What is a PARP Inhibitor?

Find out what is a PARP Inhibitor. In the era of the precision and personalized treatment, the advancements in the standard line of care using several targeted therapies has shown exponential pattern. One of the most recent discussions is around Homologous Recombination Deficiency which comprehends the use of PARP inhibitors as the upcoming ovarian cancer treatments.

What is a PARP Inhibitor?  (but first watch this video)

How does it “kill” cancer cells?

The current scenario of Poly-ADP ribose Polymerase inhibitors for ovarian cancer is not only limited to deleterious BRCA 1/2 gene mutation, rather it also focuses on various other aspects such as gene alterations other than BRCA, homologous recombination deficiency and combinations.

The most important role of PARP in the repair of single-strand DNA breaks. PARP inhibitors are responsible for inducing the accumulation of single-strand DNA damage and which might result in double strand breaks. Under normal conditions, double strand breaks in the DNA would be repaired by homologous recombination repair (HRR) pathway, which is a complex cascade involving many proteins such as BRCA1 and BRCA2.

In the tumor having deficiency in HRR pathway, the cells adapt to an alternative DNA repair mechanism mediated by non homologous end joining, which is an error prone pathway, and results in cell death. This is referred as synthetic lethality.

Homologous recombination deficiency (HRD) can be estimated through three different approaches:

1. Germline mutation screening of genes related to HR repair such as BRCA1/2, ATM, PABL2, CHEK2,  etc.
2. Somatic mutation screening of genes related to HR repair;
3. Evaluation of a genomic scar, which represents the genomic instability secondary to HRD. An HRD score can be calculated based on the loss of heterozygosity (LOH), telomeric allelic imbalance, and large-scale transitions.

HRD is harboured by approximately 13% and 15% of ovarian and triple negative breast cancers (TNBC), respectively, and it is attributable to germline BRCA1/2 mutations. Furthermore, 50% and 40% of ovarian and TNBC, respectively, are characterised by harbouring HRD in the absence of gBRCA1/2 mutations. Also, 10%–12% of advanced prostate cancer harbour germline or somatic BRCA2 inactivation and up to 25% contain a DNA repair defect. I

n Indian population, Singh et al.,2012 reported that 30.1% cases were detected positive for germline mutations in the 14 gene Truesight panel. A majority (84.9%) of the mutations were detected in the BRCA1/2 genes as compared to non-BRCA genes (15.1%). The most commonly found mutations were reported in  BRCA1, BRCA2, TP53, and PALB2.

It is  recommended that all women diagnosed with epithelial ovarian, fallopian tube, and peritoneal cancers should consider tumor testing, even in the absence of a family history of cancer. The sole benefit of tumor testing is that it identifies both somatic and germline mutations. Potentially, a single test can identify patients who may benefit from PARP inhibitors.

The indication of  HRD testing is currently applicable for  newly diagnosed Ovarian Cancer for using PARP inhibitor as a maintenance therapy for women with a BRCA1/2 mutation. BRCA1/2 carriers having recurrent Platinum Sensitive Ovarian Cancer may benefit from PARP inhibitor therapy.

As per the available data, it is established that HRD is an important indicator in the treatment of ovarian cancer. A more detailed understanding about HRD phenotype can help recognize broader group of patients who can benefit from PARP inhibitor. Out of all the approaches, the best HRD estimation is yet to be defined.  Germline or somatic mutations can be assessed using NGS, while genomic instability can be determined by evaluating the LOH, telomeric allelic imbalance, and large-scale transitions which is provided in the test called Myriad myChoice CDx. 

There are pros and cons of all the options, hence it is better to use them in complementary manner. Further studies on assessing  HRD and PARP inhibitors will help in the validation of clinical utility of these approaches.

References:

1. Singh, J., Thota, N., Singh, S., Padhi, S., Mohan, P., Deshwal, S., … & Ahmed, R. (2018). Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast cancer research and treatment, 170(1), 189-196.
2. Matsumoto, K., Nishimura, M., Onoe, T., Sakai, H., Urakawa, Y., Onda, T., & Yaegashi, N. (2019). PARP inhibitors for BRCA wild type ovarian cancer; gene alterations, homologous recombination deficiency and combination therapy. Japanese journal of clinical oncology, 49(8), 703-707.
3. Pellegrino, B., Mateo, J., Serra, V., & Balmaña, J. (2019). Controversies in oncology: are genomic tests quantifying homologous recombination repair deficiency (HRD) useful for treatment decision making?.
4. da Cunha Colombo Bonadio, R. R., Fogace, R. N., Miranda, V. C., & Diz, M. D. P. E. (2018). Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics, 73.

By- Dr. Charu Bahl