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Refining treatment is not only a key aim of research in breast cancer but a greater possibility in the clinic with neoadjuvant and adjuvant PARP inhibitors, HER2 monoclonal antibodies, and greater stratification of genomic risk.
Refining treatment, either through escalated or de-escalated strategies, is not only a key aim of research in breast cancer but a greater possibility in the clinic with neoadjuvant and adjuvant PARP inhibitors, HER2 monoclonal antibodies, and greater stratification of genomic risk, as seen in findings from several trials presented at the 2021 ASCO Annual Meeting, explained Erika P. Hamilton, MD.
“The current era is all about targeting and personalizing our approach and giving the right size treatment to the right patient,” said Hamilton, director of the Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon Research Institute, in a virtual presentation during the 2021 ASCO Direct HighlightsTM webcast in Nashville, Tennessee, a program developed by Physicians’ Education Resource® LLC.
The first trial Hamilton highlighted during the webcast, the phase 3 OlympiA trial (NCT02032823), evaluated treatment escalation in a high-risk early breast cancer population. Eligible patients included those with stage II to III, HER2-negative breast cancer with a germline pathogenic or likely pathogenic BRCA1/2 mutation. Following completion of their neoadjuvant or adjuvant therapy, 1836 patients were randomized to 300 mg of olaparib (Lynparza) twice daily for 1 year (n = 921) or placebo (n = 915).1
The median age was 42 years in the olaparib arm vs 43 years in the placebo arm. Additionally, most patients had a BRCA1 mutation (>70%) and had undergone mastectomy in both arms (>73%).
The predominant population represented in the trial had triple-negative breast cancer (>80%) and most patients had received anthracycline and taxane-based chemotherapy (>90%).
The results demonstrated that the 3-year invasive disease-free survival (IDFS) in the intention-to-treat (ITT) population was 85.9% in the olaparib arm vs 77.1% in the placebo arm (HR, 0.58; 99.5% CI, 0.41-0.82; P <.0001).
“We saw a spread in 3-year IDFS of 8.8% [between arms] that was almost KATHERINE-esque, with a pretty big magnitude of improvement,” said Hamilton.
Moreover, most events (olaparib, 7.8%; placebo, 13.1%) were distant recurrences, indicating that the use of olaparib is effective in preventing what would significantly alter a patient’s prognosis.
In the first 900 patients enrolled on study who had a median follow-up of at least 3.5 years, the 3-year IDFS rate was 86.1% with olaparib vs 77.5% with placebo (HR, 0.61; 99.5% CI, 0.39-0.95), translating to a difference of 8.6%.
The 3-year distant DFS (DDFS) was 87.5% with olaparib vs 80.4% with placebo (HR, 0.57; 99.5% CI, 0.39-0.83; P < .0001), reflecting a difference of 7.1%.
The 3-year overall survival (OS) rate was 92.0% with olaparib vs 88.3% with placebo (HR, 0.68; 99% CI, 0.44-1.05; P =.024), translating to a difference of 3.7%.
“OS was not quite significant based on the way the investigators had divided their power, but I think with longer follow-up, I feel pretty confident that we’ll see an OS benefit here,” said Hamilton.
The adverse effects (AEs) with olaparib were consistent with their use in the metastatic setting and included high rates of nausea (57%), fatigue (40%), anemia (23%), vomiting (23%), headache (20%), diarrhea (18%), neutropenia (16%), leukopenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%), and arthralgia (9%).
“These results are practice changing, and now that we have a therapeutic linked to [BRCA in this setting], I think we’ll be able to pretty much universally test our patients who are HER2-negative,” said Hamilton.
In the neoadjuvant setting, the phase 2 NEOTALA trial (NCT03499353) evaluated talazoparib (Talzenna) in patients with locally advanced BRCA1/2-mutant, HER2-negative breast cancer with a tumor larger than 1.5 cm (n = 112). Treatment was administered at a dose of 1 mg/day or 0.75 mg/day for patients with moderate renal impairment for 24 weeks and was followed by surgery within 4 to 6 weeks of completing talazoparib.2
As in OlympiA, patients were young, with a median age of 44.6 years, and the majority (78.7%) had a BRCA1 mutation. The spread of patients with stage I, II, and III disease was relatively evenly distributed, said Hamilton, at 32.8%, 44.3%, and 22.9%, respectively.
The pathologic complete response (pCR) rate by independent central review was 45.8% in the evaluable population (n = 48) vs 49.2% in the ITT population (n = 61). By investigator assessment, the pCR rates were 45.8% vs 47.5%, respectively.
“The pCR rates are really quite comparable to what we would anticipate to see with combination chemotherapy in these patients,” said Hamilton.
Moreover, the tolerability was favorable, with 73.8% of patients having completed the intended 24 weeks of treatment. A total of 90.2% of patients received talazoparib for at least 20 weeks.
No unexpected AEs were reported and included fatigue, nausea, alopecia, and anemia. Although grade 3 anemia was reported in 39.3% of patients, the overall safety profile of talazoparib compared favorably to chemotherapy, which these patients would have received otherwise, said Hamilton.
Approximately one-third of patients received a dose interruption (32.8%) or dose reduction (39.3%), requiring a red blood cell transfusion in 21.3% of patients. Permanent drug discontinuation was relatively rare, said Hamilton, with 4.9% of patients discontinuing because of an AE and 16.4% because of progressive disease.
“We’re starting to think about if we can use a targeted agent for those patients to at least downsize their cancers and maybe be able to give them less chemotherapy or perhaps omit chemotherapy altogether,” said Hamilton.
Turning to the HER2-positive setting, Hamilton highlighted the phase 2/3 WSG-ADAPT trial (NCT01779206), which evaluated de-escalated neoadjuvant treatment with pertuzumab (Perjeta) and trastuzumab (Herceptin) with or without weekly paclitaxel.3
In the study, patients with nonmetastatic HER2-positive, hormone receptor (HR)–negative disease were randomized 5:2 to trastuzumab plus pertuzumab (n = 92) or trastuzumab plus pertuzumab plus paclitaxel (n = 42) for 12 weeks followed by surgery within 3 weeks of treatment completion.
Approximately 40% of patients had T1 tumors, and about half each had T2 tumors and were node negative; T3 tumors were relatively rare, at approximately 8%, in line with expectations given that ADAPT evaluated treatment de-escalation, said Hamilton. Additionally, 88% of patients had grade 3 disease, with a Ki-67 of 50%.
The pCR rate was 34.4% with trastuzumab/pertuzumab vs 90.5% with the addition of chemotherapy. The 5-year IDFS rates were 87% vs 98%, respectively (HR, 0.32; 95% CI, 0.07-1.47; P = .144). The 5-year DDFS rate was 92% with trastuzumab/pertuzumab vs 98% with the addition of chemotherapy (HR, 0.34; 95% CI, 0.04-2.80; P =.313).
The 5-IDFS rate among patients who achieved a pCR vs not a pCR was 98% vs 82%, respectively (HR, 0.14; 95% CI, 0.03-0.64; P = .011).
“It’s only those patients that did not achieve get the chemotherapy and did not translate to pCR that we have to worry about,” said Hamilton. “[However,] we know we can salvage the non–pCR responders and have them do a little bit better with adjuvant ado-trastuzumab emtansine [T-DM1; Kadcyla],” said Hamilton.
“The investigators concluded that patients with HER2-positive breast cancer have excellent pCR and survival, even with a de-escalated regimen. I think we can all imagine quite a few patients who may be willing to do this for the chance of getting less [therapy] or [those who] are elderly or may not be fit for aggressive chemotherapy,” added Hamilton.
In the metastatic setting, the phase 3 SYSUCC-002 trial (NCT01950182) took patients with HR-positive, HER2-positive breast cancer and randomized them to endocrine therapy plus trastuzumab or chemotherapy plus trastuzumab.4
If patients weren’t de novo, they must have had a disease-free interval of more than 12 months, said Hamilton.
Because the study was done in China, pertuzumab was not included in the protocol, which stands out as a criticism of the study because, in the United States, these patients typically receive taxane with trastuzumab and pertuzumab.
The median age of patients was approximately 50 years, and about 30% of patients were premenopausal. Most patients (80.1%) had estrogen receptor (ER) and progesterone receptor (PR) positivity and visceral metastases (59%).
The results failed to demonstrate a statistically significant difference in progression-free survival (PFS; HR, 0.88; 95% CI, 0.71-1.09; P = .250) or OS (HR, 0.82; 95% CI, 0.65-1.04; P = .090) between arms.
“[In terms of subgroups,] the one that stands out to us of maybe chemotherapy being better is that group of patients that relapsed from their early disease within 24 months,” said Hamilton.
In terms of safety, the incidence of AEs in the chemotherapy arm was significantly higher vs AEs in the endocrine therapy arm, particularly with regard to leucopenia, stomatitis, fatigue, nausea, anorexia, and alopecia.
“[The investigators] concluded that trastuzumab plus endocrine therapy was noninferior to and had fewer toxicities compared with trastuzumab plus chemotherapy in patients with HR-positive, HER2-positive, metastatic breast cancer in the first-line setting,” said Hamilton. “We probably are ignoring the patients that are both HER2-positive and HR-positive and grouping them all in the HER2 basket and treating them all the same. It is true that a lot of these patients do have a little bit of a different prognosis and disease characteristics where they may benefit from endocrine therapy as well. Though, I definitely would make sure that we give patients pertuzumab in the first-line setting.”
The phase 3 NRG/NSABP B-42 trial (NCT00382070) evaluated the utility of using the breast cancer index (BCI) to predict the benefit of extended aromatase inhibitor therapy in patients with HR-positive breast cancer.5
Eligible patients with postmenopausal stage I, II, or IIIA, ER-positive or PR-positive breast cancer that was disease free after 5 years of endocrine therapy were randomized to an additional 5 years of letrozole or placebo.
However, at a median follow-up of 10.3 years, investigators failed to demonstrate the utility of the assay, suggesting that a greater emphasis should be placed on a patient’s clinical characteristics to determine whether they should pursue extended treatment, said Hamilton.
“In my clinic, I find that it’s the minority of patients that really end up getting a BCI score because they either want to stay on their endocrine therapy or they absolutely do not want to, and so a test isn’t really going to change our clinical decision making here,” said Hamilton.
Hamilton also called attention to the outcomes of patients with an ultralow risk 70-gene signature in the phase 3 MINDACT trial (NCT00433589). Eligible patients had operable invasive breast cancer, a tumor no larger than 5 cm, 0 to 3 positive lymph nodes, and no distant metastasis.6
Patients with clinically low–and genomically low–risk received no treatment, patients with clinically low–/genomically high–risk and clinically high–and genomically low–risk were randomized to chemotherapy vs not, and patients with clinically high–/genomically high–risk received chemotherapy.
A total of 15% (n = 1000) of the total population had genomic ultra-low–risk. At a median follow-up of 8.7 years, the 8-year distant metastasis-free interval (DMFI) was 97.0% and the 8-year breast cancer–specific survival rate was 99.6% in the ultra-low–risk population.
Among patients who received only endocrine therapy or no adjuvant systemic treatment, the 8-year DMFI rates were 97.8% vs 97.4%, respectively.
“It really does not appear that our ultralow patients need us to do too much other than leave them be,” said Hamilton.
In the phase 3 DAWNA-1 trial (NCT03927456), patients with HR-positive, HER2-negative, locally advanced, or metastatic breast cancer that had relapsed or progressed on prior endocrine therapy and had received at least 1 line of prior chemotherapy for recurrent/metastatic disease were randomized to 150 mg of dalpiciclib on days 1 to 21 every 4 weeks plus 500 mg of intramuscular fulvestrant (Faslodex) on days 1 and 15 of cycle 1 and day 1 every 4 weeks thereafter, or placebo plus fulvestrant.7
The results showed that the median PFS was 15.7 months with dalpiciclib vs 7.2 months with placebo (HR, 0.42; 95% CI, 0.31-0.58; P <.0001).
“If you recall with all of our CDK4/6 inhibitors, with ribociclib [Kisqali], abemaciclib [Verzenio], and palbociclib [Ibrance], the hazard ratios really across the board were in that 0.45 to 0.50 range,” said Hamilton.
Similar AEs were reported with dalpiciclib as with the other CDK4/6 inhibitors, explained Hamilton, citing a 65.0% rate of grade 3 neutropenia and a 61.3% rate of grade 1/2 anemia.
“The neutropenia tapers off after the first year of treatment, so if [patients] tolerate the first year, [they are] probably going to tolerate [the treatment for longer,” said Hamilton.
“These findings support dalpiciclib plus fulvestrant as a new treatment option in patients with HR-positive, HER2-negative advanced breast cancer who relapsed or progressed on prior endocrine therapy,” concluded Hamilton.