PARP inhibitors in combination with chemotherapy or radiotherapy
Because
of preclinical findings showing activity in combination with a large number of
chemotherapies, veliparib has been the most extensively evaluated in
combination with either chemotherapy or radiation. Veliparib and temozolomide has been
investigated in metastatic breast cancer, melanoma and colorectal cancer.
Although preclinical modeling suggested that HR-deficiency was not necessary to
obtain benefit from the combination, in the breast cancer study, the activity
of the combination was limited to patients with confirmed BRCA1 or BRCA2
mutations (74). The combination of veliparib and temozolomide
in melanoma was disappointing; after randomizing participants to either
veliparib with temozolomide compared to temozolomide plus placebo, no overall
survival benefit was observed (75). In patients with advanced colorectal cancer
who were heavily pretreated, the combination
of temozolomide plus veliparib resulted in 2 PRs, but the median time to
progression was short (11 weeks) (76). The combination of veliparib plus irinotecan
was also evaluated in 32 patients with advanced solid tumors with unknown BRCA
mutation status. At the RP2D, PARP
activity was reduced in tumor specimens and the clinical benefit rate was 61%
with 5 PRs identified (77). The combination of veliparib, doxorubicin and
cyclophosphamide has also been tested. Pharmacodynamic analysis has confirmed
that veliparib inhibits PARP activity in peripheral blood mononuclear cells at
the RP2D. Reported clinical activity at
this time has only seen in BRCA mutation carriers and the trial continues to
enroll breast cancer patients to an expansion cohort (78). Multiple trials of
veliparib in combination with either chemotherapy or radiation remain
open to accrual. These trials are being
conducted in a number of different tumor types, including prostate,
hepatocellular, pancreatic, cervical, lymphoma and myeloma.
Due to preclinical work showing
increased efficacy, rucaparib was first evaluated in combination with
temozolomide. In a total of 32 patients
evaluated, the combination of rucaparib and temolomide demonstrated preliminary
clinical activity, with 3 responses (1 complete response (CR)) and 7 patients
achieving stable disease (SD) ≥ 6 months.
In addition, tumor biopsies confirmed that rucaparib inhibited PARP
enzymatic activity in the tumor (79). Based on the phase I result, the combination
was evaluated in phase II for patients with metastatic melanoma; although
clinical activity was observed, significant toxicity, including death and
hospitalizations from myelosuppression, preventing further clinical development
(80).
Olaparib
has been tested in combination with paclitaxel, cisplatin and gemcitabine and
carboplatin in BRCA1/2 mutation carriers.
Similar to the rucaparib experience, these combinations have resulted in
significant myelosuppression, limiting the dose of olaparib that can be
administered (81-83). Further clinical trials of olaparib in
combination with other chemotherapy agents as well as radiation therapy are
ongoing.
At
the current time, it is difficult to draw conclusions regarding the future of
PARP inhibitors in combination with other anti-cancer modalities. Of the studies that have reported, it does appear
difficult to administer PARP inhibitors with chemotherapies at single-agent
dose levels since toxicity rates, particularly myelosuppression, unacceptably
increase. In addition, the question of
whether the combination offers any distinct treatment advantage over
chemotherapy alone in tumors which have functional HR has not been directly
answered. Hopefully, with many of the
active studies reporting results over the next few years, it will be possible
to address these issues and determine the role of PARP combinations, if any,
for the treatment of human cancer.
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