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First PARP inhibitor to demonstrate clinical benefit in combination with a new hormonal agent in this setting
Positive high-level results from the PROpel Phase III trial showed
At a planned interim analysis, the Independent Data Monitoring Committee (IDMC) concluded that the trial met the primary endpoint of rPFS in men with mCRPC who had not received treatment in the 1st-line setting including with new hormonal agents (NHAs) or chemotherapy.
The trial also showed a trend at this interim analysis towards improved overall survival (OS). However, the data are still immature and the trial will continue to assess OS as a key secondary endpoint. The safety and tolerability were consistent with the known profiles of each medicine.
Prostate cancer is the second-most common cancer in men and despite an increase in the number of available treatments for men with mCRPC, five-year survival remains low.1
The data will be presented at an upcoming medical meeting.
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate.2 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.3
In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.3 Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.4
Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.4 Despite advances in treatment for men with mCRPC, five-year survival is low and extending survival remains a key treatment goal.4
PROpel
PROpel is a randomised, double-blind, multi-centre Phase III trial testing the efficacy, safety, and tolerability of Lynparza versus placebo when given in addition to abiraterone in men with mCRPC who had not received prior chemotherapy or NHAs in the 1st-line setting. Men in both treatment groups will also receive either prednisone or prednisolone twice daily. The primary endpoint is rPFS and secondary endpoints include OS and time to first subsequent anticancer therapy or death.
The trial enrolled men with or without HRR gene mutations. They may have previously been treated with docetaxel at a prior stage of disease. The trial excluded men with prior treatment with abiraterone. Treatment with any other NHA must have been stopped one year or longer prior to randomisation.
Men must have had a performance status of 0-1 as defined by the
Preclinical trials in prostate cancer report a combined anti-tumour effect when PARP inhibitors and NHAs are administered together. PARP-1 is involved in the co-regulation of the androgen-receptor (AR) pathway, potentially leading to cooperation between PARP inhibitors and NHAs in blocking AR signalling.5
PARP inhibition plus androgen deprivation could significantly reduce the growth of prostate cancer cells independent of HRR gene status. Other trials revealed that treatment with NHAs inhibit the transcription of some HRR genes, therefore, inducing HRR deficiency and increased sensitivity to PARP inhibitors via non-genetic mechanisms. 6
Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs).
Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.
Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU,
It is also approved in the US, EU and
Lynparza is approved in the US,
It is also approved in the US, the EU,
Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.
Lynparza, which is being jointly developed and commercialised by
Lynparza is the foundation of
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Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.
The Company's focus is on some of the most challenging cancers. It is through persistent innovation that
References
1. IARC. Cancer Today - Estimated number of new cases in 2020, worldwide, both sexes, all ages. Available at: https://gco.iarc.fr/today/home. Accessed
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3. Cancer.Net. Treatment of metastatic castration-resistant prostate cancer. Available at: www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer. Accessed
4. Kirby, M., et al. Characterising the castration-resistant prostate cancer population: a systematic review.
5. Schiewer, M., et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12),pp 1134-49
6. Polkinghorn, W., et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3(11):1245-53
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