hope S. Rugo, MD, presented safety findings from the study, which showed that overall, adverse events were low-grade and manageable. Rates of dose modification and treatment discontinuation were also low in the study.2

In an interview with Targeted Oncology™, Rugo, professor of medicine, and director of breast oncology and clinical trials education at the University of California San Francisco Comprehensive Cancer Center, explained the results of the phase 3 CAPItello-291 study.

Targeted Oncology: Would you provide an overview of the CAPItello-291 study?

Rugo: CAPItello-291 is a phase 3, randomized, double-blind study that evaluated an AKT inhibitor called capivasertib in combination with fulvestrant compared with placebo and fulvestrant in patients who had hormone receptor-positive metastatic breast cancer that had pretreatment with an aromatase inhibitor followed by disease progression. The trial allowed chemotherapy as well as 1 line of chemotherapy, and didn't require CDK4/6 inhibitors, but 69% of patients had CDK4/6 inhibitors and about 20% of patients had a 1 line of prior chemotherapy.

The trial evaluated the addition of the AKT inhibitor, and the trial was designed to look in the intent-to-treat the overall population, and then to look as a coprimary end point of progression-free survival in the patients whose tumors had alterations in the AKT pathway. The trial showed in the patient population that about 40% of patients had alterations in the pathway. There was also a subgroup of patients, 16%, relatively low for a trial like this, who didn't have results from tumor tissue. The tumor tissue wasn't preserved enough, there wasn't enough tumor tissue sent, but they basically had no information about mutation status.

Metastatic Breast Cancer | Image Credit: © freshidea -

Image Credit: © freshidea -

Can explain the efficacy findings.

The results of the trial showed that progression-free survival was significantly improved in patients who received capivasertib with their fulvestrant, whether it was the intent-to-treat population, or the sub population of patients, again, about 40% who had an alteration in the AKT pathway, which is how they've termed it now as opposed to the PI3 kinase pathway. We were interested then in the population who are wild-type for the alterations in this pathway. In that group of patients, which included the unknown group, there was still a benefit. The hazard ratio went up a little bit, but the confidence intervals didn't cross 1. There is still that question about what is going on with the 16% of unknown patients. Hopefully, that data will be obtained by looking at a circulating tumor DNA, and that is dependent on having a good assay looking at p10 in circulating tumor DNA, where you can look at AKT and PIK3CA mutations with p10 still being developed and validated.

What were the safety findings?

The trial also looked at safety aspects. At ASCO 2023, we reported detailed safety analysis of the patients who are treated with capivasertib or with placebo on CAPItello-291 which is helpful, because anytime we have a novel agent, and this might be a novel agent that when we don't know what the regulatory approval will say, or when we'll see approval, but it may be for all comers because the data shows that it's effective in all comers, you want to know what the toxicity is, understand what dose reductions happened, and understand how to counsel our patients when the drug is approved for use. There were 3 common toxicities, diarrhea, rash, and then hyperglycemia, which was not common, but as a sort of key side effect that we wanted to evaluate.

Alpelisib [Piqray] which is the approved alpha specific PIK inhibitor for patients with PIK3CA mutations causes hyperglycemia, particularly in patients who have underlying slightly high hemoglobin A1C's and they have diabetes, but there are some patients who have normal hemoglobin A1C's that become quite hyperglycemic on alpelisib, It can cause rash and diarrhea as well. For oncologists, dealing with hyperglycemia has been the biggest challenge because there were a lot of new drugs and the standard in oral medication may not work for everybody. For the alpelisib trials, we used a hemoglobin A1C cutoff for eligibility of 6.4% for the CAPItello-291 trial, it was 7.9%. You could have up to 7.9%, just not 8% or higher. In the trial itself, the median hemoglobin A1C was in the mid 5’s, so most people didn't have uncontrolled diabetes, which is a good thing. But the rate of diabetes was quite low. We saw only 2 patients who had grade 3 hyperglycemia. Overall, it was about 16% with any grade hyperglycemia.

Diarrhea was much more common and about 9% of patients had grade 3 diarrhea, and then rash overall was in 38%. But grade 3 was not common. We also were interested in looking at the time to developing these toxicities because that's helpful when you're figuring out your follow-up and what medications you want to give patients and how to tell them when to call in. It was a median of about 1 week for diarrhea, 8 days, and a little closer to 2 weeks for rash and diarrhea. which is interesting because diarrhea has a much later timeline from alpelisib that was about 13 to 15 days for those two. Then, the discontinuation rates are an important indicator of how hard it is to control the toxicities. The discontinuation rates were extremely low, which was encouraging. Only 1 patient discontinued for hyperglycemia. The rate of discontinuation for diarrhea was very low. The highest rate was for rash, and that was 4 and a half percent. That was encouraging because by using non-sedating antihistamines, we should be able to control the rash by using it preventively. I think that might be a reasonable thing to do. It could be assertive, and then you just continue with if somebody doesn't get a rash.

Most people don't get a rash with capivasertib. It is interesting because it's dosed intermittently 4 days on 3 days off. That may help with control as well. When we looked at the medications that people used for the toxicities, loperamide [Imodium A-D] was the most common drug used to treat diarrhea. I think it's reasonable to treat diarrhea with loperamide rather than to prophylaxis because the rate of higher-grade diarrhea wasn't very high at all, 9%. That means most people are going to have mild diarrhea and intermittent. In terms of rash. using the preventive antihistamines is a reasonable plan. We didn't do that in CAPItello-291, but when people got a rash, mostly it was controlled with antihistamines, or topical corticosteroids, and very few patients took systemic corticosteroids. That's also encouraging. Then, in terms of the hyperglycemia, it's quite uncommon. Following it, the most common drug that was used was metformin, or glucofine. That is the common oral medication used for hyperglycemia. Overall, it seemed to validate the fact that the toxicity profile from alpelisib is quite good and can be easily managed with standard approaches.

What are the next steps for this trial and research moving forward in the space?

The data from CAPItello-291, which is quite intriguing, also included an initial look at overall survival based on regulatory recommendations. It already shows a trend towards improvement in overall survival. One area is to wait for the overall survival numbers so that we can have a real comparison, and that is expected in 2024. The data from CAPItello-291, which reached his primary end point in the entire population, as well as in the patient population with tumor mutations, has been submitted to the regulatory agency in the United States, and we're waiting for feedback from that. We hope potentially for approval sometime later this year. We'll see what happens with their suggestions and review. Then, the next step is moving it earlier in the course of treatment, and I think is quite reasonable. There's a lot of preclinical data that supports a triplet approach with a CDK4/6 inhibitors along with endocrine therapy. CAPItello-292 [NCT04862663], is evaluating triplet therapy with capivasertib, fulvestrant, and palbociclib [Ibrance]. Initially, either an ongoing phase 1 or phase 1b safety analysis with ribociclib [Kisqali] and will be with abemaciclib [Verzenio]. Then, the triplets can be tested in the first-line setting against standard of care, which would be endocrine therapy plus CDK4/6 inhibitors. That's an exciting next step for this drug. Of course, there's interest in where else it can be moved. Will it work better in the neoadjuvant setting or in the adjuvant setting? There are [also] many other agents that target this pathway that are under investigation.

If approved, how do you think this will impact this patient population?

I think if capivasertib is approved in all comers that many patients will go on to capivasertib when they start fulvestrant in the second- or greater-line. There is another trial, MONARCH [NCT02102490, NCT02107703, NCT02246621], that's looking at abemaciclib after first-line CDK4/6 inhibitor therapy. I think that if those trials are also positive, that it will be an interesting question to try and figure out if somebody will get capivasertib first and then abemaciclib, will you keep the same endocrine therapy and use the targeted agents in sequence, and see if we have benefit. But I think that it will be a popular treatment for patients until we have data that suggests a more tolerable or more effective treatment in the second-line setting. The issue is that it's difficult to manage the [adverse] effects of apelisib. I think that'll be an interesting question when we start using this in real life practice and in patients who don't fit eligibility criteria. Does it still hold up? Are we feeling like it's well-tolerated? Also, how does it compare with our experiences, which are now for a number of years without apelisib and even more for everolimus [Afinitor]?


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. Rugo HS, Oliveira M, Howell SJ, et al. Capivasertib (C) and fulvestrant (F) for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2– advanced breast cancer (ABC): Characterization and management of common adverse events (AEs) from the phase 3 CAPItello-291 trial. J Clin Oncol. 2023;41(suppl 16):1067-1067. doi:10.1200/JCO.2023.41.16_suppl.1067

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