PARPi selection in ovarian cancer

PARP inhibitor ovarian cancer indications

PARP inhibitor indications

Poly(ADP-ribose) polymerase (PARP) inhibitors provide a targeted treatment option for women with advanced ovarian cancer. Although patients whose cells harbour mutations in breast cancer genes 1 and 2 (BRCA1/2) appear to derive the greatest benefit, PARP inhibitors have also been demonstrated as an effective therapy in advanced ovarian cancer patients irrespective of homologous recombination deficiency (HRD) or BRCA status¹.

The BRCA1/2 genes are involved in DNA repair via the process of homologous recombination (HR). Pathogenic mutation in the BRCA1/2 genes leads to a homologous recombination deficiency (HRD)²

Regulatory approvals

The three PARP inhibitors niraparib, olaparib and rucaparib have been approved for first-line maintenance therapy for ovarian cancer by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA)^3,4. Tables 1–3 below outline the indications for use as stipulated by these regulatory agencies. Some indications make reference to specific genetic mutation (BRCA mutation) or HRD status.

Table 1. FDA and EMA approved indications for use of niraparib to treat ovarian cancer^5,6.

Table 2. FDA and EMA approved indications for use of olaparib to treat ovarian cancer^7,8.

Table 3. FDA and EMA approved indications for use of rucaparib to treat ovarian cancer^9,10.

The overlapping indications can make it difficult for health care professionals to select the right PARP inhibitor for their patients.

Selection should take into consideration both the patient’s unique clinical and molecular features, and the individual profile of the inhibitor: such as its level of toxicity and efficacy¹¹

For more information on the key clinical trials that led to the approval of niraparib, olaparib and rucaparib in ovarian cancer, review the information in section 3, PARPi efficacy and safety in ovarian cancer.

Differences between PARP inhibitors

In a network meta-analysis that indirectly compared niraparib, olaparib and rucaparib in terms of progression-free survival, overall survival and adverse events, no significant differences were found in overall survival and progression-free survival. In this study, the only significant difference was a higher risk of headaches, constipation, neutropenia and thrombocytopenia in niraparib compared to olaparib and rucaparib¹²

In a separate meta-analysis examining differences in toxicity between niraparib, olaparib and rucaparib, the following results were observed¹³:

• haematologic adverse events were significantly related to niraparib
• diarrhoea was significantly related to olaparib
• abdominal pain was significantly related to rucaparib

In September 2022, the indications for olaparib, rucaparib and niraparib for AOC in women previously treated with multiple lines of chemotherapy was voluntarily withdrawn by the manufacturers due to an increased risk of death observed during phase III clinical trial^14,15. This withdrawal applies in both the US and Europe.

Olaparib is no longer indicated for use in women with germ-line BRCA-mutated AOC who have had prior treatment with 3 or more lines of chemotherapy¹⁵. This is because of recent results from a subgroup of the SOLO3 trial, which indicated a potentially detrimental effect of olaparib on overall survival when compared with a chemotherapy control group not receiving olaparib¹⁶. This withdrawal does not apply to any other olaparib indications including as first-line maintenance of BRCA-mutated AOC, first-line maintenance treatment of homologus recombination deficiency (HRD)-positive AOC in combination with bevacizumab, and maintenance of recurrent ovarian cancer¹⁵.

Similarly, in the ongoing ARIEL4 trial, rucaparib showed a 31.3% increase in the risk of death, compared with chemotherapy controls in patients who had already received two or more lines of chemotherapy¹⁷.

The approval of niraparib was also subsequently voluntarily withdrawn, as the QUARDRA (single arm, uncontrolled nature) study evaluating its safety and efficacy in adult patients with AOC who have been treated with 3 or more prior chemotherapy regimens, did not adequately investigate or obtain the comparative overall survival data^18,19.

To learn more about the differences in side effects, refer to the information here

The following factors may contribute to the differences between PARP inhibitors¹²:

• selectivity
• binding affinity
• side effect profiles
• pharmacokinetics
• patient HRD or BRCA status

PARP inhibitor mode of action and patient stratification

Poly(ADP-ribose) polymerase (PARP) is a type of protein involved in a number of DNA damage repair pathways. PARP inhibitors (PARPi) are a targeted therapy that inhibits PARP protein activity. By inhibiting this activity in cancerous cells, PARPi can prevent them from repairing their damaged DNA, resulting in cancer cell death (apoptosis)^12,20.

Continue below to learn about DNA repair mechanisms and how PARP inhibitors exploit the DNA damage response in order to target cancer cells, thereby providing targeted treatment options in ovarian cancer.

DNA damage and DNA damage response

Genomic instability is a fundamental feature of cancer which is caused by^21,22:

• DNA damage from endogenous and exogenous (environmental) factors
• defects in DNA repair mechanisms which are tumour-specific, and
• damaged DNA being passed on to daughter cells through a failure to stall or stop the cell cycle

For cells to remain viable, they must have the ability to repair their DNA²³. Many DNA repair pathways exist, and as demonstrated in Figure 1, each repair pathway is optimised to repair a specific type of DNA damage²⁴.

Figure 1. Sources of DNA damage, damage types and the DNA damage response (DDR) (Adapted^22,24-26). A, adenine; G, guanine; ROS, reactive oxygen species; UV, ultraviolet.

The DNA damage response (DDR) is a set of mechanisms involving proteins that detect and signal the presence of DNA damage and promote repair²⁴, preventing the passing on of damaged DNA to daughter cells²¹.

In broad terms, the DNA damage response involves^24-26:

• the activation of genes involved in DNA signalling and repair
• arrest of the cell cycle to allow repair before DNA replication and cell division
• DNA repair proteins that identify the damage, remove it and restore the correct DNA sequence
• senescence or apoptosis (cell death) where repair is either impossible or the damage too severe

PARP inhibitors provide a range of targeted treatment options in the fight against ovarian cancer. They may contribute to cancer cell death in the DNA damage repair pathway, making the pathway an important target for cancer treatment²¹.

By preventing effective DNA repair, PARP inhibitors help trigger cancer cell death²¹

Mode of action

Watch Dr Mansoor Raza Mirza discuss the mode of action of PARP inhibitors, and how this forms an important clinical consideration when considering patient suitability.

PARP inhibitors target cancer cells based on their inherent deficiencies whilst avoiding cells that function normally. This targeted approach is the greatest advantage of PARP inhibitor therapy²⁷.

A variety of mechanisms work to repair DNA breaks and protect the genome. For DNA single-stranded breaks, base excision repair (BER) is one such mechanism. It involves PARP proteins, which bind to the break site and commence the repair process². PARP inhibitors target these proteins, impairing single-strand break repair². Persistent single-strand breaks lead to a build-up of DNA double-strand breaks during the process of DNA replication, which results in arrest of the cell cycle or cell death¹³.

Figures 2 and 3 illustrate the involvement of PARP1 in the detection of DNA single strand breaks and signalling for single strand break repair.

For DNA double-stranded breaks, homologous recombination (HR) and non-homologous end joining (NHEJ) are two means of repair. While HR repair is typically error-free — maintaining genomic stability — NHEJ tends to produce replication errors². The PARP1 protein is also involved in the double-strand break repair process (refer to Figure 5).

Figures 2 and 4 illustrate the homologous recombination repair pathway, including the involvement of PARP1.

In people with homologous recombination deficiency (which may or may not be caused by a BRCA1/2 mutation), this can result in unrepaired DNA damage which can lead to cancer².

Homologous recombination deficiency (HRD) is related to cancer susceptibility. However, even in the presence of HRD, so long as other DNA repair mechanisms remain functional, they can help prevent the accumulation of excessive DNA damage². Therefore, HRD alone does not lead to cell death.

Using PARP inhibitors in HRD cells means that both homologous recombination repair and base excision repair mechanisms will be blocked,. Impairment of both of these DNA repair mechanisms can result in synthetic lethality and therefore cancer cell death^2,27.

The following figures illustrate key components of these DNA repair pathways, including the involvement of PARP1 and BRCA genes².

Figure 2. DNA repair of single and double-stranded DNA breaks (Adapted²⁰). AP, apurinic/apyrimidinic; ATM, ataxia telangiectasia; BER, base excision repair; BRCA, breast cancer gene; DNA, deoxyribonucleic acid; DNA-PKcs, DNA-dependent protein kinase, catalytic subunit; DSB, double-strand break; FA, Fanconi anemia; FEN1, flap structure-specific endonuclease 1; HR, homologous recombination; KU70 and KU80, make up the Ku heterodimer; MMEJ, microhomologymediated end joining; MRN, MRE11–RAD50–NBS1 protein complex; NBN, Nibrin; NHEJ, non-homologous end joining; PARP, poly (ADP-ribose) polymerase; PALB2, partner and localiser of BRC; PARPi, PARP inhibitor; RAD51, eukaryote gene of RAD51 protein family; SSB, single-strand break.

Figure 3. The involvement of PARP1 in the detection of single-stranded DNA breaks (Adapted²⁸). APE1, apurinic/apyrimidinic endonuclease 1; APTX, aprataxin; LIG3, ligase 3; PARG, poly(ADP-ribose) glycohydrolase; PARP1, poly (ADP-ribose) polymerase 1; PNKP, polynucleotide kinase-phosphatase; Pol β, polymerase β; SSB, single-stranded break; XRCC1, X-ray repair cross-complementing 1.

Figure 4. The homologous recombination repair (HRR) pathway (Adapted²⁸). ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; BRCA1/2, breast cancer gene 1/2; Chk1/2, checkpoint kinase 1/2; MRE11, MRE11 homolog, double strand break repair nuclease; NBS1, nibrin; PALB2, partner and localizer of BRCA2; RAD50, RAD50 double strand break repair protein.

The best-known cause of HRD are germline BRCA1/2 alterations, however gene alterations in somatic cells - which are typical of tumour cells - can also be a cause of HRD².

Germline variant²⁹:

• A genetic mutation inherited from the parent
• Can be passed on to offspring
• Present in the DNA of every cell in the body

Somatic variant²⁹:

• DNA changes that occur after conception
• Not passed on to offspring
• May cause diseases such as cancer

Figure 5 illustrates how PARP inhibitors trap PARP proteins in single-stranded DNA breaks, resulting in double-stranded breaks and cell death.

Figure 5. The PARP inhibitor mode of action in single-stranded DNA breaks (Adapted²⁶). deoxyribonucleic acid; HR, homologous recombination; PARP, poly(ADP-ribose) polymerase.

DNA repair and PARP inhibitors

PARP1 is a critical component of the base excision repair pathway, in which it promotes repair of single-strand breaks (SSB) in DNA. At the sites of these breaks, PARP1 detects and binds to DNA, prompting PARP1 activation, which then catalyses PARylation events, leading to the recruitment of repair machinery to these SSB sites. PARP1 is responsible for up to 90% of PARylation activity in cells, which is required for base excision repair¹.

Research has demonstrated the significance of PARP1 in cancer cells, hence its choice as a therapeutic target. The approved PARP inhibitors niraparib, olaparib and rucaparib principally target PARP1, and it is thought that through the process of synthetic lethality, they impede replication and DNA repair in cancer cells that are deficient in BRCA1/2-dependent homologous recombination pathways^1,20.

PARP inhibitors also inhibit other PARPs. Niraparib, olaparib and rucaparib have demonstrated comparable, effective inhibition of PARP1 and PARP2, however only rucaparib has demonstrated inhibition of PARP1, PARP2 and PARP3. Furthermore, the three PARP inhibitors approved for ovarian cancer treatment have different binding affinities for PARP1, PARP2 and PARP3, resulting in variations between on-target effects of PARP inhibition²⁷.

Currently there are four models of synthetic lethality in cancer cells that are promoted by PARP inhibitors²⁰:

• base excision repair inhibition
• PARP1 trapping on damaged DNA
• ineffective BRCA1 recruitment to damaged DNA
• error-prone NHEJ being activated

Synthetic lethality

In genetic terms, synthetic lethality refers to the instance when two genetic lesions occur in the one organism or cell, and together they cause apoptosis. However, if occurring individually in that cell, the lesion would not be lethal in and of itself. This is a similar process to what has been observed in cells that are HR deficient. Although HR deficiency is not lethal on its own, cells that are HR deficient are highly sensitive to the action of PARP inhibitors on PARP activity²⁰.

PARP inhibitors in HR proficient and HR deficient tumours

PARP inhibitors block the repair of damaged DNA in cells that are homologous recombination deficient (HRD), such as those with BRCA1/2 gene mutations, selectively inducing synthetic lethality. It is thought that PARP inhibitors not only block PARylation reactions, but they trap PARP1, creating a PARPi-PARP1-DNA complex that destabilises replication forks, leading to apoptosis¹.

According to pre-clinical and clinical studies, patients with BRCA1/2 mutations derive the greatest benefit from PARP inhibitor therapy, however, PARP inhibitors have demonstrated effective treatment in women with advanced ovarian cancer irrespective of their HRD or BRCA status¹.

BRCA1/2 germline mutations are the most well-understood mechanisms of HRD, however there are other mechanisms involved in HRD, such as epigenetic alterations and germline and somatic mutations in other HR genes².

Patient Stratification

Watch the video below to learn from expert, Dr Mirza, about the requirements for ovarian cancer patient stratification for each PARP inhibitor. Dr Mirza also covers the differences between the PARP inhibitors, to give you a greater understanding of considerations to make when you are selecting the right PARP inhibitor for your patients. 

In the video, Dr Mirza outlines why it is impossible to directly compare the efficacy of PARP inhibitors to each other, and he reviews some of the differences between them. Dr Mirza also makes the distinction that despite the difficulty of directly comparing the PARP inhibitors head-to-head, they do provide options for patients in the clinic.

It is estimated that approximately 41–50% of ovarian carcinomas show evidence of homologous recombination deficiency (HRD)²

The greatest risk factor for ovarian cancer is family history of breast or ovarian cancer. Alterations in the BRCA1/2 genes are responsible for almost 40% of ovarian cancers that occur in women with a family history of the disease, and around 25% are caused by other genes including those involved in the homologous recombination repair pathway³⁰.

It is important to understand whether ovarian cancer patients have HR deficiencies because specific clinical features have been observed in this sub-population, and they have also demonstrated improved response to treatments including PARP inhibitors and platinum-based chemotherapy. Ovarian cancers with HR deficiencies behave similarly to those with BRCA mutations, this behaviour being termed the ‘BRCAness’ phenotype², which tends to include high-grade serous histology, a high rate of response to platinum agents, and improved survival rates and disease-free intervals³¹.

Women with BRCA1/2-associated hereditary breast and ovarian cancer syndrome have an increased risk of developing ovarian cancer. Molecular genetic testing can reveal whether a patient has a heterozygous germline pathogenic variant in BRCA1/2 associated with BRCA1/2 hereditary breast and ovarian cancer syndrome³².

Continue reading to learn more about PARP inhibitor efficacy and safety to help make informed treatment decisions for women with ovarian cancer.

PARP inhibitor efficacy and safety in ovarian cancer

In the following video, Dr Mansoor Raza Mirza provides an overview of data from key clinical trials that led to the approvals of PARP inhibitors for ovarian cancer.

In the video, Dr Mirza discusses the clinical trial evidence for PARP inhibitor benefits observed in ovarian cancer patients, including efficacy in the long-term, toxicity and quality of life indicators.

By blocking the repair of damaged DNA in cells that are homologous recombination deficient (HRD), such as those with BRCA1/2 gene mutations, PARP inhibitors selectively induce synthetic lethality, leading to cancer cell death¹. Clinical trial results have confirmed the improved efficacy of PARP inhibitors in ovarian cancers that harbour BRCA mutations (germline and somatic), but also in cancers where HRD is not due to a BRCA mutation². However, PARP inhibitors have also been shown to be effective therapy for ovarian cancer patients irrespective of HRD or BRCA status¹.

A network meta-analysis comparing niraparib, olaparib and rucaparib found no significant differences in overall survival and progression-free survival. However, there was a higher risk of adverse events for niraparib compared to olaparib and rucaparib¹².

In a separate meta-analysis study examining differences in toxicity, haematologic adverse events (AEs) were significantly associated with niraparib, diarrhoea with olaparib, and abdominal pain with rucaparib. Many AEs associated with PARP inhibitors are class effects¹³. For example, haematological toxicities are a common class effect of PARP inhbitors^27. The AEs observed can be associated with both on-target and off-target effects¹³.

Some of the key side effects associated with PARP inhibitor treatment for ovarian cancer are illustrated in the figure below.

Figure 6. Key side effects associated with PARP inhibitor treatment for ovarian cancer in the frontline maintenance setting (Adapted²⁷).

For more detailed information on adverse events and side effects

Despite the promising treatment options that PARP inhibitors present, it is important that healthcare professionals understand the differences in toxicity and safety profile of niraparib, olaparib and rucaparib so that they can make the best selection for their patients: not only for initial and maintenance treatment but also as patients may experience side effects and require tailored management strategies²⁷.

In the video below, Dr Mirza provides a summary of the key clinical trial data that led to approvals of the PARP inhibitors olaparib and niraparib as first-line treatment for women with ovarian cancer.

In the video, Dr Mirza discusses the clinical trials SOLO 1, PRIMA and PAOLA 1, the HRstatus of the patients assessed, and the safety of the PARP inhibitors assessed.

Figure 7 highlights the key studies that led to the approvals of niraparib, olaparib and rucaparib in ovarian cancer treatment, as well as the associated patient profiles that were assessed.

Figure 7. Timeline of targeted therapy approvals for ovarian cancer by the FDA and EMA (Adapted³³). AOC, advanced ovarian cancer; BRCA, breast cancer gene; EMA, European Medicines Agency; FDA, Food and Drug Administration; g, germline; HRD, homologous recombination deficient; HRP, homologous recombination proficient; mut, mutation; ROC, recurrent ovarian cancer; s, somatic.

Table 4 provides detail of the clinical trials that led to regulatory approval of the PARP inhibitors niraparib, olaparib and rucaparib maintenance, first-line and subsequent-line ovarian cancer settings. The table includes the trial design, treatment, histologic subtypes and survival results.

Table 4. Clinical utility of PARP inhibitors in the treatment of epithelial ovarian cancer in the front-line, maintenance and later-line settings (Adapted³⁰).

BRCA, breast cancer gene; BRCAm, BRCA mutation; BRCA1m, mutation in BRCA1 only; BRCA2m, mutation in BRCA2 only; BRCAwt, BRCA wild-type; gBRCAm, germline BRCA mutation; HGS, high-grade serous; HGSOC, high-grade serous ovarian cancer; HR, hazard ratio; HRD, homologous recombination deficient; HRP, homologous recombination proficient; LOH, loss of heterozygosity; PFS, progression-free survival; RCT, randomized controlled trial; sBRCAm, somatic BRCA mutation.

In the following video, Professor Ray-Coquard provides an overview of clinical trial data for PARP inhibitors in first-line maintenance of women with ovarian cancer.

Discover the latest updates and clinical trial data with our ESMO 2022 congress highlights 

Safety

Each approved PARP inhibitor has its own toxicity profile. It is important for healthcare professionals to understand the toxicities associated with each approved PARP inhibitor, both in monotherapy and in combination with other therapies. This understanding will help healthcare professionals achieve maximal clinical benefit for their patients²⁷.

The table below outlines the toxicities observed in the three Phase III maintenance trials that led to the approvals of niraparib, olaparib and rucaparib as a targeted ovarian cancer treatment.

Table 5. Toxicity profile of niraparib, olaparib and rucaparib as observed in three Phase III clinical trials: ENGOT-OV16/NOVA, SOLO2/ENGOT-Ov21 and ARIEL3 (Adapted²⁷).

Factors impacting PARP inhibitors in the first-line setting

Watch the video below to learn about the factors that impact PARP inhibitor efficacy in first-line treatment of ovarian cancer. Professor Ray-Coquard explains what those factors are and why they are important when selecting the right inhibitor for your patients with ovarian cancer.

In the video, Professor Ray-Coquard highlights the importance of personalising treatment for patients in line with the results observed in Phase III randomised clinical trials. She also discusses the important factors to consider in the first-line maintenance setting, such as the molecular results (HRD score) of women with ovarian cancer.

Differences in PARP inhibitor dosing and application

In the video below, Dr Mirza explains the differences between PARP inhibitors and patient-specific points to take into consideration: all contributing to the selection decision of the appropriate PARP inhibitor for a woman with ovarian cancer. The differences between inhibitors relate to differences in pharmacokinetics, pre-clinical data, clinical data, and toxicity profiles.

As Dr Mirza explains in the video, by understanding the differences between PARP inhibitors - such as dose regimen, side effects and toxicity profile - healthcare professionals will be better equipped to select the appropriate PARP inhibitor for their patients with ovarian cancer.

Table 6 provides an overview of drug-drug interactions with PARP inhibitors and the dosing schedule approved by the European Medicines Agency (EMA).

Table 6. Dosing and drug-drug interactions of PARP inhibitors in ovarian cancer (Adapted²⁷).

In the video below, Professor Ray-Coquard provides an overview of some key differences between PARP inhibitors for women with ovarian cancer. These differences impact on selection of inhibitor for patients.

As Professor Ray-Coquard explains, there is currently no observable difference in terms of efficacy between the PARP inhibitors olaparib, niraparib and rucaparib in the management of first-line or relapsed ovarian cancer. This means that dosing and side effects become primary considerations when selecting an inhibitor for a patient, particularly given the long-term treatment required especially in the first-line.

Take our interactive quiz to test your understanding of PARP inhibitors for ovarian cancer.

To learn more about side effects as well as treatment monitoring and treatment modification, continue to the next stage of your learning.

Managing ovarian cancer patients on PARPi

PARP inhibitor selection infographic

Poly(ADP-ribose) polymerase (PARP) inhibitors provide a targeted treatment option for women with ovarian cancer. PARP inhibitors are particularly effective in patients with BRCA1/2 mutations or homologous recombination deficiency (HRD), however have also demonstrated efficacy in patients irrespective of HRD or BRCA status.

Niraparib, olaparib and rucaparib are approved for first-line and maintenance treatment of ovarian cancer by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This approval was based on the results from multiple clinical trials that assessed PARP inhibitor efficacy in different settings including as a maintenance treatment in newly diagnosed and recurrent ovarian cancer, as well as treatment following chemotherapy failure.

The complexity of the studies and overlapping indications for each PARP inhibitor can make it difficult for health care professionals to select the right treatment for their patients. View the below infographic to learn more about PARP inhibitor selection in ovarian cancer.

References

1. Kim DS, Camacho CV, Kraus WL. Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance. Experimental and Molecular Medicine. 2021;53(1):42-51.
2. da Cunha Colombo Bonadio RR, Fogace RN, Miranda VC, Diz MDPE. Homologous recombination deficiency in ovarian cancer: A review of its epidemiology and management. Clinics. 2018;73(Suppl 1).
3. European Medicines Agency. Rubraca | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/rubraca#authorisation-details-section. Accessed 11 June 2021.
4. European Medicines Agency. Rubraca | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/rubraca. Accessed 12 April 2021.

5. Food and Drug Administration. Highlights of prescribing information | Zejula.  https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214876s000lbl.pdf. Accessed  5 September 2023.

6. European Medicines Agency. Annex I Summary of Product Characteristics | Zejula. https://www.ema.europa.eu/en/medicines/human/EPAR/zejula. Accessed 9 April 2021.
7. Food and Drug Administration. Highlights of Prescribing Information | Lynparza. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/00997c3f-5912-486f-a7db-930b4639cd51/00997c3f-5912-486f-a7db-930b4639cd51_viewable_rendition__v.pdf. Accessed 6 Oct 2022.
8. European Medicines Agency. Annex I Summary of Product Characteristics | Lynparza. https://www.ema.europa.eu/en/documents/product-information/lynparza-epar-product-information_en.pdf. Accessed 9 April 2021.
9. European Medicines Agency. Annex I Summary of Product Characteristics | Rubraca. https://www.ema.europa.eu/en/documents/product-information/rubraca-epar-product-information_en.pdf Accessed 9 April 2021.
10. Food and Drug Administration. Highlights of Prescribing Information | Rubraca.  https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209115s011lbl.pdf. Accessed  5 September 2023.
11. Franzese E, Centonze S, Diana A, Carlino F, Guerrera LP, Di Napoli M, et al. PARP inhibitors in ovarian cancer. Cancer Treatment Reviews. 2019;73:1-9.
12. Stemmer A, Shafran I, Stemmer SM, Tsoref D. Comparison of poly (ADP-ribose) polymerase inhibitors (parpis) as maintenance therapy for platinum-sensitive ovarian cancer: Systematic review and network meta-analysis. Cancers. 2020;12(10):1-12.
13. Madariaga A, Bowering V, Ahrari S, Oza AM, Lheureux S. Manage wisely: Poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events. International Journal of Gynecological Cancer. 2020;30(7):903-915.
14. Current report: Clovis Oncology. 2022. 2022. Available at: https://d18rn0p25nwr6d.cloudfront.net/CIK-0001466301/017377a8-ad55-47da-ac40-91c5f2a5f69f.pdf.
15. AstraZeneca. Important prescribing information| Lynparza. August 26 2022. Available at: https://www.lynparzahcp.com/content/dam/physician-services/us/590-lynparza-hcp-branded/hcp-global/pdf/solo3-dhcp-final-signed.pdf.
16. Penson RT, Valencia RV, Cibula D, Colombo N, Leath CA, 3rd, Bidzinski M, et al. Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial. J Clin Oncol. 2020;38(11):1164-1174.
17. Clovis Oncology. ARIEL4: A Study of Rucaparib Versus Chemotherapy BRCA Mutant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients. NCT02855944. 2022. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02855944. Accessed 6 October 2022.
18. Moore KN, Secord AA, Geller MA, Miller DS, Cloven N, Fleming GF, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):636-648.
19. GSK. Prescribing Information | Zejula. 2022 2022. Available at: https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Zejula_Capsules/pdf/ZEJULA-CAPSULES-PI-PIL.PDF. Accessed 13 October 2022.
20. Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: Current practice and future directions. British Journal of Cancer. 2016;115(10):1157-1173.
21. Gourley C, Balmaña J, Ledermann JA, Serra V, Dent R, Loibl S, et al. Moving from poly (ADP-ribose) polymerase inhibition to targeting DNA repair and DNA damage response in cancer therapy. Journal of Clinical Oncology. 2019;37(25):2257-2269.
22. Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481(7381):287-294.
23. Lodovichi S, Cervelli T, Pellicioli A, Galli A. Inhibition of dna repair in cancer therapy: Toward a multi-target approach. International Journal of Molecular Sciences. 2020;21(18):1-29.
24. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071-1078.
25. Sahan AZ, Hazra TK, Das S. The Pivotal role of DNA repair in infection mediated-inflammation and cancer. Frontiers in Microbiology. 2018;9(APR):663-663.
26. O'Connor MJ. Targeting the DNA Damage Response in Cancer. Molecular Cell. 2015;60:547-560.
27. LaFargue CJ, Dal Molin GZ, Sood AK, Coleman RL. Exploring and comparing adverse events between PARP inhibitors. The Lancet Oncology. 2019;20(1):e15-e28.
28. Athie A, Arce-Gallego S, Gonzalez M, Morales-Barrera R, Suarez C, Casals Galobart T, et al. Targeting DNA Repair Defects for Precision Medicine in Prostate Cancer. Current oncology reports. 2019;21(5):42-42.
29. Institute NC. NCI Dictionary of Cancer Terms. https://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed 14 June.
30. Konstantinopoulos PA, Norquist B, Lacchetti C, Armstrong D, Grisham RN, Goodfellow PJ, et al. Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline. Journal of Clinical Oncology. 2020;38(11):1222-1245.
31. Rigakos G, Razis E. BRCAness: Finding the Achilles Heel in Ovarian Cancer. The Oncologist. 2012;17(7):956-962.
32. Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. GeneReviews®. 1993.
33. Nero C, Ciccarone F, Pietragalla A, Duranti S, Daniele G, Salutari V, et al. Ovarian cancer treatments strategy: Focus on parp inhibitors and immune check point inhibitors. Cancers. 2021;13(6):1-13.