**12. PARP inhibitors in the treatment of ovarian cancers**

Since the discovery in 1980 s PARP inhibitors has gone through extensive scrutiny and research in the efficiency in management of the ovarian cancers.

The initial monotherapy with *PARP* inhibitors for patients with solid tumours with a germline *BRCA* mutation were published in 2009. This was a study on ovarian cancer patients with known *BRCA* mutation [21]. Other tumours included were breast, colon, melanoma, prostate, and sarcomas. In patients with known *BRCA1/2* mutations, single-agent treatment with Olaparib showed a 63% clinical benefit (including disease stabilisation).

Following this study there several other trials carried out for assessing the individual efficacy of the Olaparib, Niraparib and Rucaparib and with the outcomes of these trials Olaparib has gained the FDA approval as a first line maintenance treatment in the advanced ovarian cancer [22].


**31**

*Ovarian Cancer Genetics and the Implications DOI: http://dx.doi.org/10.5772/intechopen.96488*

ing ovarian cancer genetics,

The following is a summary of the trials on PARP inhibitors and the SOLO-1 trial

According to current British Gynaecological Cancer Society guidelines for test-

Women with High grade serous ovarian cancer or G3 endometrioid ovarian adenocarcinoma have >10% risk of an underlying BRCA mutation should be offered clinical genetics counselling and testing. (GRADE C) Recently it has been shown that ~18% (much higher in certain groups such as Ashkenazi Jews) of the population of women presenting with high grade serous or G3 endometrioid ovarian adenocarcinoma carry a germline BRCA mutation, 44% of whom have no positive family history. Every patient with a current or past histological diagnosis of HGSC or G3 endometrioid ovarian carcinoma therefore qualifies for BRCA counselling and testing, as advised by National institute for Health and Care Excellence, which should be discussed and offered. The above guidelines and standards are supported by the evidence from the GTEOC (Genetic Testing in Epithelial Ovarian Cancer) [24] study in which the primary objective of the study was to determine the feasibility, acceptability and cost-effectiveness of screening all newly diagnosed women with EOC for *BRCA1/ BRCA2* mutations by determining the mutation prevalence, calculating the cost for each gene mutation detected and assessing the psychological impact based on

This study has shown the mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70 [25]. Unselected genetic testing in women with

**14. Challenges in development of universal process on screening genetic** 

In Our Opinion, all the patients diagnosed with invasive, epithelial ovarian cancer should be offered germline genetic testing, regardless of histologic subtype, because Ovarian cancers with a *BRCA1/BRCA2* mutation are most likely to be of high-grade serous histology, although these mutations have been found in endometrioid and clear cell histologic subtypes as well. Endometrioid and clear cell ovarian cancers are also frequently associated with Lynch syndrome (germline mutations in *MLH1*, *MSH2*, *MSH6*, *PMS2*, and *EPCAM*). Additionally, nonepithelial ovarian cancers - Sertoli-Leydig cell tumours can be associated with other genetic disorders such as Peutz-Jeghers syndrome and DICER1-associated disorders and small cell carcinoma of the ovary, hypercalcaemic type has been linked to germline mutations in *SMARCA4*. All these mutations have got clinical relevance in the management of these patients and yet to discover the treatment options and preventing the development of the other cancer types associated with the above syndromes in the future genera-

There are several identified limitations in screening these mutations including cost of testing, lack of patient and provider education regarding the importance of genetic information, and limited availability of genetic counsellors and access to genetic testing [26]. In the era of unforeseen issues with Covid-19 there are other issues with genetic

testing including social distancing making the genetic counselling, consenting

difficult necessitating these steps to be delivered audio-visually.

EOC was acceptable to patients and is potentially less resource intensive.

being of the pivotal trials in the history of the use of PARP inhibitors [23].

**13. Current UK standards for testing ovarian cancer genetics**

questionnaire responses and qualitative interviews.

**mutations in ovarian cancers**

tions with genetic predisposition.

*surgery, NED - no evidence of disease, C - Carboplatin, P - Paclitaxel.*

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

**12. PARP inhibitors in the treatment of ovarian cancers**

(including disease stabilisation).

**Trial name PARPi assessed vs.** 

PRIMA/ ENGOT-OV26

] PAOLA-1/ ENGOT-OV25

VELIA/ GOG-3005

**Figure 3.**

*adjuvant setting [18].*

treatment in the advanced ovarian cancer [22].

**maintenance**

**other treatment agent as** 

Olaparib + bevacizumab vs. placebo + bevacizumab

Veliparib + CP → veliparib vs. veliparib + CP → placebo a vs. placebo + CP → placebo

*surgery, NED - no evidence of disease, C - Carboplatin, P - Paclitaxel.*

Since the discovery in 1980 s PARP inhibitors has gone through extensive scrutiny and research in the efficiency in management of the ovarian cancers. The initial monotherapy with *PARP* inhibitors for patients with solid tumours with a germline *BRCA* mutation were published in 2009. This was a study on ovarian cancer patients with known *BRCA* mutation [21]. Other tumours included were breast, colon, melanoma, prostate, and sarcomas. In patients with known *BRCA1/2* mutations, single-agent treatment with Olaparib showed a 63% clinical benefit

*Function of PARP proteins in DNA damage repair. Source: An update on PARP inhibitors—Moving to the* 

Following this study there several other trials carried out for assessing the individual efficacy of the Olaparib, Niraparib and Rucaparib and with the outcomes of these trials Olaparib has gained the FDA approval as a first line maintenance

SOLO-1 Olaparib vs. Placebo *BRCA1/2* mutated, CR or PR (≥30% decrease

*Key PDS - Primary debulking surgery, CR - complete response, PR - Partial response, IDS - interval debulking* 

**Population**

Niraparib vs. Placebo Stage III with visible residual tumour after PDS,

bevacizumab

(without bevacizumab)

inoperable stage III, or any stage IV ovarian cancer.

Newly diagnosed stage III/IV high-grade ovarian cancer or other non-mucinous ovarian cancers with BRCA1/2 mutation, regardless of surgical outcome NED or CR or PR after first-line platinum + taxane +

Newly diagnosed stage III/IV high-grade serous ovarian cancer in patients undergoing PDS or IDS

in tumour volume, or NED on imaging but CA-125 > ULN) to platinum-based chemotherapy

**30**

The following is a summary of the trials on PARP inhibitors and the SOLO-1 trial being of the pivotal trials in the history of the use of PARP inhibitors [23].
