PARP Inhibitors for Cancer Treatment

Poly (ADP-ribose) polymerase (PARP) are enzymes that attach polymers of ADP-ribose (PAR) to itself and other proteins. PARP play a role in DNA repair pathways; they act as sensors and initiate repair, preventing DNA mutation and allowing cellular survival after mitosis. DNA single strand break is involved in both repair pathways: the base excision repair (BER) and the nucleotide excision repair (NER). In DNA double strand break, is involved in the homologous recombination (HR) pathway (1).

If the PARP enzymes did not repair the DNA then the cancer cell would have too many mutations and so would trigger its own death. This is the premise by which PARP inhibitors were conceived as anti-cancer drugs.

PARP inhibitors (PARPi) bind to the catalytic site of the PARP enzymes, thus preventing normal enzymatic action. They attach the PARP enzymes at the DNA damaged moiety; this mechanism has been found to produce a greater cytotoxic activity than stopping the repair of single/double strand breaks (2). The breast cancer-associated protein (BRCA 1/2), alongside with PARP, participates in the homologous recombinational repair HR pathway. It has been shown that cells deficient in or with mutations in the gene coding to this protein are more sensitive than normal cells to the cytotoxic effects of PARPi (3). Because the PARPi decrease the ability of cells to repair themselves, these agents could be used as neoadjuvant agents sensitizing cancer cells in preparation for treatment by ionizing agents or conventional chemotherapy. They also could be used as monotherapy after conventional chemotherapy, (i.e. as adjuvant agents).

PARP inhibitors in clinical practice

PARPi are indicated for the treatment of ovarian cancer, fallopian tube, primary peritoneal and breast cancer. Rucaparib (Rubraca™) was the first PARPi approved by FDA on December 2016. Rucaparib is indicated as monotherapy for the treatment of patients with advanced ovarian cancer including harmful BRCA mutations (germline or somatic), who have been treated with two or three chemotherapies (4).

Niraparib (Zejula™) and Olaparib (Lymparza™) were approved in 2017. Niraparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy (5). Currently olaparib has three FDA indications for the treatment of adult patients. The first is in advanced ovarian cancer with deleterious germline BRCA mutations who have been treated with two or three chemotherapies. The second is in patients with epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. The third is in patients with deleterious or suspected deleterious germline BRCA mutation, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting (6).

The toxicity profile of PARPi is related to hematologic toxicity. Blood dyscrasias and fatigue are the most common adverse reactions. Clinical trial results suggest treatment-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) issues. PARPi should not be initiated if a patient has anemia or other blood dyscrasia. Data also shows no difference in the safety profile of PARP inhibitors in patients over 65 years old, compared to younger patients (7).

PARP inhibitors are still in research

Scientists are still looking for new PARP indicators, and are searching for new uses/indications for known PARPi agents. No PARP inhibitor is approved as radio-sensitizing. However, combinations of PARPi with radiotherapy seem very promising. Veliparib is the only PARP inhibitor in clinical phase II trial with this indication; the other PARP are still in pre-clinical experiments (9).

Prostate cancer is a focus of much PARP inhibitor research.  PARP is activated by Androgen Receptor (AR) upregulation in prostate cancer; the combined treatment of bicalutamide and olaparib showed a synergic effect on suppressing tumor xenografts of C4-2 cells. This and other data suggest that the androgen deprivation treatment and PARP inhibitor combination could be an option for treatment of early stage castration resistant prostate cancer (8).

Veliparib (ABT-888) is a PARPi being investigated to treat non-small cell lung cancer, BRCA-mutation related breast cancer, and ovarian cancer. Phase I trials found that the most common treatment-related adverse events (TRAEs; ≥60%) were thrombocytopenia, neutropenia, nausea, and anemia; the first two were the dose-limiting toxicities (9). A phase II trial aim was to demonstrate whether addition of veliparib to carboplatin [LINK] and paclitaxel improved progression-free survival in previously untreated patients with advanced/metastatic non–small cell lung cancer. The median overall survival was 11.7 and 9.1 months in the veliparib and placebo groups, respectively (HR, 0.80; 95% CI, 0.54–1.18; P = 0.27). In patients with squamous histology, median PFS (HR, 0.54; 95% CI, 0.26–1.12; P = 0.098) and OS (HR, 0.73; 95% CI, 0.43–1.24; P = 0.24) favored veliparib treatment. Patients with squamous histology had the best outcomes with veliparib combination (10).

  1. Morales JC, Li1 L, Fattah FJ, Dong Y, Bey EA, Patel M, et al. Review of Poly (ADP-ribose) Polymerase (PARP) Mechanisms of Action and Rationale for Targeting in Cancer and Other Diseases. Crit Rev Eukaryot Gene Expr. 2014;24(1):15–28.
  2. Dziadkowiec KN, Gąsiorowska E, Nowak-Markwitz E, Jankowska A. PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting. Prz Menopauzalny. 152016. p. 215-9.
  3. Kyle S, Thomas HD, Mitchell J, Curtin NJ. Exploiting the Achilles heel of cancer: the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in BRCA2-defective cancer. Br J Radiol. 2008;81 Spec No 1:S6-11.
  4. FDA. RUBRACA TM (Rucaparib) tablets. Label: FDA; 2018.
  5. FDA. ZEJULATM (niraparib) capsules. Label: FDA; 2018.
  6. FDA. LYNPARZA® (olaparib) tablets. Label: FDA; 2018.
  7. Ohmoto A, Yachida S. Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther. 2017;10:5195-208.
  8. Asim M, Tarish F, Zecchini HI, Sanjiv K, Gelali E, Massie CE, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017;8(1):374.
  9. Gray HJ, Bell-McGuinn K, Fleming GF, Cristea M, Xiong H, Sullivan D, et al. Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies. Gynecol Oncol. 2018;148(3):507-14.
  10. Ramalingam SS, Blais N, Mazieres J, Reck M, Jones CM, Juhasz E, et al. Randomized, Placebo-Controlled, Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non-Small Cell Lung Cancer. Clin Cancer Res. 2017;23(8):1937-44.