Neoadjuvant Olaparib in Triple-Negative Breast Cancer: Findings from the PARTNER Trial

Główne pojęcia

Neoadjuvant olaparib did not improve pathological complete response, event-free survival, or overall survival when added to chemotherapy in patients with triple-negative breast cancer who were BRCA wild-type.

Streszczenie

The PARTNER trial was a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer (TNBC) who were BRCA wild-type (gBRCAwt). Patients were randomized to receive neoadjuvant carboplatin with paclitaxel with or without the addition of olaparib (150mg twice daily, days 3 to 14, for 4 cycles) followed by 3 cycles of anthracycline chemotherapy before surgery.

The primary endpoint was pathological complete response (pCR), and secondary endpoints included event-free survival (EFS) and overall survival (OS). The results showed that pCR was achieved in 51% of the research arm (with olaparib) and 52% of the control arm (without olaparib), with no statistically significant difference. The estimated 36-month EFS and OS were also similar between the two arms.

However, in patients who achieved pCR, the estimated 36-month EFS and OS were significantly better compared to those who did not achieve pCR. This suggests that pCR remains an important prognostic factor in TNBC, regardless of the addition of olaparib to the neoadjuvant regimen.

The authors note that these findings are in contrast to the major benefit of olaparib (gap schedule) reported in patients with TNBC and BRCA pathogenic variants (gBRCAm), which is discussed separately.

Statystyki

Pathological complete response (pCR) rate: 51% in the research arm (with olaparib), 52% in the control arm (without olaparib)
Estimated 36-month event-free survival (EFS): 80% in the research arm, 79% in the control arm
Estimated 36-month overall survival (OS): 90% in the research arm, 87.2% in the control arm
Estimated 36-month EFS in patients with pCR: 90%
Estimated 36-month EFS in patients without pCR: 70%
Estimated 36-month OS in patients with pCR: 96%
Estimated 36-month OS in patients without pCR: 83%

Cytaty

"Neo-adjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin/paclitaxel and anthracycline chemotherapy in patients with TNBC (gBRCAwt)."
"This is in marked contrast to the major benefit of olaparib (gap schedule) in those with gBRCA pathogenic variants (gBRCAm) which is reported separately (gBRCAm article)."

Kluczowe wnioski z

The PARTNER trial of neoadjuvant olaparib in triple-negative breast cancer - Nature

by Jean E. Abra... o www.nature.com 04-08-2024

https://www.nature.com/articles/s41586-024-07384-2

Głębsze pytania

What are the potential reasons for the lack of benefit of neoadjuvant olaparib in TNBC patients with BRCA wild-type status, compared to the reported benefit in TNBC patients with BRCA pathogenic variants?

The lack of benefit of neoadjuvant olaparib in TNBC patients with BRCA wild-type status, as opposed to the reported benefit in those with BRCA pathogenic variants, could be attributed to the different mechanisms of action of olaparib in these two groups. Patients with BRCA pathogenic variants have deficiencies in DNA repair mechanisms, particularly homologous recombination, making them more susceptible to the synthetic lethality induced by PARP inhibitors like olaparib. On the other hand, TNBC patients with BRCA wild-type status do not have these inherent DNA repair deficiencies, reducing the effectiveness of olaparib in this subgroup. Additionally, the heterogeneity of TNBC, with various molecular subtypes and genetic alterations, may also play a role in the differential response to olaparib based on BRCA mutation status.

How might the findings of this trial impact the current treatment approaches and clinical decision-making for TNBC patients with different BRCA mutation status?

The findings of this trial suggest that neoadjuvant olaparib does not provide additional benefit when added to standard chemotherapy regimens in TNBC patients with BRCA wild-type status. As a result, clinicians may reconsider the use of olaparib in this specific subgroup of patients and focus on alternative treatment strategies that could offer more significant clinical benefits. For TNBC patients with BRCA pathogenic variants, the reported benefit of olaparib highlights the importance of genetic testing to identify those who may benefit from PARP inhibitors. This personalized approach to treatment selection based on BRCA mutation status could lead to more tailored and effective therapies for TNBC patients.

Given the importance of pathological complete response as a prognostic factor, what other strategies or combination therapies could be explored to improve pCR rates in TNBC patients, regardless of BRCA status?

To improve pathological complete response (pCR) rates in TNBC patients, regardless of BRCA status, several strategies and combination therapies could be explored. One approach could involve the incorporation of immunotherapy agents, such as checkpoint inhibitors, into neoadjuvant treatment regimens. Immunotherapy has shown promising results in TNBC and could enhance the tumor immune response, leading to improved pCR rates. Additionally, targeted therapies against specific molecular pathways implicated in TNBC, such as PI3K/AKT/mTOR or EGFR inhibitors, could be combined with standard chemotherapy to enhance treatment response and increase pCR rates. Furthermore, investigating novel treatment modalities, such as antibody-drug conjugates or epigenetic modifiers, may offer new avenues for improving pCR rates in TNBC patients undergoing neoadjuvant therapy.