First approved PARP inhibitorPARP inhibitor to demonstrate clinically meaningful benefits in combination with a new hormonal agent Lynparza in combination with abiraterone extended median radiographic progression-free survival benefit beyond two years in this setting This approval by the European Commission was based on results from the PROpel Phase III trial and follows the positive recommendation in the EU by the Committee for Medicinal Products for Human Use in November 2022. Updated results from a second planned analysis presented at ESMO 2022 showed a favourable trend towards improved overall survival with Lynparza plus abiraterone versus abiraterone alone (based on HR of 0.83; 95% CI 0.66-1.03; p=0.11), however, the difference did not reach statistical significance at the time of this data cut-off (analysis at 40% data maturity). Prostate cancer is the most common cancer in men in Europe, with an estimated 473,000 patients diagnosed and 108,000 deaths in 2020.1,2 Overall survival for patients with mCRPC is approximately three years in clinical trial settings, and even shorter in the real-world.3 Approximately half of patients with mCRPC may receive only one line of active treatment, with diminishing benefit of subsequent therapies.4-9 Noel Clarke, Urological Surgeon and Professor of Urological Oncology at Manchester’s Christie/Salford Royal Hospitals and Manchester University, a senior investigator of the PROpel trial, said: “The results of the PROpel Phase III trial of olaparib in combination with abiraterone as a first-line treatment show that this therapeutic combination can provide significant clinical benefit to patients with metastatic castration-resistant prostate cancer. Patients with this condition in the EU will now, for the first time, have the opportunity to benefit from this new treatment combination.” The safety and tolerability of Lynparza in combination with abiraterone in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines. There was no increase in the rate of discontinuation of abiraterone in patients treated with Lynparza in combination with abiraterone and no detrimental effect on health-related quality of life versus those treated with abiraterone alone (Functional Assessment of Cancer Therapy-Prostate questionnaire). In August, supplemental New Drug Application (sNDA) for Lynparza in combination with abiraterone and prednisone or prednisolone was accepted and granted Priority Review in the US for the treatment of adult patients with mCRPC. The Prescription Drug User Fee Act (PDUFA) date is anticipated during the first quarter of 2023. Lynparza is approved in the US based on results from the PROfound Phase III trial as monotherapy for patients with homologous recombination repair (HRR) gene-mutated mCRPC (BRCA and other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone; and in the EU, Japan, and China for patients with BRCA-mutated mCRPC who have progressed following prior therapy that included a new hormonal agent. Following this approval for Lynparza in the EU, AstraZeneca will receive a regulatory milestone payment from MSD of $105m, anticipated to be booked as Collaboration Revenue by the Company during the fourth quarter of 2022. Metastatic castration-resistant prostate cancer
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.12 Approximately 10-20% of men with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.12 Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.12 Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, there is high unmet need in this population.12,13,14,15 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, as well as prednisone or prednisolone, in men with mCRPC who had not received prior chemotherapy or NHAs in the mCRPC setting. The primary endpoint is rPFS and secondary endpoints include overall survival, time to secondary progression or death, and time to first subsequent therapy.
The PARP1 protein has been reported to be required for the transcriptional activity of androgen receptors; therefore, inhibiting PARP with Lynparza may impair the expression of androgen receptor target genes and enhance the activity of NHAs.16,19,21 Additionally, it is thought that abiraterone may alter/inhibit the transcription of some HRR genes which may induce HRR deficient phenotype, which may increase sensitivity to PARP inhibition.18,20,22,23 For more information about the trial please visit ClinicalTrials.gov.
Lynparza (olaparib) is a first-in-class PARP inhibitorPARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in 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, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells. The AstraZeneca and MSD strategic oncology collaboration In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitorPARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo and other potential new medicines as monotherapies and as combinations. The companies will also develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines independently. AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience. AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca. 1. Rawla, P. The Epidemiology of Prostate Cancer. World J Oncol. 2019;10(2):63-89. 2. IARC GloboCan. Prostate Cancer Factsheet. 2020. Available at https://gco.iarc.fr/today/data/factsheets/cancers/27-Prostate-fact-sheet.pdf. Accessed December 2022. 11. 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: December 2022. 12. Kirby M, et al. Characterising the Castration-Resistant Prostate Cancer Population: Systematic Review. Int J of Clin Pract. 2021;65(11):1180-1192.
13. UroToday. What is Changing in Advanced Prostate Cancer? Available at https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/122176-what-is-changing-in-advanced-prostate-cancer.html. Accessed December 2022. 15. UroToday. Beyond First-line Treatment of Metastatic Castrate-resistant Prostate Cancer. Available at https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html. Accessed December 2022 16. Schiewer MJ, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134-1149. 18. Li L, et al. Androgen Receptor Inhibitor–Induced “BRCAness” and PARP Inhibition are Synthetically Lethal for Castration-Resistant Prostate Cancer. Sci Signal. 2017; 10(480):eaam7479. 21. Ju B-G, et al. A Topoisomerase IIbeta-Mediated dsDNA Break Required for Regulated Transcription. Science. 2006;312(5781):1798-1802. 22. Goodwin JF, et al. A Hormone-DNA Repair Circuit Governs the Response to Genotoxic Insult. Cancer Discov. 2013;3(11):1254-1271.
23. Tarish FL, et al. Castration Radiosensitizes Prostate Cancer Tissue by Impairing DNA Double-Strand Break Repair. Sci Transl Med. 2015;7(312):312re11.