PARP Inhibitors: A Novel Approach to Treating Ovarian Cancer
PARP inhibitors are novel therapies with indication focused on ovarian cancer; however, new agents are being studied for other cancers as well.
Ovarian cancer ranks fifth in cancer-related deaths among women.1 Ovarian cancer was originally thought to only began in the ovaries, but recent evidence shows that many ovarian cancers may start in the cells of the far end of the fallopian tubes.2 Because the ovaries are composed of different cell types, various tumors can develop. Epithelial tumors start from the cells that cover the outer surface of the ovary, making up most ovarian tumors. Germ cell tumors start from the ova, which are the cells that produce eggs. Stromal tumors start from the structural tissue cells that hold the ovaries together and produce estrogen and progesterone.2 Each type of tumor has different subtypes and grades based on tumor differentiation.2
Risk factors for ovarian cancer include being overweight or obese, having children after age 35 or never having a full-term pregnancy, fertility treatment, and having a family history of ovarian, breast, or colorectal cancer.3 Factors that can lower the risk of ovarian cancer include full-term pregnancy before 26 years of age, breastfeeding, and birth control.3 Common symptoms of ovarian cancer include bloating, pelvic or abdominal pain, trouble eating or feeling full quickly, and urinary symptoms, such as urgency or frequency.4 Treatment typically involves surgical removal of the tumor and chemotherapy, radiation, hormone therapy, or targeted therapy with poly (ADP-ribose) polymerase (PARP) inhibitors.5
The National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer recommend several clinical options, including salpingo-oopherectomy, which is removal of the ovaries and fallopian tubes, plus comprehensive surgical staging.6 Comprehensive surgical staging considers whether future female fertility is desired and recommends that every effort be made during a primary procedure to achieve maximum cytoreduction (ie, removing as much visible cancer as possible).6 For poor surgical candidates or those with a low likelihood of optimal cytoreduction, neoadjuvant therapy is recommended as primary treatment, which can include chemotherapy, radiation, and other treatments.6
Adjuvant therapy is used to decrease the risk of disease recurrence or to primarily treat residual disease.6 Adjuvant and neoadjuvant therapy for ovarian cancer include paclitaxel, carboplatin, liposomal doxorubicin, and docetaxel.6 Bevacizumab also can be used as a single agent, after combination with carboplatin/paclitaxel, for stage III or IV disease following initial surgical resection.6 Agents used for recurrence therapy are very similar to those that are used for adjuvant and neoadjuvant treatments.6 Although there are several chemotherapy options, PARP inhibitors are a newer, targeted approach for patients with ovarian cancer who are in complete or partial response to first-line chemotherapy.
Indications of PARP Inhibitors
PARP inhibitors are responsible for preventing DNA restoration, killing cancer cells in the process. These agents predominately work with breast cancer (BRCA) gene mutations, as they also impair DNA repair, resulting in multiple modes of attack.7,8 The mechanism of action of PARP inhibitors is a novel approach to treating ovarian cancer. PARP is involved in the cell survival pathway by recruiting repair proteins to correct dysfunctional DNA. Inhibiting this process leads to cell death in the presence of a BRCA mutation. If BRCA is working correctly, then PARP inhibitors are ineffective, as the BRCA-proficient cell will repair the DNA mutation, leading to cell survival.8 There are 3 available PARP inhibitors approved by the FDA to treat ovarian cancer (Table 1).9,10 These products can be used for fallopian tube and primary peritoneal cancers; however, their clinical settings may be different. For example, niraparib is used when olaparib and rucaparib have failed.9,10 Additionally, talazoparib is the first PARP inhibitor used for human epidermal growth factor receptor 2 breast cancer in patients with a BRCA mutation.10
Adverse Events and Drug Interactions of PARP Inhibitors
Adverse events (AEs) are attributable to all cancer agents, and PARP inhibitors are not an exclusion. Gastrointestinal (GI) toxicities, such as nausea and vomiting, are present with all PARP inhibitors, but certain antiemetics should be avoided. Cytochrome (CYP) P450 3A4 inhibitors, such as aprepitant, interact with olaparib and rucaparib by increasing its plasma concentrations.11 However, niraparib is an exception, as it has no significant CYP interactions because it is metabolized by carboxylesterases.12 Because PARP inhibitors are classified under the moderate- to high-emetic risk category, the NCCN guidelines recommend patients be initiated on a serotonin (5-HT3) receptor antagonist 30 minutes prior to a PARP inhibitor.13 Additionally, consuming food with these products can ameliorate additional GI issues. Other notable AEs of PARP inhibitors include anemia, neutropenia, and fatigue, which can be mitigated with both pharmacologic and nonpharmacologic strategies (Table 2).9,10
PARP inhibitors are novel therapies with indications focused on ovarian cancer; however, new agents are being studied for other cancers as well. Veliparib is a PARP inhibitor in clinical trials for the treatment of non-small cell lung cancer.15 Likewise, pamiparib is studied as a combination regimen to treat advanced solid tumors.16 As more PARP inhibitors enter the market, it is important to recognize where they fall in therapy.
AEs are certainly legitimate concerns, but they are manageable, often only requiring dose modification. These agents have limited distribution channels, being dispensed only at specialty pharmacies. However, patients may reach out to their local pharmacist for questions or concerns. Consequently, it is important to understand PARP inhibitors and their implications for treating cancer. Future trials will tell if PARP inhibitors can extend their benefit beyond treating breast and ovarian cancers.
- Ovarian Cancer Statistics | How Common is Ovarian Cancer. (2019). Retrieved 15 October 2019, from https://www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html.
- What is Ovarian Cancer | Ovarian Tumors and Cysts. (2019). Retrieved 15 October 2019, from https://www.cancer.org/cancer/ovarian-cancer/about/what-is-ovarian-cancer.html.
- Ovarian Cancer Risk Factors. (2019). Retrieved 15 October 2019, from https://www.cancer.org/cancer/ovarian-cancer/causes-risks-prevention/risk-factors.html.
- Signs and Symptoms of Ovarian Cancer | Early Signs of Ovarian Cancer. (2019). Retrieved 15 October 2019, from https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/signs-and-symptoms.html.
- Ovarian Cancer Treatment | How to Treat Ovarian Cancer. (2019). Retrieved 15 October 2019, from https://www.cancer.org/cancer/ovarian-cancer/treating.html.
- NCCN Guidelines: Ovarian Cancer (2019). Retrieved 15 October 2019, from https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf.
- New discovery could open up PARP inhibitors to more cancer patients. (2019). Retrieved 15 October 2019, from https://www.fiercebiotech.com/research/new-pathway-could-open-up-parp-inhibitors-to-more-patients.
- Dziadkowiec, K. N., Gąsiorowska, E., Nowak-Markwitz, E., & Jankowska, A. (2016). PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting. Przeglad menopauzalny = Menopause review, 15(4), 215—219. doi:10.5114/pm.2016.65667.
- Armstrong, D., Alvarez, R., Bakkum-Gamez, J., Barroilhet, L., Behbakht, K., & Berchuck, A. et al. (2019). NCCN Guidelines Insights: Ovarian Cancer, Version 1.2019. Journal of The National Comprehensive Cancer Network, 17(8), 896-909. doi: 10.6004/jnccn.2019.0039.
- Exman, P., Barroso-Sousa, R., & Tolaney, S. M. (2019). Evidence to date: talazoparib in the treatment of breast cancer. OncoTargets and therapy, 12, 5177—5187. doi:10.2147/OTT.S184971.
- Moore, K. N., & Monk, B. J. (2016). Patient Counseling and Management of Symptoms During Olaparib Therapy for Recurrent Ovarian Cancer. The Oncologist, 21(8), 954—963. doi:10.1634/theoncologist.2015-0268.
- DailyMed. (n.d.). Retrieved from https://dailymed.nlm.nih.gov/dailymed/.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Antiemesis. (2019, February 28). Retrieved 15 October 2019, from https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf.
- Cancer, C. (2019). Managing Side Effects of Chemotherapy - Chemocare. Retrieved 15 October 2019, from http://chemocare.com/chemotherapy/side-effects/.
- Veliparib. (2019). Retrieved 15 October 2019, from https://www.abbvie.com/our-science/pipeline/veliparib.html.
- Friedlander, M., Meniawy, T., Markman, B., Mileshkin, L., Harnett, P., Millward, M., … Gao, B. (2019). Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. The Lancet Oncology, 20(9), 1306-1315. doi:10.1016/s1470-2045(19)30396-1.