PARP inhibitors in combination with chemotherapy or radiotherapy − Rakyat Biologi

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.