Increasing PARP inhibitor activity via several mechanisms of action

Hendrik-Tobias Arkenau, MD, PhD, FRCP, Sarah Cannon Research Institute, London, UK

What is your take-home message from ESMO 2019 in relation to the use of PARP inhibitors in solid tumors?
Several studies showing favorable results with PARP inhibitors have been reported at this year’s ESMO Congress. In particular, the results of the PAOLA study can be considered a major breakthrough [1]. The addition of olaparib to bevacizumab maintenance therapy in patients with ovarian cancer after first-line chemotherapy resulted in improved progression-free survival, not only in patients whose tumors were BRCA-mutant, but also in those with BRCA wildtype. In the overall population, PFS was increased by 6 months. For patients with BRCA mutations, PFS was 37.2 vs. 21.7 months with olaparib plus bevacizumab and bevacizumab, respectively. Also, new PARP inhibitors were discussed in the drug development therapeutic sessions, for example pamiparib that showed interesting results in small-cell lung cancer (SCLC) but also in pancreatic cancer and others.

What are the most important outcomes from the trial investigating pamiparib in combination with low-dose temozolomide in locally advanced or metastatic tumors [2]?
We know that PARP inhibitors alone have been very successful in patients with BRCA mutations, significantly improving survival. They have been widely approved for the treatment of ovarian and breast cancer and most recently in BRCA-mutant pancreatic and prostate cancer. I think that the field is moving forward with respect to how PARP inhibition can be extended beyond the BRCA mutational status, and in this context the study presented at ESMO is very interesting. In theory, low-dose temozolomide is a strong DNA-damaging agent and the PARP inhibitor pamiparib enhances this effect by inducing cell apoptosis. The combination has been proven to be safe. However, tumors for which we usually do not use PARP inhibitors, especially SCLC, have also been responsive. Patients with extended-stage SCLC showed response rates of > 30 % and an overall disease control rate of more than 70 %.

Will biomarkers help to inform patient selection?
Preclinical work and a biomarker study of this study showed that homologous repair deficiency (HRD) effectively predicted response in patients who had a high HRD score; therefore, this may be a useful biomarker and needs to be validated in future larger studies. Importantly, the treatment even worked beyond BRCA mutations. Other gene alterations in ATR, PALB-2, P53, RAD-1, among others, have to be considered in the treatment selection for those patients with such mutations.
In addition, by combining PARP inhibitors with other drugs, for example anti-angiogenic compounds like bevacizumab, we can achieve something called ‘chemical BRCAness’, which means that in patients who do not have a BRCA mutation, it is possible to effectively mimic a phenotype of BRCAness through a hypoxia-induced process. This strategy was elegantly demonstrated in the PAOLA study. I think that this is where the future of combination therapies lies.
However, there were other interesting combinations presented at ESMO and other meetings, for example PARP inhibitors plus other DNA damage repair pathway drugs such as ATR and CHCK 1 or 2 inhibitors. The translational work conducted in those studies indicated increased responses in the presence of pathway alterations including aberrations of ATR, CHCK 1/2 and others, thus supporting pamiparib plus temozolomide here. Interestingly, the risk of secondary resistance after single-agent use of PARP inhibitors is often driven by ATR aberrations, which means that combining PARP inhibitors with ATR inhibitors is a potential strategy to overcome resistance.

What challenges might arise in the context of combining PARP inhibitors with other drugs?
The combination of PARP inhibition with classical chemotherapies confers a risk of potential overlapping toxicities, particularly of the bone marrow. Low hemoglobin, neutropenia and thrombo­cytopenia often occur. In the study presented at ESMO, these adverse events proved manageable. Of course, a big question is how to combine PARP inhibition with immunotherapy. We know that immune checkpoint inhibitors generally elicit higher responses in tumors that express PD-L1, and there is very good preclinical evidence indicating that PARP inhibition can actually increase PD-L1 expression [3]. Potential combinations of PARP inhibitors with DNA damage repair-directed therapies, cytotoxic drugs, anti-angiogenic agents and immunotherapy represent an exciting field of research. Combinations and sequencing of these drugs in an ideal manner will have to be investigated.

REFERENCES

1. Ray-Coquard I et al., Phase III PAOLA-1/ENGOT-ov25: maintenance olaparib with bevacizumab in patients with newly diagnosed, advanced OC treated with platinum-based chemotherapy and bevacizumab as standard of care. ESMO 2019, abstract LBA2_PR
2. Stradella A et al., Updated results of the PARP1/2 inhibitor pamiparib in combination with low-dose temozolomide in patients with locally advanced or metastatic solid tumors. ESMO 2019, abstract 451PD
3. Jiao S et al., PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res 2017; 23(14): 3711-3720