PARP inhibitors and mechanisms of resistance
PARP inhibitors
Poly (ADP ribose) polymerase inhibitors (PARPi) cause an accumulation of unresolved DNA damage in tumours with BRCA1/2 mutations, leading to cell death. As platinum salts may also have the same action, there may be overlapping resistance with PARPi and the efficacy of PARPi in patients with prior platinum therapy is unknown. A systematic review presented at SABCS 2022 from pooled analysis (olaparib, talazoparib, niraparib, and veliparib) showed that PARPi improved PFS in breast cancer patients with prior treatment with platinum-based therapy compared to the control group [HR 0.72; 95% CI, 0.53–0.97; p=0.03]22. In comparison, the population without previous platinum exposure had a similar but slightly greater benefit from PARPi [HR 0.68; 95% CI, 0.52–0.89; p=0.005]22.
These results decrease the concern of cross-resistance between drug classes. However, more extensive studies are needed22
Professor Coombes discusses his highlights on HER2– high-risk breast cancer studies, as presented at SABCS 2022.
Olaparib is approved for the treatment of HER2- patients with a BRCA germline mutation. According to the author of the OPHELIA study, there is no evidence that HER2+ tumours are resistant to PARPi23. This study enrolled HER2+ advanced breast cancer (aBC) patients who had received previous therapy23. Patients received olaparib (O) twice daily, plus trastuzumab (T), until disease progression or unacceptable toxicity.
The primary endpoint of investigator-assessed clinical benefit rate (CBR) for at least 24 weeks was met (80.0%, 4 of 5 pts; 95% CI, 28.4% to 99.5%; p< 0.001)23. The overall response rate (ORR) was 60.0% (95% CI, 17.4% to 94.7%), and the median duration of response (DoR) was 3.8 months (95% CI, 2.5 to 8.3 months)23. HER2 overexpression in germline BRCA-mutated ABC is infrequent. Although a small study, the activity observed indicates that the O+T combination might be of help for this group of patients23.
Safety and PFS from the Phase II GeparOLA study investigating neoadjuvant chemotherapy treatments (NACT) in early HER2-low breast cancer (eBC) and homologous recombination deficiency (HRD) have previously been reported. Peter Fasching presented long-term survival data with a median follow-up of 49.8 months24. Patients (n=106) were treated with neoadjuvant paclitaxel plus either olaparib (PO) or carboplatinum (PCb), followed by enterocyclin-based therapy (EC) in a 2:1 ratio. At baseline, there was an inequality between the two treatment arms with respect to nodal positivity (25% PO vs 45% PCb). Not all HRD tumours had BRCA mutations. There was no difference in pCR rates in the BRCA mutated tumours, whereas pCR was significantly different in the BRCA wildtype patients treated with PO or PCb (50% to 37.5%, respectively), as can be seen in the following figure.
Long-term efficacy endpoints in the overall study population included invasive disease-free survival (iDFS) (88.5% PCb versus 76% PO), with similar results for distant disease-free survival (DDFS) (93.4% PCb versus 81.2 PO). Olaparib can replace carboplatinum in HER2-negative eBC patients with HRD, g/t BRCA mutation. However, those without a g/tBRCA mutation platinum containing NACT may result in a better outcome. Further trials are needed24.
Figure 1. Subgroup PCR rate in the GeparOLA Study (Adapted24).
Many advanced triple-negative breast cancer (aTNBC) patients carry HRD associated with platinum sensitivity. In the DORA trial, the efficacy of maintenance olaparib (O) with or without the immune checkpoint inhibitor (ICI) durvalumab (D) was investigated in aTNBC patients following clinical benefit from platinum chemotherapy (NCT03167619). After a median follow-up of 9.8 months, the median PFS was 3.95 versus 6.1 months in the O monotherapy and O+D arm, respectively25. A secondary endpoint of disease clinical benefit rate (CBR) was 39.1% and 36.4% (17.2%-59.3%) in the O and O+D arms, respectively25.
A subset of non-gBRCA-altered aTNBC patients who derived clinical benefit from platinum-based chemotherapy had a durable disease control with a chemotherapy-free maintenance strategy of olaparib +/- durvalumab25
Talazoparib (TALA) is an orally available PARP inhibitor approved for the treatment of HER2-negative locally advanced or metastatic BC with germline BRCA mutations. TALA has shown clinical benefit in the EMBRACA phase III trial for patients with germline BRCA1/2-mutated locally advanced or metastatic HER2- breast cancer. In this Phase IV real-world evidence study, the primary endpoint, Time to Treatment Discontinuation (TTD), was 9.6 months, with 34.5% of patients still on treatment at 12 months26. In subgroup analysis, the median TTD was similar independent of HR status, germline versus somatic mutation, or prior platinum exposure26. Refer to the following figure for more information.
Figure 2. Results from the ViTAL trial (Adapted26).
In the following video, Professor Coombes highlights some key findings from SABCS 2022 regarding minimal residual disease in high-risk breast cancer survivors.
Mechanisms of resistance
PARPi resistance can take multiple forms, and most data have come from pre-clinical studies. Many of these resistance mechanisms are unknown in the clinical setting, which is the focus of most current research into PARPi resistance. One mechanism of resistance is reversion-mediated resistance which are mutations that restore the function of a dysfunctional gene. More information is also required on which biomarkers are necessary to refine the best use of PARPi. For example, distinguishing between different BRCA1 and BRCA 2 mutations may predict the likelihood of the mutation reverting and likely predict the emergence of resistance. Clinical grade assays for identifying these mutations are needed. In addition, currently, there are no biomarkers that detect non-reversion mechanisms of PARPi resistance. Better biomarkers are also required for the existing status of homologous recombination (HR) function and those that predict dose-limiting toxicity.
More information is needed to avoid PARPi resistance mechanisms by targeting those caused by reversion or non-reversion mutations and looking at drug combinations to prevent PARPi resistance