The Pursuit of Targeted Agents Broadens the HR+  Breast Cancer Treatment Paradigm

The key to future advances in the management of hormone receptor–positive advanced breast cancer lies in the continued discovery of actionable mutations and the cultivation of increasingly specific therapies directed against these mutations, according to Lauren E. Nye, MD.

In an interview with OncLive following a State of the Science Summit on breast cancer, which she chaired, Nye discussed key points from her presentation, including reasons to look beyond CDK4/6 inhibitors when determining treatments for patients with hormone receptor–positive advanced breast cancer. She also highlighted the array of targetable mutations that have emerged for subsets of patients and unanswered questions in this area that may propel further research.

Nye emphasized the importance of considering targeted therapies for patients in this population, noting the availability of alpelisib (Piqray), capivasertib (Truqap), and elacestrant (Orserdu) for patients with certain actionable mutations. In the pivotal phase 3 SOLAR-1 trial (NCT02437318), alpelisib in combination with fulvestrant (Faslodex; n = 169) elicited a median progression-free survival (PFS) of 11.0 months (95% CI, 7.5-14.5) vs 5.7 months (95% CI, 3.7-7.4) with placebo plus fulvestrant (n = 172) in patients with PIK3CA-mutated hormone receptor–positive, HER2-negative, advanced breast cancer who experienced disease progression following endocrine therapy (HR, 0.65; 95% CI, 0.50-0.85; P < .001).¹

Moreover, findings from the phase 3 CAPItello-291 trial (NCT04305496) confirmed the efficacy of capivasertib plus fulvestrant in patients with PIK3CA/AKT1/PTEN-altered hormone receptor–positive, HER2-negative, advanced breast cancer who experienced disease progression on or following treatment with an aromatase inhibitor with or without a CDK4/6 inhibitor. In this population, patients who received the combination of capivasertib plus fulvestrant (n = 155) achieved a median PFS of 7.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7) for those treated with placebo plus fulvestrant (n = 134; HR, 0.50; 95% CI, 0.38-0.65; P < .0001).²

Additionally, in the phase 3 EMERALD trial (NCT03778931), elacestrant (n = 115) significantly prolonged the median PFS vs standard of care (SOC; n = 113) for patients with pretreated estrogen receptor–positive, HER2-negative advanced breast cancer harboring ESR1 mutations (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).³

“The treatment landscape is incredibly different [from what] it was a decade ago, and now we have to figure out how to sequence these agents and find agents that have less toxicity for our patients,” Nye said in the interview. Nye is the clinical medical director of breast cancer prevention at the University of Kansas Cancer Center in Kansas City.

OncLive: Although endocrine therapy in combination with CDK4/6 inhibitors is a SOC for patients with advanced breast cancer, what is the significance of the novel regimens?

Nye: Over the past decade, the treatment of [patients with] metastatic hormone receptor–positive breast cancer has changed significantly. [Previously, we only had] endocrine therapy [followed by] CDK4/6 inhibitors before moving on to chemotherapy. We now have an array of targeted therapies, as well as antibody–drug conjugates, that we can use before moving on to chemotherapy. [These treatment decisions] require tumor testing to determine [whether patients] have mutations we can target with these new agents. However, a handful of mutations that tend to be induced by these treatments are now targetable: ESR1, PIK3CA, AKT, and PTEN. We also have drugs for HER2-activating mutations.

For patients with PIK3CA mutations, we now have the option of considering alpelisib plus fulvestrant as well as capivasertib plus fulvestrant. With capivasertib, we can [treat] patients with PIK3CA mutations [as well as those with] AKT1 and PTEN alterations. In patients with ESR1 mutations, which tend to be mutations induced by adjuvant aromatase inhibitors, we have elacestrant as an option.

What research is planned or ongoing to address unanswered questions regarding sequencing therapies?

The big questions emerging are: How and when do we test the tumor? Do we test it at each progression? Do we use solid tumor testing or do we do liquid testing?

Further studies are asking: In what order should these agents be placed? The problem with those studies is that by the time we get the results, new agents have come along. We’re lucky that we have all these options, but it’s also going to take some critical thinking to figure out what the best agents are for the patients in front of us.

What is your main message for colleagues regarding choosing optimal treatments for patients with breast cancer?

Currently, we have a lot of opportunities for targeted therapies. We’re trying to get more specific in how we target and treat breast cancer. However, at the same time, we’re trying to pull back on toxicities [that emerge with] local therapies such as surgery and radiation. [We need to] consider the toxicities and agents we’re using as we’re deciding what drug to use for the patient sitting in front of us.

References

1. André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904
2. Turner NC, Oliveira M, Howell SJ, et al; CAPItello-291 Study Group. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
3. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338