CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: March 04, 2025
Expiration: September 03, 2025
OlympiA: 10-Year Follow-up With Adjuvant Olaparib in gBRCA1/2-Mutated/HER2-Negative EBC
Heather McArthur, MD, MPH:
A notable EBC study from SABCS 2024 was the 10-year update from the phase III OlympiA trial.1 This was a trial evaluating adjuvant olaparib given for 1 year in patients with germline BRCA1/2 (gBRCA)–mutated estrogen receptor (ER)-positive/HER2-negative EBC of stage II/III or in patients who did not achieve pCR to (neo)adjuvant chemotherapy (N = 1836).
Previously, in the prespecified interim analysis of the OlympiA trial, olaparib given after (neo)adjuvant chemotherapy was shown to improve the primary endpoint of IDFS, and secondary endpoints of distant disease–free survival (DDFS) and OS, in patients with high-risk, gBRCA1/2-mutant, HER2-negative EBC.2,3
The report at SABCS 2024 was the third prespecified interim analysis after 10 years from when the first patient enrolled in the study and after a median follow-up of 6.1 years (maximum: 9.6 years).
OlympiA (10-Year Update): First IDFS Events
Heather McArthur, MD, MPH:
Regarding the first IDFS events reported, 28% were reported with placebo vs 19% with olaparib, most of those being distant recurrences (16.3% vs 11.5%, respectively). In the current analysis, 4.4% vs 2.8% of IDFS events were central nervous system (CNS) recurrences in the placebo arm vs the olaparib arm, respectively.
OlympiA (10-Year Update): IDFS
Heather McArthur, MD, MPH:
In the overall population, the hazard ratio for IDFS at 6 years was 0.65 (95% CI: 0.535-0.784). In other words, we saw a 35% reduction in the risk of recurrence with the use of olaparib compared with placebo in OlympiA.
We also see that these differences increased from a previous 4-year IDFS rate of 8.4% to the 6-year IDFS rate of 9.4%. The benefit was observed regardless of the subgroup interrogated.
Also notable is the subgroup of patients who had triple-negative breast cancer (TNBC) and those with HR-positive breast cancer, who achieved a very comparable benefit with the use of olaparib, with hazard ratios of 0.681 and 0.652, respectively.
OlympiA (10-Year Update): DDFS
Heather McArthur, MD, MPH:
In DDFS, we continue to see a very consistent benefit using olaparib, with a hazard ratio of 0.65.
The investigators also reported data for DDFS subgroups based on previous chemotherapy in the adjuvant or neoadjuvant setting, previous platinum exposure, HR status, and BRCA1/2 mutation, and saw a benefit across all of these subgroups.
OlympiA (10-Year Update): OS
Heather McArthur, MD, MPH:
When we look at the updated OS from OlympiA, we see a survival difference of 4.4% at 6 years compared with 3.2% at 4 years. These OS data suggest that indeed the benefit in DFS might be translating into an OS benefit. Here again, we see consistent and comparable improvements for all the subgroups that were interrogated.
OlympiA (10-Year Update): Safety Summary
Heather McArthur, MD, MPH:
Regarding AEs of special interest with a PARP inhibitor, including myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), these rates remained very low in the 10-year update from the OlympiA trial. Compared with 0.2% in the previous analysis, the rate of MDS/AML was 0.4% in the 10-year update, and there was not a notable difference in new primary malignancies in patients receiving olaparib compared with those receiving placebo (eg, of the breast, ovary/fallopian tube, pancreas, or other). Of note, there appeared to be a lower number of cases of ovary/fallopian tube cancers in the olaparib arm compared with the placebo arm (5 vs 14, respectively).
OlympiA (10-Year Update): Takeaways
Heather McArthur, MD, MPH:
After a median follow-up of 6.1 years, the addition of 12 months of adjuvant olaparib vs placebo after (neo)adjuvant chemotherapy in patients with BRCA mutation–associated, high-risk HER2-negative breast cancer continued to show IDFS, DDFS, and OS benefits. Moreover, benefits were observed across all patient subgroups.
Joyce O’Shaughnessy, MD:
We also find it reassuring that there were no new safety signals, and that there was no evidence of increased rates of MDS/AML in this longer follow-up.
Another remarkable aspect about this trial is that those women who received placebo and those who received adjuvant olaparib went on to successfully becoming pregnant, and the 2 groups also had the same number of children born. It was terrific to see that the women who had the year of olaparib treatment were not adversely affected in their fertility.
NATALEE: Impact of Dose Reductions on Efficacy in Patients With HR-Positive/HER2-Negative EBC
Joyce O’Shaughnessy, MD:
Two interesting reports from SABCS 2024 presented for EBC that are worth mentioning are updates from the phase III NATALEE trial. This trial is evaluating adjuvant therapy with ribociclib plus an NSAI vs the NSAI alone in patients with stage II/III, HR-positive/HER2-negative EBC.
As a reminder, in a previous report from the NATALEE study, we saw a statistically significant and clinically meaningful IDFS benefit with ribociclib plus an NSAI vs the NSAI alone that continued to deepen after all patients had stopped receiving ribociclib therapy (hazard ratio: 0.715; 95% CI: 0.609-0.840; 4-year absolute benefit: 4.9%; median follow-up of 44.2 months).4
In one of the reports at SABCS 2024, Hamilton and colleagues presented an exploratory analysis of efficacy in patients with and without a dose reduction in the NATALEE trial.5 In the main study, patients with HR-positive/HER2-negative EBC received ribociclib at a dose of 400 mg QD, 3 weeks on/1 week off, for 3 years plus an NSAI or the NSAI alone, and men and premenopausal women also received goserelin. Only one dose reduction of ribociclib, from 400 mg QD to 200 mg QD, was allowed for the management of AEs.
NATALEE Impact of Dose Reductions: AEs, IDFS by RDI and Adjusted RDI
Joyce O’Shaughnessy, MD:
Approximately 27% of patients underwent dose reductions. The median time to dose reduction was 3.3 months. AEs were the main reason for pursuing a dose reduction, and among the most common AEs were neutropenia (14%), increased liver enzymes (~2.0%), and fatigue (1.0%).
Based on the report at SABCS 2024, dose reductions did not appear to affect IDFS rates, and patients with low, medium, or high RDIs had a similar number of events (low RDI, events: 81; medium RDI, events: 89; and high RDI, events: 92) and similar IDFS rates (low vs high hazard ratio: 0.931; 95% CI: 0.60-1.15; medium vs high hazard ratio: 0.985; 95% CI: 0.85-1.48).
When looking at patients who discontinued ribociclib earlier than 36 month from initiating therapy, the adjusted number of events remained comparable for all patients (low RDI, events: 60; medium RDI, events: 106; high RDI, events: 96) and IDFS rates when comparing low or medium RDI vs high RDI were also comparable (low vs high hazard ratio: 0.83; 95% CI: 0.60-1.15; medium vs high hazard ratio: 1.12; 95% CI: 0.85-1.48).
Taken together, these data are reassuring and suggest that it is possible to implement a ribociclib dose reduction (to 200 mg QD) when needed to help mitigate AEs, without compromising efficacy.
NATALEE: DDFS Across Key Subgroups With Ribociclib Plus NSAI in HR-Positive/HER2-Negative EBC
Joyce O’Shaughnessy, MD:
The other report from the NATALEE study worth mentioning looked at DDFS in key subgroups from the overall study with a median follow-up, in this analysis, of 44.2 months.6
Across all study groups assessed, the combination of ribociclib and an NSAI yielded a DDFS benefit (hazard ratio: 0.715; nominal P <.0001). The DDFS benefit was consistent irrespective of anatomic stage (stage IIA [n = 1001], hazard ratio: 0.396; stage IIB [n = 1045], hazard ratio: 0.806; stage IIIA [n = 1832], hazard ratio: 0.697; stage IIIB [n = 317], hazard ratio: 0.569; and stage IIIC [n = 890], hazard ratio: 0.878) and nodal status (N0 [n = 613], hazard ratio: 0.696; node positive [n = 4480], hazard ratio: 0.726). The DDFS benefit was similar in other clinically relevant subgroups (eg, by menopausal status and Ki-67 status).
The subgroup analyses from NATALEE provide additional support to the initial trial conclusions for the benefit with ribociclib plus an NSAI vs the NSAI alone. Here we also see that patients who received ribociclib plus the NSAI had a consistently lower risk of distant recurrence across clinically relevant subgroups, supporting the current use and approved indication of this therapy.
Phase II SOLTI VALENTINE: Neoadjuvant HER3-DXd With or Without Letrozole for High-risk, HR-Positive/HER2-Negative EBC
Heather McArthur, MD, MPH:
We also saw data presented from a promising antibody–drug conjugate (ADC) targeting HER3 in the open-label phase II SOLTI VALENTINE study. This was a perioperative study of neoadjuvant treatment with patritumab deruxtecan (HER3-DXd) for 6 cycles alone or in combination with letrozole vs chemotherapy (either doxorubicin/cyclophosphamide or epirubicin/cyclophosphamide) for 4 cycles, then weekly paclitaxel for 12 weeks, in patients with high-risk, HR-positive/HER2-negative EBC that was classified as primary operable (tumors ≥1 cm by magnetic resonance imaging; N = 122).7 The primary endpoint was pCR.
The idea behind this study design is that the earlier in the course of disease that one applies these combination strategies, the more likely they are to be effective in achieving disease control. It is also worth noting that this is a high-risk patient population, as noted by a Ki-67 of ≥20% and/or high genomic signature risk.
SOLTI VALENTINE: Baseline Characteristics
Heather McArthur, MD, MPH:
Taking a look here at the baseline characteristics for the study, we can see that the 3 arms were relatively well balanced. The median age of study participants was 50 years. Approximately 40% of patients in the HER3-DXd arms were T3/T4, which is typical of more advanced disease, whereas the proportion of T3/T4 patients in the chemotherapy arm was approximately 30%. Most patients had histologic grade 1/2 disease (~66% to ~83%), and HER3 positivity by immunohistochemistry (IHC) was high in ≥80% of patients. PAM50 scores suggested mostly luminal A (~29% to ~43%) and luminal B status (~48% to ~54%) as well.
SOLTI VALENTINE: pCR at Surgery (Primary Endpoint) and ORR
Heather McArthur, MD, MPH:
HER3-DXd yielded pCR and overall response rates (ORRs) similar to those with standard multiagent chemotherapy. Looking at the data a bit more closely, we can see a modestly better response to treatment in favor of the combination of HER3-DXd with letrozole vs multiagent chemotherapy (81.3% vs 70.8%). Study investigators also noted that the proportion of samples staining positive for Ki-67 declined at Day 1 of cycle 2, with additional reduction observed at surgery.
SOLTI VALENTINE: Safety Summary
Heather McArthur, MD, MPH:
Regarding safety, the most common AEs of any grade for HER3-DXd alone, for HER3-DXd with letrozole, and for multiagent chemotherapy were: fatigue (50%, 69%, and 79%, respectively); nausea (56%, 73%, and 58%, respectively); alopecia (52%, 69%, and 46%, respectively); diarrhea (42%, 54%, and 8%, respectively); stomatitis (14%, 18%, and 42%, respectively); and elevated transaminase levels (14%, 38%, and 21%, respectively).
Treatment with HER3-DXd alone and treatment with HER3-DXd with letrozole were associated with fewer grade ≥3 AEs when compared with multiagent chemotherapy (14.0% and 14.6%, respectively, vs 45.8%).
There were no reported cases of interstitial lung disease/pneumonitis or treatment-related deaths in this study.
SOLTI VALENTINE: Takeaways
Heather McArthur, MD, MPH:
Data from the SOLTI VALENTINE study showed that treatment with HER3-DXd alone or in combination with letrozole yielded pCR rates and/or ORR estimates that are comparable with those attained with multiagent anthracycline-based and taxane-based chemotherapy. The safety profile of HER3-DXd alone or in combination with letrozole was manageable and modestly better than with multiagent chemotherapy, prompting interest in further development of HER3-DXd for use in this patient population.
Joyce O’Shaughnessy, MD:
I agree. This study is of importance because, as you said, there will be further development of this anti-HER3 ADC in EBC as well as in the metastatic setting.
Pending confirmatory data in a larger patient cohort, I think HER3-DXd is a candidate to replace preoperative chemotherapy or to potentially replace adjuvant chemotherapy. I think the results from SOLTI VALENTINE are impressive. For me, this new treatment is at least as good as multiagent chemotherapy, and getting away from the use of anthracycline-based chemotherapy would be a step in the right direction.
Real-world Study for HR-Positive/HER2-Negative EBC at High Risk of Recurrence Based on Nodal Status
Joyce O’Shaughnessy, MD:
At SABCS 2024, we saw data presented from a real-world study looking at the risk of recurrence based on nodal status and high-risk features in patients with HR-positive/HER2-negative EBC.8
This is a helpful study because we now are beginning to think through which patients should receive adjuvant ribociclib in the early disease setting.9
Tumor involvement of axillary lymph nodes (ALNs) is the most significant prognostic marker of disease recurrence in patients with HR-positive/HER2-negative EBC. Most patients (72%) at presentation have 1-3 ALNs involved, and disease outcomes for those with N1 disease remain quite variable.
Patients in the monarchE trial were selected based on having a high risk of recurrence, including having node-positive disease (1-3, 4-9, or ≥10 ALNs); ≥5-cm tumors; and/or grade 3 disease (N1, high risk).
Real-world Study for HR-Positive/HER2-Negative EBC at High Risk of Recurrence: Methods/Results
Joyce O’Shaughnessy, MD:
Tolaney and colleagues presented data at SABCS 2024 from looking at patients who had the same clinical pathologic features as those enrolled in the monarchE cohort 1 population.10 The goals were to describe recurrence based on node status in a real-world population using the monarchE criteria and to describe the real risk of recurrence in patients with N1 disease.
The investigators showed that patients with N1 grade 3 or N1 and T3/T4 disease indeed do have a higher risk of recurrence compared with N1 patients who do not have grade 3 disease or T3/T4 disease. They also showed that recurrence by IDFS by nodal status was 2-fold greater for those with N1, higher-risk disease vs N1, non–high-risk disease, with a delta difference of 15% for risk of recurrence at 5 years, which is quite remarkable.
For patients with lower-risk N1 disease or node-negative disease, vs being node negative with grade 3 or T3/T4 disease, or having a Ki-67 of ≥20%, there is a similar level of risk in these very-high-risk, node-negative patients compared with patients with the lower-risk N1 disease.
These high-risk, node-negative patients with grade 3 disease or T3/T4 disease or a high Ki-67, or even high genomic risk as assessed with MammaPrint or Oncotype DX, have a higher risk than patients with lower-risk, 1- to 3-node–positive disease—with lower risk being defined as not grade 3 and not T3/T4, and not having a Ki-67 of ≥20%.
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