Latest news on PARP and other DNA-damage response targets

Cancer-specific DNA repair defects are common in malignant tissue, but they provide an opportunity for therapeutic attack.

A look at current clinical developments and prospects

Cancer-specific DNA repair defects are common in malignant tissue, but they provide an opportunity for therapeutic attack.

The concept of synthetic lethality between genetic defects of BRCA genes and pharmacological inhibition of the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP) led to the development of PARP inhibitors. The current clinical developments of this substance class, meaningful combinations, and other substances that can interfere with the DNA damage response (DDR) were presented and discussed at a symposium chaired by Timothy A. Yap, MD Anderson Cancer Center, Houston, Texas, USA, on 31 May at the Annual Meeting 2019 of ASCO (American Society of Clinical Oncology) (Source 1).

Current applications for PARP inhibitors

Starting in 2003, PARP inhibitors were initially investigated in combination with cytotoxic substances. However, all these studies showed that the inhibition of DNA repair also potentiated the toxicity of chemotherapeutic agents in normal tissue, in particular, strong myelosuppression. To date, no successful clinical strategy has been developed to combine PARP inhibitors with cytotoxic chemotherapy.

First preclinical data, published in 2005, demonstrated the concept of synthetic lethality between BRCA-1/2 gene mutations and pharmacological PARP inhibition and indicated that PARP inhibitors also work in monotherapy. Further investigations underlined the importance of the correct dosage. In December 2014, the results of various clinical trials in the United States and Europe led to the approval of Olaparib as maintenance therapy for women with BRCA-associated ovarian cancer. Additional PARP inhibitors are now available in niraparib (USA and Europe 2017), rucaparib (USA 2016, Europe 2018) and talazoparib (USA 2018).

According to Elizabeth Ruth Plummer, Newcastle upon Tyne Hospitals, an important field of application is maintenance therapy for high-grade serous ovarian carcinoma in patients with BRCA mutations. The benefit of maintenance therapy after response to platinum-containing second-line chemotherapy for olaparib, rucaparib, and niraparib has been demonstrated in the Phase III studies SOLO2, ARIEL3, and NOVA. The SOLO1 study showed that olaparib reduces the risk of disease progression or death by 70% compared to placebo after response to platinum-containing first-line therapy. Rucaparib was the first PARP inhibitor to be approved by the FDA for third-line therapy, based on the results of the ARIEL2 study.

Another important indication is breast cancer in patients with BRCA mutations. In the OlympiAD study, olaparib extended PFS from 4.2 months under standard therapy to 7.0 months (HR 0.58) after two pre-therapies in patients with HER2-negative metastatic breast cancer. The FDA has approved olaparib for this indication. In the EMBRACA study, talazoparib extended PFS by 3 months compared to standard therapy (from 5.6 to 8.6 months, HR 0.54) in patients with BRCA-1/2 mutations in the germline pretreated with a maximum of three therapies.

Plummer sees prostate carcinoma as the next indication. Results from the TRITON-2 study with rucaparib and from the TOPARP-A and TOPARP-B studies with olaparib, for example, are available. Another interesting indication could be pancreatic carcinoma, for which the results of the POLO study were presented at the ASCO plenary session. (Further esanum coverage of this study can be found here).

Combination partner for PARP inhibitors

Not all patients with BRCA-1/2 mutations respond to PARP inhibitors, explained Timothy A. Yap, MD Anderson Cancer Center, Houston, USA. And the development of resistance is almost inevitable. Rational combinations offer the potential for a deeper and longer response as well as for a broader application of PARP inhibitors. Possible combinations are, for example, targeted therapeutics, other DDR inhibitors, and immunotherapeutics.

One strategy is to induce chemical BRCAness and thereby increase the sensitivity of cells to PARP inhibitors. BRCAness is a phenomenon in which tumors without BRCA mutation show a homologous recombination repair deficiency (HRD). Yap cited angiogenesis inhibitors such as cediranib, MEK inhibitors such as selumetinib, PI3K inhibitors such as buparlisib or alpelisib as examples of inducers of a chemical BRCAness. However, only very few clinical data are available on this subject. Also, only preclinical data are available from the combination with other DDR inhibitors, such as ATR and WEE1 inhibitors.

PD-1/PD-L1 inhibitors are an intensely studied substance group in oncology: "They are the chili of oncology, chili makes everything sharper," says Yap. There are currently more than 1100 combination studies with this substance group. "The combination of DDR inhibition and PD-1/PD-L1 inhibitors is a rational antitumor strategy." The Phase I/II basket study MEDIOLA is investigating the combination of olaparib and durvalumab in platinum-sensitive BRCA-1/2 mutated ovarian cancer. The Phase III DUO-O trial will evaluate randomized, double-blind, placebo-controlled and multicenter durvalumab in combination with chemotherapy and bevacizumab, followed by maintenance therapy with durvalumab, bevacizumab and olaparib in patients with newly diagnosed advanced ovarian cancer. Other combinations currently being investigated in clinical trials are pembrolizumab and olaparib in castration-resistant prostate cancer and niraparib and pembrolizumab in ovarian cancer.

New DDR modulators

Nilofer Azad, from the Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland (USA), reported that numerous DDR inhibitors are currently in clinical development. These include, for example, inhibitors of kinases such as ATR (such as Berzosertib), ATM, CHK1-/CHK2 or CHK1 (such as Rabusertib, Prexasertib) or proteins such as WEE1 (such as Adavosertib). ATR and CHK1 inhibitors are the most advanced in clinical development. The basic strategy for the application of ATR, CHK1 and WEE1 inhibitors is based on the fact that they prevent the survival of cancer cells under increased replication stress. ATR and CHK1 inhibitors work particularly well in combination with DNA-damaging agents such as gemcitabine and cisplatin.

DDR: The DNA Damaging Revolution, Educational Symposium, 2019 ASCO Annual Meeting, Chicago, 31 May to 4 June 2019