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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 669

Niraparib, olaparib, and rucaparib are FDA-approved for maintenance therapy of patients with platinum-
sensitive, recurrent ovarian cancer, regardless of BRCA mutation status, based on randomized trials that
demonstrated improvement in PFS with PARPi maintenance compared to placebo following a complete
or partial response to platinum-based treatment [22-24] . A better response was demonstrated in patients with
germline BRCA mutations compared to the general population. Niraparib and rucaparib maintenance
trials also showed that patients with deficiencies in HR, as defined by various assays, have a better response
to PARPi maintenance than patients without any deficiency in DNA repair [23,24] . Further validation of
HRD assays is ongoing. Because bevacizumab yields improved PFS in the treatment (in combination with
carboplatin and either gemcitabine or paclitaxel) and maintenance of platinum-sensitive recurrent ovarian
cancer when compared to standard chemotherapy alone [25,26] , with a trend towards improved overall
[26]
survival in one trial , it is an alternative to PARPi maintenance, especially for patients without pathogenic
BRCA mutations or other deficiencies in HR.

More recently, PARPis are moving to the frontline maintenance setting in ovarian cancer, particularly in
germline BRCA-mutation carriers. SOLO1 is a randomized phase 3 trial evaluating olaparib as maintenance
therapy in BRCA-mutated patients with newly diagnosed advanced ovarian cancer who had a complete or
partial response to platinum chemotherapy. Almost all patients had germline BRCA mutations; only 2 of
391 patients had a somatic BRCA mutation. The primary endpoint was PFS, which was significantly longer
[27]
in the olaparib arm compared to placebo (hazard ratio 0.30, P < 0.001) . While compelling and practice
changing, the generalizability of this data depends in part on the definition of a deleterious germline BRCA
mutation, especially since there are growing databases evaluating “variants of unknown significance”. As
Spriggs and Longo noted in an editorial, SOLO1 did not include any information on the actual identity or
distribution of the deleterious germline BRCA variants, which could have been useful in assigning clinical
[28]
effects to specific variants . Also, overall survival data are not yet mature, and therefore bevacizumab
remains a standard maintenance option. Niraparib is also being evaluated in a frontline maintenance
therapy trial, with results pending (NCT01847274). This study is not limited to patients with BRCA
mutations; eligible patients could have either a germline BRCA mutation or high-grade serous histology.

OVERVIEW OF TRIALS LEADING TO PARP INHIBITOR APPROVAL IN BREAST CANCER
OlympiAD and EMBRACA were randomized phase 3 trials that compared olaparib and talazoparib,
respectively, with physician’s choice chemotherapy (not including platinum chemotherapy) in patients
with germline BRCA mutations and metastatic HER2-negative breast cancer who had received prior
chemotherapy [33,34] . Patients must not have progressed on platinum-based chemotherapy in the metastatic
setting. The primary endpoint, progression-free survival, was significantly longer in the PARP inhibitor
arms, leading to FDA approval for both of these drugs. Overall survival data is still immature for
EMBRACA. OlympiAD was not powered to detect a difference in overall survival, although there was a
nonsignificant trend towards improvement in the olaparib arm.

STATUS OF TRIALS WITH OTHER PARPIS
Veliparib has demonstrated less toxicity in combination with chemotherapy than the other PARPis,
and continues to be evaluated in ongoing combination chemotherapy therapy trials. A phase 1 study of
veliparib in combination with carboplatin and paclitaxel in advanced solid malignancies showed acceptable
[35]
toxicity and promising antitumor activity . Another phase 1 trial of veliparib this time in combination
with low dose oral cyclophosphamide in refractory solid tumors and lymphomas also demonstrated
[36]
acceptable toxicity and activity, but the maximum tolerated veliparib dose was much lower . The drug
has also shown single agent activity. A phase 2 study of single agent veliparib in patients with recurrent
ovarian cancer who carry a germline BRCA mutation demonstrated an objective response rate (the primary
endpoint) of 26%. 60% of the patients were platinum resistant, and these patients had a lower objective