In the past ten years, humans have gained a better understanding of the complexity of cancer. There are a lot of genetic inconsistencies between different patients, between primary or metastatic tumors, and even between the same tumor in different regions. The heterogeneity of this tumor can explain why the effects of drugs vary from person to person, and it can also explain why patients have relapse of drug resistance. It is true that the complexity of cancer poses serious challenges for researchers, but it also continues to promote the progress of cancer therapy. Recently, "Science" magazine launched a special issue of cancer, introducing the current cutting-edge cancer treatments. When the new TESARO ovarian cancer drug ZEJULA (niraparib) is on the market, we will send readers an in-depth inventory of PARP inhibitors from Science.


PARP inhibitor is a cancer therapy that targets Poly ADP-ribose Polymerase. It is the first anti-cancer drug that has successfully used the concept of Synthetic Lethality and has been approved for clinical use. Its principle is not difficult to understand: cancer patients with BRCA1 or BRCA2 germline mutations carry specific DNA repair defects, so they are particularly sensitive to PARP inhibitors that can also hinder DNA repair. Because of this feature, the efficacy of PARP inhibitors is expected to extend to other tumors with the same DNA repair defects. For this reason, the research and development of PARP inhibitors has become a hot spot in the field of anti-cancer.

In simple terms, synthetic lethality refers to the fact that when two different genes or proteins change at the same time, it will cause cell death, and if only one of these two genes/proteins is abnormal, it will not cause cell death. The role of PARP1 is to bind to DNA damage sites (mostly single-stranded DNA breaks) and catalyze the synthesis of poly ADP ribose chains on protein substrates. Through this catalysis, PARP1 can recruit other DNA repair proteins to the damage site to repair DNA damage together. The PARP inhibitor binds to the catalytic site of PARP1 or PARP2, causing the PARP protein to fail to fall off the site of DNA damage. PRAP, which is bound to DNA, will cause DNA replication forks to stall and DNA replication cannot proceed smoothly during DNA replication. At this time, cells usually trigger a repair method called Homologous Recombination Repair (HRR) to repair this error. BRCA1, BRCA2 and other proteins called "BRCAness" (BRCAness) play an important role in HRR. When the function of these proteins is impaired and HRR malfunctions, other DNA repair methods used by cells usually introduce large-scale genomes. Recombination, leading to cell death.

The original purpose of developing PARP inhibitors was to use PARP together with other therapies that cause DNA damage to cancer cells (such as radiotherapy and chemotherapy) to enhance the efficacy of other therapies by weakening the ability of cancer cells to repair DNA damage. But in 2005, researchers found that tumor cells carrying BRCA mutations were 1,000 times more sensitive to PARP inhibitors than tumor cells carrying wild-type BRCA genes. This major discovery has greatly promoted the clinical application of PARP inhibitors as monotherapy.

It should be pointed out that although PARP inhibitors are usually associated with BRCA1 or BRCA2 germline gene mutations, they may also have therapeutic effects on other tumors. Although many tumor cells do not have BRCA1/2 germline gene mutations, these tumor cells may also be sensitive to PARP inhibitors due to other reasons that cause HRR defects. This will greatly expand the application range of PARP inhibitors. Studies have shown that some patients with high-grade serous ovarian cancer (High-grade Serous Ovarian Cancer), advanced prostate cancer and pancreatic cancer may benefit from PARP inhibitor therapy. To this end, researchers are vigorously developing diagnostic methods for detecting the HRR function of tumor cells and searching for biomarkers related to HRR defects.

Clinical development of PARP inhibitors

The PARP inhibitor that first entered clinical trials was rucaparib (Pfizer/Clovis), a combination therapy with the chemotherapy drug temozolomide. Following the discovery of a synthetic lethal relationship between PARP inhibition and BRCA gene mutations in preclinical studies, olaparib (KuDOS/AstraZeneca) was advanced to a phase 1 clinical trial to treat breast cancer patients with BRCA1 or BRCA2 germline gene mutations. The test results showed that 63% of patients could benefit from it, supporting the hypothesis of synthetic lethality. Subsequent phase 2 clinical trials involving breast, ovarian, pancreatic, and prostate cancer patients with BRCA germline gene mutations further verified the efficacy of olaparib. The FDA therefore approved olaparib for the treatment of patients with advanced ovarian cancer who have received three therapies and carry BRCA germline gene mutations.

Subsequently, olaparib has shown promising effects in the treatment of other tumors that may carry HRR defects. In clinical trials for the treatment of high-grade serous ovarian cancer, olaparib as a maintenance therapy can reduce the chance of recurrence and prolong progression-free survival in patients who have received platinum-based chemotherapy. Therefore, the European Medicines Agency approved it for the treatment of high-grade gynecological cancers that carry BRCA gene mutations and are sensitive to platinum-based therapy. In a phase 2 clinical trial for the treatment of metastatic, castration-resistant prostate cancer (Castration-Resistant Prostate Cancer), 30% of patients responded to olaparib, and half of the patients’ tumors carried BRCA2 or ATM gene defects.

After olaparib was approved to treat ovarian cancer, niraparib (Mersk/TESARO) as a maintenance therapy also performed well in phase 3 clinical trials for the treatment of ovarian cancer. Niraparib not only prolongs the progression-free survival of patients with BRCA germline gene mutations, but also shows tumors that do not carry BRCA germline gene mutations but exhibit genomic mutation characteristics similar to those that carry BRCA germline gene mutations. Similar efficacy. Today, niraparib has been approved by the US FDA for the maintenance treatment of female patients with recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

Recently, rucaparib as a maintenance therapy has also significantly extended the progression-free survival of patients in the treatment of platinum-sensitive high-grade ovarian cancer. In the phase 2 clinical trial named ARIEL2, rucapariba not only has therapeutic effects on tumors with mutations in the BCRA gene, but also on tumors with wild-type BRCA genes but whose cells show Loss of Heterozygosity (LOH) It is also very significant. LOH may represent an HRR defect. Rucaparib has also been approved by the FDA to treat patients with advanced ovarian cancer who carry BRCA germline or system gene mutations and have received more than two chemotherapy.

The new generation of PARP inhibitor talazoparib (Lead/Biomarin/Medivation/Pfizer) has also begun to show clinical potential. In a recent study, 13 early breast cancer patients with BRCA germline gene mutations were treated with talazoparib without chemotherapy or surgery. After two months, the tumor volume of all patients had shrunk.

Due to the design of clinical trials and differences in patient groups, it is still too early to determine which PARP inhibitor has the best efficacy. With the emergence of more mature clinical Phase 3 trial results in the future, we may be able to distinguish which PARP inhibitor is a better choice in specific clinical situations.

Prospects of PARP inhibitor combination therapy

Although the original purpose of developing PARP inhibitors was to make tumor cells more sensitive to chemotherapy that causes DNA damage, the combination of PARP inhibitors and chemotherapy has mixed clinical manifestations. The main reason is that the toxic side effects of chemotherapy on healthy cells often limit the dose of drugs that can be used, and the combined use of PARP inhibitors usually enhances the toxic side effects on healthy cells. Current preclinical studies have shown that a combination therapy consisting of high-dose PARP inhibitors and relatively low-dose chemotherapy can achieve the effect of inhibiting tumor cell proliferation. The safety and effectiveness of this combination are being tested in clinical trials.

Preclinical studies have shown that a series of targeted drugs such as PI3 kinase signaling pathway inhibitors can cause or enhance the HRR defects of tumor cells, making tumor cells more sensitive to PARP inhibitors. Another strategy is to combine PARP inhibitors with drugs that disrupt the ability of tumor cells to pause the cell cycle. Because tumor cells need to pause the cell cycle to perform DNA repair, drugs that disrupt this function may make tumor cells more sensitive to PARP inhibitors.

Finally, a combination therapy consisting of PARP inhibitors and immune checkpoint inhibitors that inhibit CTLA4 and PD1/PDL-1 functions is also undergoing clinical trials. The reason for this combination is that most tumors with HRR defects carry more gene mutations, and thus may produce more new antigens, which will induce a stronger anti-cancer immune response.

The starting point of most combination therapies is to enhance the effect of PARP inhibitors by increasing DNA damage or inhibiting DNA repair mechanisms. However, there are also combination therapies that combine PARP inhibitors with drugs whose mechanism of action does not seem to be related, such as the recent combination therapy of olaparib and the anti-angiogenic drug cediranib. One potential advantage of this combination therapy is that because the two drugs have completely different modes of action, it is difficult for tumors to develop resistance to the combination therapy.

The future of PARP inhibitors

It took more than ten years from the discovery of the lethal relationship between PARP inhibitors and BRCA synthesis to the approval of the first PARP inhibitor. Nowadays, PARP inhibitors are still a very hot research field, and there are many clinical trials in progress. It is optimistic that more PARP inhibitors will be approved to treat more cancers in the near future. The following three major breakthroughs will help PARP inhibitors benefit cancer patients:

1. Discover the most suitable patients for PARP inhibitor therapy. By further analyzing the mechanism of PARP inhibitors to kill tumors, more precise biomarkers can be found to realize the segmentation of cancer patients. 2. Anti-drug resistance. Tumors can become resistant to PARP inhibitors through a variety of mechanisms. This includes secondary mutations in the BRCA gene to restore HRR defects, other gene mutations to restore HRR function, and PARP gene mutations to cause PARP protein deletion, and so on. Research on the mechanism of resistance can discover biomarkers that predict tumor resistance, and help find clinical methods to delay or prevent resistance. 3. Optimize combination therapy. This goal can be achieved by the following means: further understanding the successful mechanism of combination therapy, identifying combination therapies that can target drug resistance, and discovering biomarkers that can predict the efficacy of PARP inhibitor combination therapy.

Reference materials:

[1] PARP inhibitors: Synthetic lethality in the clinic
[2] Stocking oncology’s medicine cabinet