Novel PROTAC May Usher in New Class of Drugs for ESR1+, ER+/HER2– Breast Cancer

Seth A. Wander, MD, PhD

For patients with estrogen receptor (ER)-positive, HER2-negative breast cancer, fulvestrant (Faslodex) has been the standard of care (SOC) for those who have experienced disease progression following a CDK4/6 inhibitor and endocrine therapy.¹ The development of novel next-generation hormonal agents is poised to change the landscape for patients, offering additional oral solutions to lessen the burden of the invasive delivery of the SOC and provide agents that are active against acquired variants such as ESR1.^1,2

“This is an exciting area. Hormone receptor–positive breast cancer is the most common type of breast cancer. For many years, antiestrogen therapy and hormonal therapies have been the backbone of treatment, both in the early and advanced or metastatic disease stages,” Seth A. Wander, MD, PhD, said in an interview with OncologyLive. “We’ve learned over the past several years, from clinical experience and translational research efforts, about many of the different mechanisms that can drive resistance to these drugs and provoke either relapse or progression in this large patient population. One of the big imperatives in the field is to develop novel, tolerable next-generation, estrogen-targeting agents that can overcome many of these resistance mechanisms.” Wander is an assistant professor of Medicine at Harvard Medical School and a clinical assistant in medicine at Massachusetts General Hospital, both in Boston.

“Fulvestrant monotherapy is still, in many ways, the widely appreciated SOC after progression on an aromatase inhibitor and a CDK4/6 inhibitor,” Wander said. “If the patient has a PIK3CA mutation, which occurs in approximately 40% of patients, then the SOC would be fulvestrant with a PI3K inhibitor such as alpelisib [Piqray]. However, for patients who are PIK3CA wild type, the current SOC would be fulvestrant monotherapy.” Wander noted that despite this being the next option, there is an understanding that those who demonstrate resistance to CDK4/6 inhibition will not likely benefit from fulvestrant monotherapy.¹

Proteolysis-targeting chimeras (PROTACs) are protein degraders that have been in development for the past 2 decades and have recently demonstrated early signals of advancement in this setting, with novel agent vepdegestrant (ARV-471).^2,3 “There’s an important unmet clinical need to develop better hormonal agents such as PROTACs to prove—for example, in the ESR1-mutant population and in patients with other mutations that might drive resistance to hormonal agents—that there may be better options moving forward,” Wander said.

“We know from [data of] multiple studies that the median PFS with fulvestrant alone is approximately 2 months so not a great option and most clinicians are not using fulvestrant after a CDK4/6 inhibitor,” Rinath M. Jeselsohn, MD, said. Jeselsohn is an assistant professor of medicine at Harvard Medical School and the director for ER+ Translational Discovery Research at Dana-Farber Cancer Institute in Boston, Massachusetts. She added that alternatives for this population now include the oral selective estrogen receptor degrader (SERD) elacestrant (Orserdu), which is approved for patients with ER-positive, HER2-negative, ESR1-mutated, advanced or metastatic breast cancer with disease progression after at least 1 line of endocrine therapy.⁴ “There is also possibility for everolimus [Afinitor] in combination with exemestane, and there are also data for this agent in combination with fulvestrant for this patient population. There are [also] chemotherapy options such as capecitabine and further down there are options for patients with HER2-low disease with [fam-trastuzumab deruxtecan-nxki (Enhertu)],” she said.

“Our expanding arsenal of knowledge about ESR1 is a great example of the power of both precision oncology and translational research,” Wander said. “In sequencing efforts exploring the genetic makeup of tumors, particularly in the primary or untreated setting, only rarely was ESR1 mutated. It wasn’t until we started sequencing metastatic biopsies or biopsies from patients who had relapsed after therapy with hormonal agents that we started to see increasing rates of mutation in the gene that encodes the ER. These mutations typically occur in the ligand-binding domain and allow the [ER] to be constitutively active, even in the absence of the estrogen ligand. Drugs such as aromatase inhibitors that work by dropping the level of estrogen or dropping the level of the ligand are not effective against a mutant form of the receptor that’s constantly active. That’s where we see these mutations develop.

“This underscores the importance of considering next-generation sequencing in the resistance setting. If you have a sequencing result from a primary tumor or an untreated metastatic sample, it’s important to potentially look after the patient progresses on first-line therapy, because you miss that ESR1 mutation earlier on,” Wander said.

Early efficacy of vepdegestrant was evaluated in the phase 2 VERITAC study (NCT04072952).³ Patients with heavily pretreated ER-positive, HER2-negative advanced breast cancer were administered 1 of 2 doses of vepdegestrant (200 mg or 500 mg) once daily. Among those in the 200-mg cohort (n = 35), the clinical benefit rate (CBR) was 37.1% (95% CI, 21.5%-55.1%) and was 38.9% (95% CI, 23.1%-56.5%) in the 500-mg cohort (n = 36). In the combined analysis (n = 71), the CBR was 38.0% (95% CI, 26.8%-50.3%).³

Investigators also analyzed outcomes in the ESR1-mutant populations of each cohort. Among the 19 patients treated with the 200-mg dose, the CBR was 47.4% (95% CI, 24.4%-71.1%), and among the 22 patients treated with the 500-mg dose, the CBR was 54.4% (95% CI, 32.2%-75.6%). Among all patients with an ESR1 mutation (n = 41), the CBR was 51.2% (95% CI, 35.1%-67.1%). For those with ESR1 wild-type disease (n = 25), the CBR was 20%.³

Investigators noted that these findings were consistent with the phase 1 dose escalation data, in which the response rates were 40% among all patients and 50% among those with ESR1-mutant disease. Further, the median ER degradation with the 200-mg dose was 69% (range, 28%-95%), with a mean ER degradation of 71%.³

Progression-free survival (PFS) was also assessed among all treated patients and those with ESR1-mutant disease across doses. The median PFS for the overall cohort was 3.7 months (95% CI, 1.9-8.3) vs 5.7 months (95% CI, 3.6-9.4) for those with ESR1-mutant disease. Among those treated with the 200-mg dose (n = 35), the median PFS was 3.5 months (95% CI, 1.8-7.8) and was 5.5 months (95% CI, 1.8-8.5) for those who received this dose and had an ESR1 mutation.³

In terms of treatment-emergent adverse events (TEAEs), 3 events leading to dose reductions were reported in the 500-mg arm, including increased alanine aminotransferase levels, neutropenia, and fatigue. All patients were reduced to 400 mg once daily. Treatment discontinuation due to TEAEs was reported for 1 patient in the 200-mg cohort due to QT prolongation, and in 2 patients in the 500-mg cohort due to electrocardiogram T-wave abnormality and back pain/spinal cord compression. Overall, 21 patients had a grade 3/4 TEAE, and 1 patient death was reported in the 200-mg cohort and was associated with acute respiratory failure in the disease progression setting; it was determined to not be associated with vepdegestrant treatment.³

Grade 1, grade 2, and grade 3/4 treatment-related AEs were reported among 34%, 31%, and 7% of patients overall. The most common were fatigue, nausea, arthralgia, hot flush, and increased aspartate aminotransferase levels, all of which were grade 1 or grade 2, with only 1 grade 3/4 nausea event.³

Of note, in a post-hoc analysis of the phase 2 trial, investigators analyzed data from 8 patients with enrollment criteria for the planned phase 3 trial. These patients did not have prior fulvestrant or prior chemotherapy in the metastatic setting. All patients had prior CDK4/6 inhibition and were treated in the VERITAC expansion cohort. The CBR was 62.5%, and as of the November 2022 data cutoff, 5 patients continued therapy, with durations of treatment ranging from 8 to 14 months. The median PFS was not reached at data cutoff.³

“One of the big imperatives in the field is to develop novel, tolerable next-generation estrogen-targeting agents that can overcome many of these resistance mechanisms,” Wander said. “PROTACs are an exciting type of agent moving forward in the clinic.”

PHASE 3 PROTAC TRIALS ARE UNDERWAY

“This is one of the most active areas of research for clinicians who focus on breast cancer,” Wander said. “Understanding what to do in the second-line setting after patients progress on standard hormonal therapy, typically with a CDK4/6 inhibitor in the first-line setting, is the largest unmet need in hormone receptor–positive metastatic breast cancer.” Thus, investigators have pursued the phase 3 VERITAC-2 trial (NCT05654623), which will randomly assign patients 1:1 to either vepdegestrant 200 mg orally once daily or fulvestrant 500 mg administered intramuscularly on days 1 and 15 of cycle 1, followed by administration on day 1 of all subsequent cycles.^5,6

Eligible participants must have received a CDK4/6 inhibitor and any ER-directed therapy must have demonstrated activity in ESR1-mutant tumors. No prior treatment with fulvestrant or prior chemotherapy for locally advanced or metastatic disease will be permitted. The primary end point of the trial is PFS by blinded independent review. This will be assessed among 2 populations: those with ESR1-mutant disease and the intention-to-treat population (Figure).^5,6

Figure. VERITAC-2 Trial Design

“[VERITAC-2] is a phase 3 study in which patients will be randomly assigned to either vepdegestrant [or] fulvestrant,” Jeselsohn explained. “This is a patient population that has had 1 line of endocrine treatment and 1 line of CDK4/6 inhibitor, patients will have had to show disease stability with endocrine treatment for at least 6 months, which is something that was also in the eligibility criteria for VERITAC. Since patients will be randomly assigned to fulvestrant no prior fulvestrant will be allowed in this patient population. The primary end point of this study will be PFS.”

Of note, eligible participants must have received a CDK4/6 inhibitor and any ER-directed therapy must have demonstrated activity in ESR1-mutant tumors. Further, the primary end point—PFS by blinded independent review—will be assessed among 2 populations: those with ESR1-mutant disease and the intention-to-treat population. Secondary end points of the trial include safety, overall survival, overall response rate, duration of response, and the rate of confirmed complete or partial response or stable disease measured at week 24 or later.^5,6 Enrollment for the trial is ongoing.

“We still have more questions than answers. We’ve learned much about ESR1 and how these mutations arise, where they occur in the protein, and which drugs provoke their development. We’ve learned how [drugs] can provoke resistance—and in some cases, sensitivity—to some of the traditional and novel agents,” Wander said. “We need to understand more about how these mutations interact with other mutations in the cell. We need to understand which of these novel anti-estrogen agents—whether the PROTACs or the novel, next-generation SERDs—can target these ESR1 mutations. Are there differences between the mutations? Not all ESR1 mutations are likely to be equal regarding their ability to provoke resistance to these agents or their ability to upregulate downstream effects in the ER pathway. These are still early days. We’re asking the right questions and starting to develop some of the tools, both analytical research tools and clinical treatment tools, to move forward to deal with this common challenge in the clinic.”

Other ongoing studies with vepdegestrant include the umbrella TACTIVE-U study, in which the PROTAC will be combined with either abemaciclib (Verzenio) in the phase 1/2 substudy A (NCT05548127), or ribociclib (Kisqali) in the phase 2 substudy B (NCT05573555).⁷

References

1. Herzog SK, Fuqua SAW. ESR1 mutations and therapeutic resistance in metastatic breast cancer: progress and remaining challenges. Br J Cancer. 2022;126(2):174-186. doi:10.1038/s41416-021-01564-x
2. Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022;21(3):181-200. doi:10.1038/s41573-021-00371-6
3. Schott AF, Hurvitz S, Ma C, et al. ARV-471, a PROTAC estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study. Cancer Res. 2023;83(suppl 5):GS3-03. doi:10.1158/1538-7445.SABCS22-GS3-03
4. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed August 20, 2023. bit.ly/3Hbxxln
5. A study to learn about a new medicine called ARV-471 (PF-07850327) in people who have advanced metastatic breast cancer. (VERITAC-2). ClinicalTrials.gov. Updated August 16, 2023. Accessed August 20, 2023. https://clinicaltrials.gov/study/NCT05654623
6. Campone M, Ma CX, De Laurentiis M, et al. VERITAC-2: a global, randomized phase 3 study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. J Clin Oncol. 2023;41(suppl 16):TPS1122. doi:10.1200/JCO.2023.41.16_suppl.TPS1122
7. Layman RM, Jerzak KJ, Hilton JF, et al. TACTIVE-U: phase 1b/2 umbrella study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer. J Clin Oncol. 2023;41(suppl 16):TPS1121. doi:10.1200/JCO.2023.41.16_suppl.TPS1121