Impact case study database

Clinical development of PARP inhibitors. ICR research led to significant impact in the clinical development of PARP inhibitors in the pharmaceutical industry, as well as inhibitors of other proteins involved in HRR (such as ATM and ATR). The ICR patented the discovery that PARP inhibition is selectively lethal in cells deficient in HRR (Patent No: US8143241) and licensed this patent to KuDOS who have then sub-licensed the biomarker patent to other companies who are developing PARP inhibitors. Four PARP inhibitors have licensing approvals: olaparib (AstraZeneca), rucaparib (Clovis), niraparib (Tesaro/GSK), and talazoparib (Pfizer). There has been huge interest in PARP inhibitors and as of 2017 there were more than 200 clinical trials for PARP inhibitors either completed or ongoing [A].

First regulatory approvals of olaparib. A phase 1 trial in BRCA1 and BRCA2 mutation carriers, led by Professor de Bono (ICR Team Leader, UOA1), and including Professors Tutt and Ashworth—provided clinical proof of concept for the synthetic lethal approach, using the PARP inhibitor olaparib. A key phase 2 clinical trial, Study 19, demonstrated that women with ovarian cancer with germline or somatic BRCA1 or BRCA2 mutations showed the most profound benefit from olaparib maintenance therapy, which significantly extended their progression-free survival by, on average, 7 months. These results led to olaparib approval in December 2014 by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a monotherapy for the maintenance treatment of women with BRCA-mutant high-grade serous ovarian cancer patients, who have had either a complete or partial response to platinum-based chemotherapy [B]. The inclusion of both BRCA1/2 germline and somatically mutated tumours in these approvals made olaparib the first targeted treatment for an inherited cancer disorder—it was also the first BRCAness-targeted therapy. NICE approval of olaparib in this indication followed in January 2016. The Appraisal Committee

“concluded that a drug treatment that improves quality of life and extends periods of remission for patients with BRCA mutation- positive ovarian cancer would be highly valued by patients and their families.” [C]

The uptake of olaparib following the NICE recommendation in January 2016 is shown by the rapid, and continuing, increase in the national use of olaparib ( Figure 1) [D]. In addition, there is a Cochrane systematic review on PARP inhibitors in ovarian cancer—considered an indicator of a change in clinical practice [E].

Further regulatory approvals. Based on the results of the SOLO1 trial, olaparib is also approved in the EU, US, Canada, Japan, and Brazil for first-line maintenance of germline/somatic BRCA1/2-mutated high-grade epithelial ovarian cancer—providing significant benefits to patients across the world. The SOLO1 trial results showed that the mean time to progression in those treated with olaparib was greater than 40.7 months (the point of the follow-up), compared to a median time of 13.8 months for the placebo group [F]. Based on the results from the PAOLA-1 phase 3 trial, in September 2020 olaparib was approved in EU as a first-line maintenance treatment with bevacizumab for HRR-mutated advanced ovarian cancer.

Figure 1: Prescribing rates of olaparib in the NHS in England adapted from [D]

Two other PARP inhibitors have also received regulatory approval for the treatment of ovarian cancer patients. Niraparib (Zejula) is now approved in over 35 countries (including the US and Europe). In April 2020, the FDA approved niraparib as a first-line monotherapy maintenance treatment for women with platinum-responsive advanced ovarian cancer, regardless of biomarker status. This new indication is supported by data from the phase 3 PRIMA study. Rucaparib (Rubraca) was approved by the FDA in 2016 and the EMA in 2018.

Impact in breast cancer. The first approvals of PARP inhibitors were in ovarian cancer, but there has been impact in other cancers. An international phase 3 clinical trial, OLYMPIAD, showed that olaparib delayed the progression of advanced breast cancer in women with inherited BRCA mutations for 42% longer than standard chemotherapies. Based on this, in January 2018 the FDA approved olaparib for advanced breast cancer in women who have inherited BRCA1 or BRCA2 mutations, and in April 2019 EMA approval followed. As of 2020, olaparib is approved in nearly 40 countries for germline BRCA-mutant HER2-negative metastatic breast cancer previously treated with chemotherapy [F].

ICR pre-clinical work ( Ref. 3) showed the efficacy of another PARP inhibitor, talazoparib, and in 2018 this was approved by the FDA and EMA in BRCA germline mutated advanced breast cancer [G]. The approval of talazoparib was based on data from the EMBRACA phase 3 study, which showed a 46% reduction in the risk of disease progression and a more-than-doubled overall response rate (63%) compared to chemotherapy (27%). This provides patients with limited treatment options an effective, once-daily, alternative treatment to chemotherapy.

Impact in other cancers. In 2019, the phase 3 POLO trial in pancreatic cancer showed that in metastatic pancreatic cancer patients with a germline BRCA mutation, progression-free survival was longer with maintenance olaparib (7.4 months) than with placebo (3.8 months). In December 2019, the FDA approved olaparib for the maintenance treatment of BRCA-mutated metastatic pancreatic adenocarcinoma, as detected by an FDA-approved test [H]. Pancreatic cancer is a deadly cancer with a high unmet medical need with approximately 460,000 new cases worldwide in 2018. There was previously no precision medicine treatment options for BRCA-mutated pancreatic cancer patients.

Based on the concept of BRCAness, genomic sequencing has revealed that mutations in HRR proteins occur in a significant proportion of metastatic castration-resistant prostate cancers (mCRPC). Data from the PROFOUND phase 3 clinical trial has shown the efficacy of olaparib in mCRPC and this led to approval of olaparib in mCRPC with HRR defects in May 2020 [I]. Before this approval, olaparib had already been used to treat more than 30,000 patients worldwide and this will only increase as there were approximately 1,300,000 new cases of prostate cancer worldwide in 2018. FDA have also approved another PARP inhibitor, rucaparib, in mCRPC.

Clinical development of other inhibitors targeting HRR proteins. The success of using PARP inhibitors to exploit synthetic lethality was a result of the ICR’s underpinning research, and has led to renewed research interest in using these approaches to target other HRR proteins for cancer therapy. Some of the most promising targets are ATR and ATM. ATR is involved in sensing DNA damage and activating the DNA damage checkpoint and ATM is recruited and activated by DNA double-strand breaks. ATM and ATR inhibitors are being investigated as single agents, as well as in combination with chemotherapy, radiation therapy, PARP inhibition, and/or immunotherapy. Potent inhibitors of ATR activity in clinical development as of December 2020 include VX-970 (16 trials on clinicaltrials.gov), AZD6738 (30 trials) and BAY1895344 (8 trials). A phase 1 trial involving the ATM inhibitor AZD0156 is ongoing (NCT02588105) and there are 3 registered trials of AZD1390 (NCT03423628, NCT03215381, and NCT04550104) [J].

Pharmaceutical industry impact. Multiple companies have developed PARP inhibitors, generating value through sales of approved drugs. As of 2020, olaparib (Lynparza) is approved in 78 countries for the treatment of ovarian cancer; 76 countries for the treatment of metastatic breast cancer, and in 55 countries for the treatment of pancreatic cancer. It is also approved in the US, the EU, and Japan for mCRPC. In 2020, AstraZeneca reported olaparib sales of over USD1,776,000,000 worldwide, compared to USD1,198,000,000 in 2019 [H]. Worldwide rights to talazoparib, originally developed by BioMarin Pharmaceutica, were acquired by Medivation in August 2015 for USD410,000,000, with additional payments of up to USD160,000,000 in royalties and milestones. In 2016, Medivation was acquired by Pfizer for USD14,000,000,000. In January 2019, GSK completed the acquisition of Tesaro for USD5,100,000,000. Tesaro was a commercial-stage biopharmaceutical company with a major marketed product, Zejula (niraparib), a PARP inhibitor approved in ovarian cancer [K]. Further, as PARP inhibitor therapies are given to patients with HRR mutations, a need for companion gene tests has emerged—to date the FDA has approved two BRCA tests as companion diagnostic devices (BRACAnalysis CDx and FoundationFocus CDxBRCA), providing further commercial impact.