The human body has several mechanisms of maintaining genomic integrity in response to errors that occur during DNA synthesis; deficiency in one such mechanism, homologous recombination repair (HRR which is used to correct double strand breaks) has been identified as clinically relevant to a variety of cancers, including breast, ovarian and prostate (see figure 1 for genes involved in the HRR mechanism).

jai

Over the past decade specific genes within the HRR pathway (most notably BRCA 1/2) have become the target of therapies in the treatment of the cancers where clinical outcomes have been especially poor. One class of targeted therapies that exploits HRR deficiencies are Poly adenosine phosphate ribose polymerase inhibitors (PARPi). The inhibition of PARP enzymes which are essential in the repair of single and double stranded DNA breaks, which has been shown to slow the progression of tumour cells with HRR deficiencies as they are less able to survive without the repair mechanism.

Most recently in ovarian cancer (where ~12% of incident patients [2] possess a BRCA 1/2 mutation and 41%-50% possess a HRR deficiency of some kind [3,4,5]), the National Institute for Health Care and Excellence (NICE) have approved the use of maintenance Rubraca (rucaparib, Clovis Oncology) through the Cancer Drugs Fund (CDF) for relapsed platinum sensitive ovarian, fallopian tube and peritoneal cancers regardless of BRCA mutation status [6].  This comes after results from the phase III ARIEL 3 trial in which Rubraca vs Placebo where median progression free survival (PFS) was 10.4 months and 5.4 months respectively. In patients with BRCA 1/2 mutations median PFS for Rubraca treated patients was 16.6 months.

This is an advancement in the use of Rubraca within the EU where it gained conditional marketing authorisation for BRCA mutated patients with two or more previous lines of therapy only, in May 2018 [7]. In the USA Rubraca was initially approved in 2016 for use on patients with BRCA mutations with two or more lines of previous therapy [8], the indication was later expanded in April 2018 to include maintenance treatment for recurrent platinum sensitive patients [9].

Further development in PARPi efficacy has been realised through AstraZeneca and Merck’s latest PROfound trial where Lynparza (olaparib) significantly increased median PFS of metastatic castrate resistant prostate cancer (mCRPC) patients [10]. Castrate resistant prostate cancer affects around ~43% of incident prostate cancer patients [2] across the western developed world (figure representative of the EU5 and USA) ~4-5+% of which are estimated to a BRCA mutation and/or another kind of HRR deficiency [11] (this study refers to metastatic patients not specifically castrate resistant). Castrate resistant prostate cancer has a high unmet need with relatively poor clinical outcomes in patients who are not responsive to hormone therapy or pre-treated patients who have progressed. In the overall population of the PROfound trial median PFS was 5.82 vs 3.52 months and median OS (overall survival) was 7.39 vs 3.55 months in olaparib vs hormone therapy treated patients respectively [10].

The latest advancements in PARP inhibitors continue to reshape the treatment landscape of oncologic disease areas, where high unmet need has previously been regarded as an unavoidable consequence of an inability to overcome tumour’s immune escape abilities. With increasing PFS and OS the market for cancer treatments continues to increase and interest in identifying therapeutic targets for treatment widens to include a growing array of tumour types.

References:

[1] Pellegrino B. et al. ESMO Open 2019;4:e000480. Controversies in oncology: Are genomic testing quantifying homologous recombination repair deficiency (HRD) useful for treatment decision making?

[2] Black Swan Analysis Epiomic Segmentation Database. https://www.epiomic.com/. Accessed 21/10/19

[3] Elvin J., A. et al. Comprehensive Genomic Profiling (CGP) with Loss of Heterozygosity (LOH) Identifies Therapeutically Relevant Subsets of Ovarian Cancer (OC) J Clin Oncol. 2017;34:15.

[4] Pennington K., P. et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20(3):764–75.

[5] Norquist B., S. et al. Mutations in homologous recombination genes and response to treatment in GOG 218: an NRG Oncology study. Gynecol Oncol. 2016;141:2.

[6] Another Treatment Option for Ovarian Cancer Approved for the Cancer Drugs Fund. National Institute for Clinical Excellence. Published October 11, 2019. https://bit.ly/2MsIiDC. Accessed 21/10/19

[7] Rubraca: EPAR – Medicine overview. Published May 24, 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/rubraca. Accessed 21/10/19.

[8] Rubraca FDA label 2016. Published December 19, 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf. Accessed 21/10/19.

[9] Rubraca FDA label 2018. Published April 6, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf Accessed 21/10/19.

[10] Hussain, M. et al. PROFOUND: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (MCRPC) with homologous recombination repair (HRR) gene alterations’. Annals of Oncology. 2019; 30:5. 

[11] Nicolosi P. et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5(4):523-528.

Jai Bains 

Oncology Market Forecasting Analyst