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Page 676 Murthy et al. Cancer Drug Resist 2019;2:665-79 I http://dx.doi.org/10.20517/cdr.2019.002

Novel agents, such as ATM, ATR, and WEE1 inhibitors, are also being evaluated in combination with
PARPis, as part of strategies to evade PARP inhibitor resistance and augment synthetic lethality, as
described in the above PARP inhibitor resistance sections. Combinations of PARPis plus chemotherapy,
and PARPis plus signal transduction inhibitors such as PI3 kinase inhibitors (NCT01623349) are
additionally being studied.

Based on earlier data that has motivated many of these combination therapy trials, we may anticipate
positive signals from at least a few of the ongoing studies. Ultimately, however, the tolerability of
combination regimens will need to be assessed and may be an impediment to eventual use in the clinic.

Sequencing PARP inhibitor treatment
An unresolved question in the treatment of BRCA-associated advanced breast cancer is how to
sequence PARPis with platinum chemotherapy, since both these agents are active in the disease
and work through DNA damage. Ovarian cancer data demonstrates olaparib responses even in
platinum-resistant patients, and the phase 2 ABRAZO trial that evaluated talazoparib in patients with
advanced breast cancer and germline BRCA mutations showed a PFS of 4 months for patients who had
[79]
progressed at least 8 weeks after the last dose of platinum chemotherapy . Therefore, treating with a
PARP inhibitor following progression on platinum-based chemotherapy has some basis. There is less data
on treating first with a PARP inhibitor followed by platinum chemotherapy. A phase 2 trial of patients
with germline BRCA 1/2-mutated metastatic breast cancer assessed single-agent veliparib, another PARPi,
followed by veliparib plus carboplatin at disease progression. The post-progression treatment with veliparib
and carboplatin at the maximum tolerated doses (150 mg BID, and AUC of 5, respectively) yielded minimal
[80]
benefit; only one patient out of 30 had a response . However, since PARPis are reasonably well tolerated,
treatment with a PARP inhibitor early in the disease course may be the preferred approach for some
patients. Overall, the optimal sequence of DNA damaging agent treatment in breast cancer still needs to be
determined.

The activity of PARPis and platinum chemotherapy following progression on the other agent also needs
to be further investigated in ovarian and other cancers. Differences in resistance mechanisms between
platinum compounds and PARPis could inform these treatment decisions in the future, but at this point,
requires further study. Even less is known about the potential activity of a specific PARP inhibitor following
progression on another PARP inhibitor, but because the clinical PARPis have different chemical structures,
targets, trapping potency, and other off-target effects, this would be a valuable clinical question to explore.

DECLARATIONS
Authors’ contributions
Conception and writing of this review article: Murthy P, Muggia F

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.