PROpel Phase III trial positive results of Lynparza plus abiraterone in 1st-line metastatic castration-resistant prostate cancer published in New England Journal of Medicine Evidence
Combination reduced risk of disease progression by 34% vs. standard-of-care in patients irrespective of homologous recombination repair gene mutation status
Results from the PROpel Phase III trial showed that AstraZeneca and MSD’s Lynparza (olaparib) in combination with abiraterone significantly improved radiographic progression-free survival (rPFS) versus abiraterone alone as a 1st-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations. The results, showing the combination reduced the risk of disease progression or death by 34% versus abiraterone alone (based on a hazard ratio [HR] of 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.0001), are now published in the New England Journal of Medicine (NEJM) Evidence.1
Prostate cancer is the second most common cancer in male patients, causing approximately 375,000 deaths in 2020.1 In clinical trial settings, overall survival for patients with mCRPC is approximately 3 years, while in the real-world setting this is shorter.2-5 Approximately half of patients with mCRPC may receive only one line of active treatment, with diminishing benefit of subsequent therapies.6-10 HRR gene mutations occur in approximately 20-30% of patients with mCRPC.3,11
Noel Clarke, Urological Surgeon and Professor of Urological Oncology at The Christie/Salford Royal Hospitals and University of Manchester; the PROpel trial joint Chief Investigator and joint lead author of the NEJM Evidence manuscript, said: “It is critically important that we identify new first-line treatment options for patients with metastatic castration-resistant prostate cancer. The data published in NEJM Evidence emphasise the therapeutic potential of combining olaparib with abiraterone and prednisone and demonstrate efficacy in a wider group of patients beyond those with documented DNA repair deficiency.”
Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “These data demonstrate that the combination of Lynparza with abiraterone and prednisone afforded patients a median radiographic progression-free survival of over two years, regardless of biomarker status. If approved, the combination will offer patients with and without HRR gene mutations a much needed new treatment option.”
Dr Eliav Barr, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “Publication of the PROpel data in NEJM Evidence reflects the benefit seen with the combination of Lynparza plus abiraterone and prednisone in the first-line setting of metastatic castration-resistant prostate cancer, and we are pleased that these data have been selected for one of the first issues of this new journal."
In September 2021, at a planned interim analysis, the Independent Data Monitoring Committee concluded that the PROpel trial met the primary endpoint of rPFS. The results were presented in February 2022 during 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium and additional data on Safety and Tolerability as well as Pharmacokinetics were presented at ASCO 2022 on 6 June 2022.
In the PROpel Phase III trial, on the primary endpoint, olaparib in combination with abiraterone improved median rPFS to 24.8 months versus 16.6 for abiraterone alone. Results also showed that olaparib in combination with abiraterone extended median rPFS by BICR (blinded independent central review) analysis by almost a year, with a median rPFS of 27.6 months versus 16.4 with abiraterone alone. Results also showed a favourable trend towards improved overall survival (OS) with olaparib plus abiraterone versus abiraterone alone, however the difference did not reach statistical significance at the time of this data cut-off (28.6% maturity; based on a HR of 0.86; 95% CI 0.66-1.12; P=0.29). Data from the additional secondary efficacy endpoints of time to first subsequent therapy (TFST) (HR, 0.74; 95% CI, 0.61-0.90) and second progression-free survival (PFS2) (HR, 0.69; 95% CI, 0.51-0.94); and exploratory endpoints including objective response rate (ORR) (odds ratio, 1.60; 95% CI,1.02-2.53) as well as prostate-specific antigen levels, determining time to PSA progression (HR, 0.55; 95% CI, 0.45-0.68), further support the treatment benefit of olaparib and abiraterone compared to abiraterone alone in the overall trial population.
The safety and tolerability of olaparib in combination with abiraterone 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 olaparib in combination with abiraterone, and no detrimental effect on health-related quality of life versus those treated with abiraterone alone (FACT-P (Functional Assessment of Cancer Therapy-Prostate) questionnaire).
Lynparza is approved in the US for patients with HRR gene-mutated mCRPC (BRCA-mutated 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 (NHA).
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate.12 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.13
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.6 Approximately 10-20% of patients with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these patients will have metastases at the time of CRPC diagnosis.6
Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.5 Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, once patients failed first line therapy, the treatment effect of second line anti-cancer therapy appears to diminish significantly hence there is high unmet medical need in this population.6,8,9,14
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 overall survival (OS), time to disease progression or death (PFS2), and time to first subsequent therapy (TFST).
For more information about the trial please visit ClinicalTrials.gov.
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 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 poly-ADP ribose polymerase (PARP) proteins 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. In the PROpel Phase III trial, Lynparza is combined with abiraterone, an NHA which targets the androgen receptor (AR) pathway.
Androgen receptor signalling engages a transcriptional programme that is critical for tumour cell growth and survival in prostate cancer.15,16 Preclinical models have identified interactions between PARP signalling and the AR pathway which support the observation of a combined anti-tumour effect of Lynparza and NHAs, like abiraterone, in both HRR deficient and HRR proficient prostate cancer.17,18,19
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 NHAs15,18,20 Additionally, it is thought that abiraterone may alter/inhibit the transcription of some HRR genes which may induce HRR deficiency and increase sensitivity to PARP inhibition.17,19,21,22
Lynparza is currently approved in a number of countries across PARP-dependent tumour types with defects and dependencies in the DDR pathway including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for gBRCAm, HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (US only); for gBRCAm metastatic pancreatic cancer; and HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm only in the EU and Japan).
Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, 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 (olaparib), the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.
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.
AstraZeneca in oncology
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1. AstraZeneca. Lynparza plus abiraterone reduced risk of disease progression by 34% vs. standard-of-care in 1st-line metastatic castration-resistant prostate cancer. Available at https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/lynparza-combo-delays-progression-risk-in-prostate-cancer.html. Accessed May 2022.
- Ng K, et al.Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Advances and Treatment Strategies in the First-Line Setting. Oncol Ther.2020;8:209–230.
- Shore N, et al.Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors. Adv Ther. 2021;38:4520–4540.
- Wallis C, et al. Real-World Use of Androgen-Deprivation Therapy: Intensification Among Older Canadian Men With de Novo Metastatic Prostate Cancer. JNCI Cancer Spectrum.2021;5(6):pkab082.
- George D, et al.Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States. Clinical Genitourinary Cancer. 2020 Aug;18(4):284-294.
- Kirby, M, et al. Characterising the castration-resistant prostate cancer population: a systematic review. International Journal of Clinical Practice, 2021;65(11):1180-1192.
- Smith MR, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23(13):2918-25.
- 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 May 2022.
- Liu J, et al. Second-line Hormonal Therapy for the Management of Metastatic Castration-resistant Prostate Cancer: a Real-World Data Study Using a Claims Database. Scientific Report. 2020;10(4240):2020.
- George DJ, et al. Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States. Clin Genitourin Cancer. 2020; 18:284-294.
- Mateo J, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med.2015; 373:1697-1708.
- Chowdhury S, et al. Real-world outcomes in first-line treatment of metastatic castration-resistant prostate cancer: the prostate cancer registry. Target Oncol. 2020;15(3):301-15.
- 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 May 2022.
- 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 May 2022.
- Schiewer MJ, et al.Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov.2012;2(12):1134-1149.
- Schiewer MJ & Knudsen KE. AMPed up to treat prostate cancer: novel AMPK activators emerge for cancer therapy. EMBO Mol Med. 2014;6(4):439-441.
- 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.
- Polkinghorn WR, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov.2013;3(11):1245-1253.
- Asim M, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017;374(8).
- Ju B-G, et al. A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science. 2006;312(5781):1798-1802.
- Goodwin JF, et al. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 2013;3(11):1254-1271.
- Tarish FL, et al. Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair. Sci Transl Med. 2015; 7(312):312re11.