Lynparza: The First PARPi To Treat Homologous Recombination Repair Defects MCRPC To Extend Overall Survival!

- Mar 02, 2020-

AstraZeneca and Merck & Co recently announced the further positive results of the Phase III PROfound trial of the targeted anticancer drug Lynparza (Lipzhuo, generic name: olaparib, olaparib tablets) in the treatment of prostate cancer .

The study enrolled 387 male patients with metastatic castration-resistant prostate cancer (mCRPC) who had homologous recombination repair gene mutations (HRRm) in their tumors and had previously received new hormone drugs (NHA, such as Xtandi or Zytiga) progressed after treatment. The study evaluated the efficacy and safety of Lynparza relative to the standard care drugs Xtandi (enzalutamide, enzalutamide) or Zytiga (abiraterone acetate, abiraterone acetate).

The results of the trial showed that in patients with mCRPC carrying BRCA1 / 2 or ATM gene mutations (a subgroup of HRR gene mutations), Lynparza treatment was the key secondary endpoint-overall survival compared with enzalutamide or abiraterone The period (OS) has statistically and clinically significant improvements. According to the results, in patients with mCRPC with BRCA1 / 2 or ATM mutations, Lynparza is the only PARP inhibitor that prolongs overall survival (OS) compared to novel hormone drugs (NHA). Detailed data will be announced at the upcoming medical conference.

It is worth mentioning that the PROfound study is the first phase III study to evaluate a targeted drug to obtain a positive result in a prostate cancer patient population selected by biomarkers. In August 2019, the study reached the primary endpoint. The results showed that among mCRPC patients with BRCA 1/2 or ATM gene mutations, Lynparza was statistically significant in terms of the primary endpoint, radiological progression-free survival (rPFS) and Improvement of clinical significance. Specifically, in patients with mutations in the BRCA1 / 2 or ATM genes, the progression-free survival of patients receiving Lynparza was doubled compared with patients receiving abiraterone or enzalutamide (median) rPFS: 7.4 months vs 3.6 months), the risk of disease progression or death was significantly reduced by 66% (HR = 0.34 [95% CI: 0.25-0.47], p <0.0001).

In addition, the study also reached the key secondary endpoint of rPFS in mCRPC patients carrying HRRm genes (BRCA 1/2, ATM, CDK12 and 11 other HRRm genes): in the entire HRRm patient population, as opposed to receiving abiraterone or en Compared with patients treated with zalutamide, patients receiving Lynparza had significantly longer radiographic progression-free survival (median rPFS: 5.8 months vs 3.5 months), and the risk of disease progression or death was significantly reduced by 51% (HR = 0.49 [ 95% CI: 0.38-0.63], p <0.0001). In this study, Lynparza's safety and tolerability were consistent with those observed in previous clinical studies.

Currently, a supplemental new drug application (sNDA) from Lynparza is undergoing priority review by the US FDA. The sNDA is based on data from the PROfound study and seeks to approve Lynparza for the progression of the disease after receiving a new hormone drug (NHA), carrying harmful or suspected harmful germline or somatic homologous recombination repair gene mutations (HRRm), metastatic Patients with potential resistant prostate cancer (mCRPC). The FDA has designated the sNDA's prescription drug user fee method (PDUFA) target date to be the second quarter of 2020.

At present, AstraZeneca and Merck are also exploring other trials of prostate cancer, including the ongoing phase III PROpel trial to evaluate Lynparza as a first-line therapy in combination with abiraterone for mCRPC patients with or without HRR mutations.

Prostate cancer is the second most common cancer among men. It is estimated that there are 1.3 million newly diagnosed prostate cancer patients worldwide in 2018, and it is associated with a significant mortality rate. The development of prostate cancer is usually driven by male sex hormones (including testosterone). In patients with mCRPC, although androgen deprivation therapy prevents male sex hormones, prostate cancer can still grow and spread to other parts of the body.

About 10-20% of patients with advanced prostate cancer will develop CRPC within five years, and at least 84% of men will have metastases at the time of CRPC diagnosis. Of the men who did not transfer at the time of CRPC diagnosis, 33% were likely to transfer within two years. Despite the progress made in the treatment of mCRPC men, the 5-year survival rate is very low, and prolonging survival is still the key goal of treating these men.

About 20-30% of mCRPC patients have HRR mutations. The HRR gene can accurately repair damaged DNA in normal cells. HRR deficiency (HRD) means that DNA damage cannot be repaired and may cause normal cell death. This is different in cancer cells, where mutations in the HRR pathway cause abnormal cell growth and cancer. HRD is an effective target for PARP inhibitors, such as Lynparza. PARP inhibitors block DNA damage repair mechanisms by capturing PARP combined with DNA single-strand breaks, causing replication forks to stall, collapse and produce DNA double-strand breaks, which in turn leads to cancer cell death.

Lynparza (Lipuzhuo): has been listed in China, and is included in the National Medical Insurance Catalog

Lynparza is a first-in-class, oral poly ADP ribose polymerase (PARP) inhibitor, which can take advantage of the defects of the tumor DNA damage repair (DDR) pathway to kill cancer cells preferentially. The potential of a wide range of tumor types.

Lynparza is the world's first PARP inhibitor, which was approved by the US FDA for the first time in December 2014. So far, the drug has been approved by many countries around the world for the maintenance treatment of platinum-sensitive recurrent ovarian cancer (regardless of BRCA status). The drug is approved as first-line maintenance therapy in the United States, the European Union, Japan, China and some other countries. It is used for BRCA mutation (BRCAm) advanced ovarian cancer after platinum-containing chemotherapy. In addition, it has been approved for BRCAm HER2-negative metastatic breast cancer that has previously received chemotherapy in several countries including the United States and Japan. In the European Union, this indication includes locally advanced breast cancer. In addition, Lynparza is approved in the United States and several other countries for the treatment of reproductive system BRCAm metastatic pancreatic cancer. Currently, Lynparza's treatment of ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer is under review in other jurisdictions.

AstraZeneca and Merck reached a global strategic cooperation in oncology in July 2017 to jointly develop and commercialize Lynparza and another MEK inhibitor, selumetinib, to treat many types of tumors. In the category of PARP inhibitors, Lynparza has the most extensive and advanced clinical trial development projects. Currently, the two parties are collaborating to investigate the therapeutic potential of Lynparza as a monotherapy and combination therapy for a wide range of tumors.

In the Chinese market, Lynparza was approved in August 2018 for maintenance treatment of platinum-sensitive recurrent ovarian cancer. Lynparza is the first targeted drug approved for the treatment of ovarian cancer in the Chinese market, marking the entry of Chinese ovarian cancer treatment into the era of PARP inhibitors. In December 2019, Lynparza was approved again for first-line maintenance treatment of patients with advanced ovarian cancer with BRCA mutations. Benefiting from China's vigorous support for pharmaceutical innovation and accelerating the clinical need for new drug approvals, Lynparza became the first PARP inhibitor approved in China for first-line maintenance therapy of ovarian cancer. On November 28, 2019, Lynparza was included in the National Medical Insurance Catalog. (