Oral SERDS Improve Survival in HR+, HER2- Metastatic Breast Cancer

CASE SUMMARY

A 56-year-old, postmenopausal woman presents with a palpable right breast mass with no clinically abnormal axillary lymph nodes. Core biopsy showed the patient had grade II invasive ductal carcinoma (IDC), was estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) and had HER2 immunohistochemistry (IHC) of 0; Ki-67 was at 33%. Lumpectomy and sentinel lymph node (SLN) biopsy showed a 3.0 c grade 2 IDC, but 2 SLNs were negative for malignant cells. The patient had a 21-gene recurrence score of 27 then received docetaxel and cyclophosphamide for 4 cycles followed by radiation therapy and completed 5 years of adjuvant aromatase inhibitor (AI).

Three years later after completion, she reported right-sided abdominal pain and mild nausea. A CT scan showed 3 suspicious liver lesions (right lobe, largest 2 cm) and a liver biopsy showed adenocarcinoma consistent with breast primary ER+/PR+, HER2 IHC 0. Her liver enzymes were normal and comprehensive molecular testing from the tissue biopsy showed no actionable alterations. AI plus palbociclib (Ibrance) was initiated. The therapy was tolerated well, with grade 2 neutropenia that did not require dose modification of palbociclib. Twenty months later, follow-up imaging showed increased size of both liver nodules and 2 new lung nodules, the largest measuring 0.9 cm. Her ECOG performance status was 0, and liver enzymes were normal.

DISCUSSION QUESTIONS

• What efficacy and/or safety data most impacts your decision to prescribe oral selective estrogen receptor degraders (SERDs)?
• Does recent data regarding elacestrant (Orserdu) change your practice for the ESR1-mutated or the dual mutation ESR1/PI3K subgroups?

HOPE S. RUGO, MD​, FASCO: If you treat patients in the third-line setting with endocrine therapy, a lot of them are going to progress at their first scan. So, that's what [data from the EMERLAD trial (NCT03778931)] were reflecting; slightly over 40% of patients progressed at their first scan.¹ Then, the [progression-free survival (PFS) results] separated between the study arms and they stayed separated over time. What we can see is that the median PFS delta is relatively small, but the differences at 12 months seem to be even greater than what you see at 6 months [between the study arms].¹

What's interesting [in the intent-to-treat population] is that at the 12-month PFS rate, 9.4% [95% CI, 4.0%-14.8%] vs 22.3% [95% CI, 15.2%-29.4%] were free from disease progression in the elacestrant arm [compared with] standard of care, respectively.¹ If we look at the 12-month PFS with [elacestrant compared with] the fulvestrant [Faslodex] arm, it's still high at 10.2% [95% CI, 3.4%-16.9%] vs 22.3% [95% CI, 15.2%-29.4%], respectively. Looking at the population of patients on the study who had ESR1 mutations [n = 115], the PFS HRs are even better at 0.55 [95% CI, 0.39-0.77, P = .0005] with elacestrant compared with all endocrine therapies and 0.50 [95% CI, 0.34-0.74, P = .0005] compared with fulvestrant.

Hope S. Rugo, MD​, FASCO

Professor of Medicine

Winterhof Family Professor of Breast Cancer

Director, Breast Oncology and Clinical Trials Education

University of California, San Francisco

Helen Diller Family Comprehensive Cancer Center​

San Francisco, CA​

So, the 12-month PFS rate in the fulvestrant treated arm [compared with elacestrant] was 8.4% [95% CI, 0.2%-16.6%] vs 26.8% [95% CI, 16.2%-37.4%], respectively, which is remarkable. When looking at standard-of-care endocrine therapy [compared with elacestrant] the 12-month PFS rates were 8.2% [95% CI, 1.3%-15.1%] vs 26.8% [95% CI, 16.2%-37.4%]. So, there is an impressive improvement over fulvestrant, which is mostly what we're using in the second-line setting, and other endocrine therapies.¹

DISCUSION QUESTIONS

• How do you manage endocrine therapy-related fatigue, gastrointestinal toxicity, musculoskeletal pain for your patients?
• How does this compare with elacestrant?

RUGO: All grades of nausea were only seen in a little over a third of patients [on elacestrant], so it definitely seems to be controllable.1 All grades of nausea with endocrine therapy alone was 18.8%.... [To help treat the patient's nausea], I'm a big believer in olanzapine [Zyprexa]. I think it works well and it can help the patient sleep. There was more fatigue overall [in the elacestrant arm] at 19.0%, but it wasn't seen higher in grade 3/4; those rates were the same in both arms [at less than 1%]. There was more fatigue than we think about, but [it was] not increased by giving elacestrant vs standard endocrine therapy, so maybe [it is] related to the disease burden more than anything. There was also some decreased appetite, which was associated with the nausea.

Otherwise, the toxicities were almost identical between the 2 arms. [The total amount of] adverse events that were either grade 3 or 4 weren't that much different at 27.0% with elacestrant compared with 20.5% [in the endocrine therapy arm]. There was no increase in mortality, but 3% of patients needed a dose reduction with elacestrant, and 6.3% of patients discontinued the study drug.¹

SAYEH LAVASANI, MD: I use olanzapine in this setting [as well], and I give it to my patients on chemotherapy. I think that is a good addition to the anti-nausea regimen [for patients on elacestrant as well].

MERIN STEPHEN, MD: I haven't had a chance to use it yet, but I think I should be checking [for mutations] with every progression, because sometimes I don't check either the solid tumor or the circulating tumor DNA with every progression. Now, [these data are] reinforcing me to do so.

RUGO: If somebody had, [for example], a liver full of tumor and you have to give them chemotherapy, it's not going to benefit them much. But in most situations, it's in the earlier lines of therapy and I think it helps. I do think that prophylaxis is helpful [to stop] nausea, but with endocrine therapy, fatigue, gastrointestinal toxicities, and musculoskeletal pain are a challenge to manage in our patients with metastatic disease. If there's a lot of gastrointestinal toxicity [with the patient, then] I have a low threshold for dose reducing.

^Reference:

^{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.}