Clinical Insights Into Advancements in Epithelial Ovarian Cancer Treatment

Ovarian cancer is one of the mostcommon gynecologic cancers andholds the highest mortality rateamong cancers that affect the female reproductive system.¹ It is a difficult-to-treat disease because of the limited number of targeted therapy options available and a high rate of recurrence.²

In 2023, the National Cancer Institute estimates there will be almost 20,000 new diagnoses and more than 13,000 deaths attributed to ovarian cancer in the United States; it is the fifth leading cause of cancer death in women.^2-4 Epithelial ovarian cancer (EOC) accounts for approximately 90% of all ovarian malignancies, and the 5-year survival rate for metastatic EOC is approximately only 31%.^1-3 Current clinical research focuses on advancements in the management of EOC with novel targeted molecular therapies, focusing particularly on PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICIs).^1,2,5

Background

Ovaries are the glands found on each side of the uterus in females that produce the hormones estrogen and progesterone, as well as ova, or eggs, for reproduction.⁶ The ovaries are made up of 3 main types of cells that may develop different types of tumors: epithelial tumors that start from the cells covering the outer surface of the ovary, germ cell tumors that arise from the ova, and stromal tumors that begin from structural tissue that holds the ovary together and produces both estrogen and progesterone.⁶

Ovarian cancers were previously believed to originate only in the ovaries, but data from recent studies suggest that many ovarian cancers may actually arise from the cells in the distal end of the fallopian tubes.⁶ The most common histological subtypes of EOC are classified as high-grade serous, endometrioid, clear cell, mucinous, and low-grade serous.⁶ Each of these subtypes behaves as a separate and distinct disease with differences in clinical presentation and mutations, as well as response to treatment.^1,6 Approximately 15% of patients with EOC harbor BRCA1/2 mutations and approximately 50% of EOCs exhibit defective DNA repair via homologous recombination deficiencies (HRDs), which serve as prognostic and predictive biomarkers.^1,7

Current Clinical Insights Into Treatment of Epithelial Ovarian Cancer

Typically, the standard treatment strategy for EOC involves cytoreductive surgery with pre- or postoperative chemotherapy, usually a platinum agent in combination with a taxane.^1,2,8,9 However, up to 80% of patients relapse within 12 to 18 months.¹ There is no single therapeutic agent currently recommended as the treatment of choice for recurrent EOC. Many patients receive the same chemotherapy (depending on previous response and mutation status), such as bevacizumab (Avastin; Genentech), or targeted therapies including PARPi.^1,2,8,9

PARPi target and exploit genetic mutations that interfere with DNA damage repair and the HR pathway, most notably BRCA.^8-11 BRCA mutations and other HRDs make it more difficult for cells to repair DNA damage, leading to synthetic lethality.^10,11 Olaparib (Lynparza; AstraZeneca), rucaparib (Rubraca; Clovis Oncology), and niraparib (Zejula; GSK) have all received FDA approval for the treatment of EOC in different settings.^1,2,9 As of October 2022, all 3 manufacturers had voluntarily withdrawn their recommendation of these products in the third- and fourth-line treatments of ovarian cancer because of safety concerns related to overall survival.² Accordingly, the National Comprehensive Cancer Network (NCCN) has also withdrawn its support, classifying these products as category 3 recommendations and stating, “Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.”^2,9 However, both NCCN recommendations and FDA indications remain in place for the use of these PARPi for first-line maintenance therapy (categories 1 and 2A per BRCA status).^2,9

Additionally, in November 2022, GSK also restricted the use of niraparib following an FDA request that it be used only for patients with deleterious or suspected deleterious germline BRCA mutations (gBRCAMUT).² A fourth PARPi being investigated for the treatment of EOC is veliparib (ABT-888; AbbVie), which has demonstrated a lower PARP-trapping capability vs the other 3 FDA-approved products, but a decreased toxicity when combined with chemotherapeutic agents and radiotherapy.^1,5

Representing a significant advancement in the treatment of advanced ovarian cancer, PARPi have changed the landscape for current therapeutic strategies, particularly for patients with BRCA1/2 mutations or other HRD mutations.^1,10,11 However, investigators are also seeking to determine which patients among the non-^BRCAMUT and non-HRD populations are also most likely to benefit.^1,2,5 PARPi have increasing indications as monotherapies, but resistance and need for improved efficacy have led researchers to focus on combination therapies, including use with ICIs. The Figure illustrates the current treatment algorithm for advanced EOC and where PARPi may be most applicable in clinical use.⁵

ICIs are novel immunotherapy agents that block checkpoint proteins from binding with their partner proteins, allowing the body’s T cells to destroy cancer cells.¹² Despite the success of immunotherapy in other types of cancer, the use of monotherapy antibodies that inhibit the surface proteins, including CTLA4, PD-1 expressed by activated T cells, and its ligand PD-L1, has achieved only modest results in EOC, and hence has not yet been FDA approved for treatment in this indication.^1,2,10,13 Some examples of ICIs in investigative combinations include the PD-1 inhibitors pembrolizumab (Keytruda; Merck & Co) and nivolumab (Opdivo; Bristol Myers Squibb).^1,11,13 Other examples include the PD-L1 inhibitors avelumab (Bavencio; EMD Serono/Pfizer), atezolizumab (Tecentriq; Genentech), and durvalumab (Imfinzi; AstraZeneca Pharmaceuticals).^1,11,13 Additionally, combinations with the PD-1/PD-L1/2 inhibitor dostarlimab-gxly (Jemperli; GSK) or CTLA4 inhibitor tremelimumab (Imjudo; AstraZeneca Pharmaceuticals) are also being studied.^1,11,13

Data from most recent studies show a potential synergistic effect whereby PARPi might heighten sensitivity to ICIs because they indirectly impact the tumor microenvironment by increasing genomic instability and immune pathway activation and inhibiting these surface proteins.^10,14,15 Additional studies are necessary to investigate potential PARPi/ICI combinations in groups of patients who have clinically unmet anticancer needs, with the goal of improving outcomes for patients diagnosed with EOC. With other research underway focusing on the identification of new possible targets, data regarding the future role of ICIs, tumor vaccines, and adoptive T-cell therapies may also play a role in personalized immunologic treatment for patients with EOC.¹

Conclusion

Considerations for EOC therapy selection involve many factors. These include treatment indication, FDA approval, platinum sensitivity, molecular analyses (eg, BRCA, HRD), and testing strategies.^1,8 Other issues may include risk stratification, identifying the likelihood of patient response to PARPi, previous treatment lines, and response to prior therapy.^1,8 Finally, patient-specific factors such as performance status, end organ status, and toxicities to prior regimens, as well as toxicity profiles, patient adherence, and cost/value, should be considered.^1,8 Furthermore, specialty pharmacists are uniquely positioned to optimize patient outcomes in those receiving treatment for EOC through patient education, management of adverse events, adherence strategies, and mitigation of financial toxicity.

References

1. Revythis A, Limbu A, Mikropoulos C, et al. Recent insights into PARP and immunocheckpoint inhibitors in epithelial ovarian cancer. Int J Environ Res Public Health. 2022;19(14):8577. doi:10.3390/ijerph19148577

2. PARP inhibitor update: ovarian cancer. IPD Analytics. October 28, 2022. Accessed December 12, 2022. secure.ipdanalytics.com/User/Pharma/RxStrategy/Recent/Reports

3. Cancer stat facts: ovarian cancer. National Cancer Institute. Accessed December 12, 2022. seer.cancer.gov/statfacts/html/ovary.html

4. Key statistics for ovarian cancer. American Cancer Society. Updated January 12, 2023. Accessed December 12, 2023. www.cancer.org/cancer/ovarian-cancer/about/keystatistics.html

5. Target report: poly ADP-ribose polymerase (PARP). Biomedtracker Pharma Intelligence. Pharma Intelligence UK Limited. December 2022. Accessed December 12, 2022. www.biomedtracker.com/targetreport.cfm?targetid=665

6. What is ovarian cancer? American Cancer Society. Updated April 11, 2018. Accessed December 12, 2022. www.cancer.org/cancer/ovarian-cancer/about/what-is-ovarian-cancer.html

7. Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 2015;13:188. doi:10.1186/s12916-015-0425-1

8. Neff RT, Senter L, Salani R. BRCA mutation in ovarian cancer: testing, implications and treatment considerations. Ther Adv Med Oncol. 2017;9(8):519-531. doi:10.1177/1758834017714993

9. NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer/fallopian tube cancer/primary peritoneal cancer, version 5.2022. Accessed December 12, 2022. www.nccn.org/guidelines/guidelines-detail?category=1&id=1453

10. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137-1154. doi:10.1158/2159-8290.CD-15-0714

11. Bruin MAC, Sonke GS, Beijnen JH, Huitema ADR. Pharmacokinetics and pharmacodynamics of PARP inhibitors in oncology. Clin Pharmacokinet. 2022;61(12):1649-1675. doi:10.1007/s40262-022-01167-6

12. Hunia J, Gawalski K, Szredzka A, Suskiewicz MJ, Nowis D. The potential of PARP inhibitors in targeted cancer therapy and immunotherapy. Front Mol Biosci. 2022;9:1073797. doi:10.3389/fmolb.2022.1073797

13. Immune checkpoint inhibitors. National Cancer Institute. Updated April 7, 2022. Accessed December 12, 2022. www.cancer.gov/about-cancer/treatment/types/ immunotherapy/checkpoint-inhibitors

14. Biomedtracker - Pharma Intelligence. Informa Business Intelligence. Accessed December 12, 2022. biomedtracker.com 15. Kim DS, Camacho CV, Kraus WL. Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance. Exp Mol Med. 2021;53(1):42-51. doi:10.1038/s12276-021-00557-3

About the Author

Rachel K. Anderson, PharmD, CSP, is a clinical program manager at AllianceRx Walgreens Pharmacy in Pittsburgh, Pennsylvania.