PARP Inhibitors and Ovarian Cancer: Insights from a Preclinical Study

Professor Deborah Marsh, an internationally recognised ovarian cancer researcher, leads the Translational Oncology Group at the University of Technology Sydney. Her team are particularly interested in identifying new, more efficient therapies for the treatment of ovarian cancer.

This is a plain language summary of one of the team’s studies, led by co-first authors Kristie Dickson and Tao Xie, published in the International Journal of Molecular Sciences in 2021 and titled ‘PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer’.

What was the study about?

The study assessed treatments used for ovarian cancer, specifically poly (ADP-ribose) polymerase inhibitors – or PARP inhibitors – for treating high-grade serous ovarian cancer.

What is high-grade serous ovarian cancer?

Ovarian cancer is classified as a low survival cancer, as less than 50% of women are alive five years after their initial diagnosis, according to Cancer Australia. High-grade serous ovarian cancer is the most common and aggressive type of ovarian cancer. New therapies that target specific pathways in cancer cells are providing hope for women with this type of ovarian cancer.

What are PARP inhibitors?

PARP inhibitors are a type of drug that inhibit cancer cells from repairing their damaged DNA. When cancer cells are unable to repair their DNA, they die. PARP inhibitors work particularly well when specific mutations in genes known as BRCA1 and BRCA2 are present in the cancer cells.

Several PARP inhibitors, including olaparib, niraparib, and rucaparib, have been shown, in clinical trials conducted worldwide, to improve survival for women with high-grade serous ovarian cancer with specific gene mutations. Investigation of new PARP inhibitors is also underway. Hence, additional treatments are likely to become available for clinical use in the future.

In Australia, the currently approved PARP inhibitors for clinical use in people with high-grade serous ovarian cancer are olaparib (Lynparza) and niraparib (Zejula).

Why was this study done?

Although PARP inhibitors act similarly – that is, they inhibit cancer cells from repairing their damaged DNA – there are differences in their chemical structures that may influence their effectiveness.

This study was performed to understand how the efficacy of PARP inhibitors may vary based on the type of mutation present in high-grade serous ovarian cancer. While still at a preclinical stage, this information may, in the future, be important to healthcare professionals involved in treatment choices for people with high-grade serous ovarian cancer, as it ensures that the most appropriate treatment can be given to the right person.

What did the study look at?

The study was conducted in a laboratory using four cell lines reflective of high-grade serous ovarian cancers with either mutated or normal BRCA1 or BRCA2. Other cell lines, including one resistant to a PARP inhibitor, were also used.

Each cell line was treated with five different PARP inhibitors – olaparib, niraparib, rucaparib, talazoparib and veliparib. Following treatment, each PARP inhibitor was assessed for efficacy based on its ability to kill ovarian cancer cells.

What did the study show?

Differences in efficacy between the five PARP inhibitors were observed across the different cell lines. Both in terms of their ability to stop the growth of cancer cells during treatment and prevent further development after treatment.

The response to PARP inhibitor treatment also differed between the cell lines, indicating that the type of mutation present in ovarian cancer may influence the efficacy of PARP inhibitors.

Why is this study important?

In a preclinical model, the study shows that very specific molecular features of an individual’s cancer might influence how well specific PARP inhibitors work.

Next steps?

PARP inhibitors are revolutionising the treatment of certain types of ovarian cancer and extending the lives of affected women. Extensive data is being generated worldwide, reflecting how ovarian cancers, with different mutations, respond to PARP inhibitors. Longer term, this data will inform clinical choices for treatment.

The routine incorporation of living models of disease, such as three-dimensional bio-printed organoids generated from the primary tumour of an individual, into the clinical management of patients will also assist with choosing suitable new therapies for women with ovarian cancer in the future.

Where can I find more information on the researchers and this study?

Professor Deborah Marsh: profiles.uts.edu.au/Deborah.Marsh

The original article, ‘PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer’, was published in the International Journal of Molecular Sciences in 2021. You can access the full article for free here: www.mdpi.com/1422-0067/22/16/8506.

An associated review article, titled ‘Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival’, highlights some of the questions and challenges of PARP inhibitors in women with ovarian cancer. You can access the full article for free here: www.mdpi.com/2072-6694/14/19/4621.

Can you tell me more about ovarian cancer?

The ovaries are a pair of small, oval-shaped organs in the lower abdomen responsible for releasing eggs during the female reproductive cycle. Until recently, it was thought that all ovarian cancer arose in the ovaries. It is now known that many ovarian cancers originate in the fallopian tube and then shed onto and grow on the ovaries.

In Australia this year, a little over 1,800 women will likely be told they have ovarian cancer, according to Cancer Australia. The survival rate for women with ovarian cancer is low for several reasons. Ovarian cancer is difficult to diagnose and is often detected at a more advanced stage when it is more challenging to treat.

Delays in diagnosing ovarian cancer can occur because the symptoms are like others frequently experienced by women – abdominal pain or discomfort, bloating, feeling full quickly while eating, and changes in urgency or frequency of urination. If any of these symptoms persist, women should consult their doctor.

While surgery and chemotherapy are still the mainstay treatment for ovarian cancer, new therapies based on molecular events in the cell – such as the PARP inhibitors – are beginning to improve the survival rates for women in Australia and around the world.

There is a clear need for earlier detection and improved treatment options for women with ovarian cancer.

Where can I find more information on ovarian cancer?

• Ovarian Cancer Australia: www.ovariancancer.net.au

• Cancer Council NSW: www.cancercouncil.com.au/ovarian-cancer/

• Cancer Australia: www.canceraustralia.gov.au/cancer-types/ovariancancer/overview

• Healthdirect Australia: www.healthdirect.gov.au/ovarian-cancer

This article was published on LinkedIn on 28 February 2023.