Though endocrine remedy together with a CDK4/6 inhibitor stays the first frontline remedy choice for sufferers with estrogen receptor (ER)–optimistic/HER2-negative metastatic breast most cancers, tumors will usually grow to be immune to endocrine remedy and clinicians should then think about alternate approaches within the second line and past, in response to Pooja Murthy, MD.
“Sequencing within the second-line setting is changing into an more and more sophisticated query. Now we have new brokers which were FDA accredited, equivalent to capivasertib [Truqap] and elacestrant [Orserdu], and extra [research] is being executed within the translational area concerning mechanisms of endocrine remedy resistance,” Murthy stated in an interview with OncLive®. “After development on a CDK4/6 inhibitor, fulvestrant [Faslodex] alone has restricted exercise. The median progression-free survival [PFS] throughout trials was modest at [approximately] 2 to three months. Due to this fact, within the second line setting mixture approaches or next-generation medicines are key. [Additionally], molecular testing is more and more essential to tell subsequent line remedy [selection]. Growing this concept of estrogen dependence vs independence [to identify] sufferers who might profit extra from a technique that continues to focus on the estrogen pathway equivalent to oral SERDs vs one other strategy goes to be key.”
The section 3 EMERALD research (NCT03778931) examined elacestrant in postmenopausal sufferers with ER-positive/HER2-negative superior or metastatic breast most cancers. Sufferers with ESR1-mutated illness who obtained elacestrant (HR, 0.55; 95% CI, 0.39-0.77; P = .0005) and people within the intention-to-treat inhabitants (HR, 0.70; 95% CI, 0.55-0.88; P = .0018) skilled a statistically vital PFS profit in contrast with those that obtained investigator’s alternative of endocrine remedy. Findings from EMERALD supported the January 2023 FDA approval of elacestrant in postmenopausal ladies or grownup males with ER-positive, HER2-negative, superior or metastatic breast most cancers harboring an ESR1 mutation who skilled illness development on at the least 1 line of endocrine remedy.1
The section 3 CAPItello-291 research (NCT04305496) evaluated capivasertib together with fulvestrant in sufferers with hormone receptor-positive/HER2-negative breast most cancers following illness development throughout or after remedy with an aromatase inhibitor, with or with out prior CDK4/6 inhibitor remedy. Sufferers within the capivasertib arm (n = 355) skilled a median PFS of seven.2 months (95% CI, 5.5-7.4) in contrast with 3.6 months (95% CI, 2.8-3.7) within the placebo plus fulvestrant arm (n = 353; HR, 0.60; 95% CI, 0.51-0.71; P < .001). Notably, sufferers with PIK3CA/AKT1/PTEN-altered illness achieved a median PFS of seven.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7), respectively (HR, 0.50; 95% CI, 0.38-0.65; P < .001).2
Within the interview, Murthy, an assistant professor of Medical Medication at Weill Cornell Medication and an attending doctor at NewYork-Presbyterian Queens in New York, mentioned second-line remedy issues for sufferers with ER-positive/HER2-negative metastatic breast most cancers shared throughout her presentation at a current OncLive State of the Science Summit™ on breast most cancers.
OncLive: What remedy sequencing issues ought to clinicians concentrate on following development on first-line endocrine remedy plus a CDK4/6 inhibitor?
Murthy: Within the second-line setting, I at all times [conduct] molecular testing. When a affected person has progressive illness, and sometimes they’re progressing [following] a CDK4/6 inhibitor and endocrine remedy, we have a look at the molecular testing outcomes to assist information the following line of remedy. The opposite issues are a affected person’s medical options [such as] how lengthy they have been on first-line endocrine remedy, websites of metastatic illness, and tempo of development. This [information] helps inform the idea of the affected person growing endocrine resistance vs continued endocrine dependency. That could be a key determination level within the area and helps inform subsequent remedy.
What have been the important thing information from the EMERALD trial with elacestrant vs customary endocrine monotherapy?
EMERALD was an essential trial; it was the primary potential section 3 trial with revealed outcomes supporting using an oral SERD on this setting. In EMERALD, elacestrant was in contrast with customary of care endocrine remedy at development. All sufferers had obtained a previous CDK4/6 inhibitor. Elacestrant demonstrated an improved PFS in contrast with customary of care endocrine remedy.
[Additionally], the secondary evaluation of this trial confirmed that there have been sure affected person populations who benefited extra [from treatment with elacestrant vs standard endocrine therapy]. Knowledge confirmed that for sufferers with an ESR1 mutation [there was] a deeper separation of the curves. Additionally, for sufferers who had an extended length of remedy on a first-line CDK4/6 inhibitor and endocrine remedy—notably greater than 12 months and greater than 18 months—[data] demonstrated an excellent wider separation of the curves.
There’s a particular affected person inhabitants benefitting from remedy with elacestrant, notably sufferers with ESR1-mutated illness who’ve a protracted length of remedy on prior CDK4/6 inhibitor [therapy]. In EMERALD, there was a clinically significant distinction; the median PFS for this affected person inhabitants was roughly 9 months in contrast with roughly 2 or 3 months within the standard-of-care arm.
What was the importance of information from CAPItello-291 with capivasertib or placebo plus fulvestrant?
CAPItello-291 was a section 3 double-blind placebo-controlled trial evaluating capivasertib, which is an AKT inhibitor, together with fulvestrant vs placebo plus fulvestrant. Knowledge demonstrated improved PFS within the capivasertib arm, notably in sufferers who had a mutation within the PIK3CA/AKT1/PTEN pathway, [which led to the combination’s] FDA approval for these sufferers.
How do any security considerations noticed in EMERALD or CAPItello-291 contribute to sequencing choices?
In EMERALD, elacestrant was very properly tolerated; there have been primarily solely grade 1 and a pair of toxicities. Dosing is as soon as every day and it’s an oral agent, which many sufferers want. Elacestrant is a really tolerable choice.
[With] capivasertib, we take into consideration the section 3 SOLAR-1 [NCT02437318] information once we take into consideration CAPItello-291. Alpelisib [Piqray] was accredited on this area and in SOLAR-1, roughly 25% of sufferers discontinued remedy [with alpelisib] on account of toxicities. There have been greater charges of grade 3 and 4 hyperglycemia, diarrhea, and rash.
Cross trial comparisons are considerably problematic, however capivasertib appeared to be higher tolerated. There was much less hyperglycemia, many of the toxicities have been grade 1 and grade 2, and there was much less remedy discontinuation. It’s a beautiful choice, particularly within the metastatic setting [where] sufferers are searching for extra tolerable remedies. Capivasertib plus fulvestrant does require sufferers to return in additional incessantly for laboratory checks, and fulvestrant is a month-to-month injection. That must be considered, however it’s a pretty properly tolerated remedy choice.
What are some unmet wants or unanswered questions that persist concerning remedy choice within the second line?
I’m very to see the event of biomarkers on this area. One of many key ideas is differentiating which sufferers have continued estrogen dependency vs activation of various pathways. Having biomarkers so as to add nuance to this thought course of is essential. Additionally, extra work [is needed] on the mutations themselves. The best way we’re fascinated by it beforehand, and up till now, is that if sufferers have an ESR1 mutation or a PIK3CA mutation, however there are completely different mutations [including] completely different ESR1 mutations. Which sufferers with these mutations might profit from one oral SERD vs different oral SERDs in growth will likely be essential to know.
References
- Shah M, Lingam H, Gao X, et al. US Meals and Drug Administration approval abstract: elacestrant for estrogen receptor-positive, human epidermal progress issue receptor 2-negative, ESR1-mutated superior or metastatic breast most cancers. J Clin Oncol. 2024;42(10):1193-1201. doi:10.1200/JCO.23.02112
- Turner NC, Oliveira M, Howell SJ, et al; CAPItello-291 Examine Group. Capivasertib in hormone receptor–optimistic superior breast most cancers. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
