Neoadjuvant Olaparib Monotherapy Proposed For TNBC With HRD

Rédigé le 26/11/2020
Sylvain LADOIRE

Triple-negative breast cancer patients with homologous recombination deficiency may benefit from upfront olaparib treatment

PETREMAC trial findings indicate that over half of patients with stage II–III triple-negative breast cancer (TNBC) may benefit from neoadjuvant therapy with the PARP inhibitor olaparib, with homologous recombination (HR) deficiency found to predict response. 

“While the benefit of PARP inhibitor monotherapy in TNBC needs confirmation, it presents a potential sequential approach for TNBC downstaging prior to chemotherapy”, suggest Hans Petter Eikesdal, from Haukeland University Hospital in Bergen, Norway, and co-workers.  

The analysis published in the Annals of Oncology focuses on 32 participants with treatment-naïve TNBC larger than 2 cm in size who were unselected for BRCA or TP53 mutation status and assigned to receive olaparib 300 mg twice daily for up to 10 weeks before beginning chemotherapy. 

One patient achieved a clinical complete response and 17 a partial response, giving an objective response rate of 56.3%. 

“Of notice, acquired resistance to platinum agents is associated with secondary mutations restoring HR function, and may promote PARP inhibitor resistance”, the investigators hypothesise. 

“Thus, prior exposure to DNA crosslinking agents such as platinum and probably cyclophosphamide may explain the discrepancy between our results in treatment-naïve patients and the negative finding observed previously in late-stage metastatic breast cancer.”

Closer analysis of the 18 responding patients revealed that 55.6% had a somatic or germline HR mutation compared with just 7.1% of the 14 nonresponders. And for those without HR mutations, BRCA1 hypermethylation was significantly more common in patients who responded than those who did not (75.0% of 8 vs 23.1% of 13 patients).

Somatic HR mutations and/or BRCA1 methylation were identified in 85.7% of the 14 responders without germline PALB2 or BRCA1/2 mutations compared with 23.1% of 13 nonresponders without these germline mutations, a significant difference.

Altogether, 88.9% of the responding patients in the study had HR mutations or BRCA1 methylation, the team summarises. 

The researchers also found that pretreatment tumour infiltrating lymphocyte counts were higher in patients who responded to olaparib than those who did not, and high PD-L1 expression in immune and tumour cells was significantly associated with the likelihood of olaparib response. 

Based on these post-hoc analyses, the researchers “advocate further testing of olaparib in concert with chemotherapy and potentially immunotherapy in sequential neoadjuvant regimens for TNBCs harboring HR mutations or BRCA1 methylation.”

They note that that the HR somatic mutations identified in these participants have been found across breast cancer subtypes, indicating “that PARP inhibition may be of potential benefit in a wider selection of patients with breast cancer.”

And they continue that “the findings that PARP inhibitor monotherapy may work in breast and prostatic carcinomas harboring somatic HR mutations indicate that PARP [inhibition] may be effective in other types of cancer with HR deficiency as well.” 

 

Reference 

Eikesdal HP, Yndestad S, Elzawahry A, et al. Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Ann Oncol; Advance online publication 23 November 2020. Doi: 10.1016/j.annonc.2020.11.009.