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Murthy et al. Cancer Drug Resist 2019;2:665-79 I http://dx.doi.org/10.20517/cdr.2019.002 Page 675

Many other resistance mechanisms are emerging, and with them, strategies to evade resistance, or to
use gene or protein expression as predictive biomarkers, are also developing. We note that epigenetic
changes, including BRCA gene methylation, and microRNA and long non-coding RNA regulation, have
been found to correlate with PARPi resistance [71,72] , and could be developed into biomarkers. Since HR is
highly cell cycle dependent (depends on the sister chromatid for DNA repair), regulation of the cell cycle
may be a way to re-establish an HRD state in tumors with HR reversion mutations. Inhibition of WEE1, a
[73]
cell cycle regulator, had activity in some patients with BRCA-deficient tumors in a phase 1 clinical trial .
Combination therapies of cell cycle regulators with PARP inhibition may therefore hold promise as a
way to circumvent PARPi resistance, if toxicities are manageable. Targeting complimentary DNA repair
pathways, such as the microhomology-mediated end-joining pathway, together with PARP inhibition could
represent another strategy to prevent or mitigate resistance, by augmenting synthetic lethality in a tumor
with HRD.

FUTURE PERSPECTIVES

Biomarkers
There is much interest in evaluating biomarkers for PARP inhibition, both because intrinsic or developing
resistance are concerns, and also to more precisely expand the eligible patient population beyond patients
with BRCA mutations. So far, the main clinically validated biomarker for response to PARPis is the
presence of germline or somatic BRCA mutations. Assays for HRD, as used in the ARIEL and NOVA
trials, require further clinical validation before they are used in clinic, and continue to be evaluated, such
[74]
as in the QUADRA trial . Many other potential biomarkers are emerging, as above, and may predict
for PARP inhibitor resistance. Correlative studies in PARP inhibitor trials should yield valuable data on
these emerging biomarkers. An ongoing clinical trial is evaluating long-term responders on olaparib
(NCT02489058), and may show important information on predictive factors for response.

A central difficulty in the clinical use of biomarkers for PARP inhibitor response is the evolving nature of
the tumor; a marker may represent genomic scarring, or evidence of prior repair deficiency, and may not
represent the current state and capabilities of the tumor. Therefore, frequent genomic assessment of the
tumor may be required to dynamically assess resistance and fully inform treatment decisions. Because
tissue biopsies require invasive procedures, “liquid biopsies”, or plasma circulating tumor DNA, would
capture emerging biomarkers and may provide sufficient information to guide treatment decisions in the
future [59,60] .

Monotherapy versus combination therapy
Preclinical and some clinical data indicate that immune checkpoint inhibition may synergize with PARP
inhibition in tumors with HRD, and that tumors with defective DNA repair are especially sensitive
to immunotherapy [75-77] . One study evaluated BRCA1-deficient mice with triple negative breast cancer
and found that cisplatin combined with dual checkpoint blockade augmented antitumor immunity,
attenuated tumor growth, and improved survival. BRCA1-deficient tumor models were also found to have
an increased somatic mutation burden, greater number of tumor-infiltrating lymphocytes, and increased
[78]
expression of immunomodulatory genes (PD-1 and CTLA4) compared to BRCA-wild type tumor models .
Compelled by these and other data, several ongoing clinical trials are evaluating PARPis in combination
with immune checkpoint inhibitors in breast and ovarian cancers. Angiogenesis inhibitors (cediranib) in
combination with PARP inhibition have demonstrated encouraging activity in a phase 2 platinum-sensitive
[30]
ovarian cancer clinical trial , with notable activity even in patients without BRCA mutations. Several
other ongoing clinical trials are evaluating angiogenesis inhibitors in combination with PARP inhibition in
ovarian and other cancers.