What’s next for targeting cancer DNA repair with PARP inhibitors?
DNA damage response (DDR) inhibitors, such as poly (ADP-ribose) polymerase (PARP) inhibitors, are a type of targeted therapy used to treat cancers with existing defects in DNA repair, such as BRCA mutant cancers.
DDR inhibitors block critical DNA repair pathways that these cancers rely on to repair their DNA as they grow and divide. Other important DDR players being targeted by researchers are ataxia telangiectasia and Rad3-related (ATR) kinase, ataxia telangiectasia mutated (ATM) kinase, Wee1 kinase, checkpoint kinase 1 and 2 (CHK1/2) and DNA-dependent protein kinase (DNA-PK).
With dozens of Phase I clinical trials underway, Yap and his team are working to discover the next big breakthrough with DDR inhibitors, so that more patients can benefit and those who are responding experience longer, deeper responses.
Proven success with PARP inhibitors
In recent years, PARP inhibitors have emerged as a new therapy for a few advanced cancers for which there have been limited treatment options. The PARP inhibitors olaparib, niraparib and rucaparib are approved by the Food and Drug Administration (FDA) for patients with BRCA-related and non-BRCA–related advanced ovarian cancer in the advanced and maintenance settings, respectively; and thanks to the EMBRACA trial, the PARP inhibitor talazoparib was approved this past summer for patients with metastatic BRCA1/2-positive, HER2-negative breast cancer.
Despite the success of DDR inhibitors, there’s room to improve.
“We need more patients to benefit and we need deeper, more durable responses,” Yap says. “And I believe we can do that through rational combinations in selected molecular subtypes of patients.”
Advancement through combinations
As Yap describes it, the beauty of DDR inhibitors, such as PARP inhibitors, is their ability to be used in combination regimens with other therapies to improve a patient’s response.
“I see PARP inhibitors as a foundational class of drugs,” Yap says. “Like PD-1 and PD-L1 immune checkpoint inhibitors, we can build a whole program on PARP inhibitors that can work in multiple cancers and different molecular subtypes of those cancers.”
Yap is working within three different classes of combinations:
DDR inhibitor plus DDR inhibitor — When one DDR agent, such as a PARP inhibitor, is combined with another type of DDR inhibitor, patients may be able to overcome resistance seen with DDR inhibitor monotherapies.
DDR inhibitor plus other targeted therapies — For tumors that don’t have existing DNA repair defects, Yap and his team are inducing a “chemical BRCAness.” For example, by suppressing the BRCA protein using PI3K inhibitors, the cancer cells become susceptible to DDR inhibitors, similar to BRCA-positive tumors.
DDR inhibitor plus immunotherapy — Studies have shown that DDR inhibitors activate the immune system. Furthermore, in a lab setting, a synergy has been noted between the two classes of drugs when they’re combined. Recently, MD Anderson researchers discovered that a combination of immune checkpoint blockade and targeted therapies that block normal DNA damage repair achieved significant tumor regression in mouse models of small cell lung cancer, suggesting a promising new approach for treating patients with this aggressive cancer.
Yap hypothesizes that there are different levels of sensitivity to these drugs within each gene mutation and that there’s also context dependency between different tumor types.
“The likelihood of a response in a BRCA1-mutant ovarian cancer and a BRCA1-mutant pancreatic cancer is unlikely to be the same,” he says. “But that’s what we’re working to find out.”
Quality of life improvements
Since DDR inhibitors are administered orally, the convenience potentially can improve patients’ quality of life.
“It’s changing how we treat patients,” Yap says.
The convenience has allowed patients from across the country to participate in these unique trials that aren’t available anywhere else. Depending on the trial, participants may have to come to MD Anderson to see their care team every two to three weeks for evaluation.
Myelosuppression, GI tract rank high as potential side effects
Patients are informed about the signs of possible side effects, and they’re monitored closely. If a patient experiences an adverse event, he or she may be taken off the DDR inhibitor for a short period of time until the side effect returns to a safe and tolerable level. Side effects involving the gastrointestinal tract can effectively be treated with medications. In the case of myelosuppression, a blood transfusion may also be needed.
“It’s an exciting time for these new agents,” Yap says. “But we still have a lot to learn to reduce the toxicity, as well as widen the number of patients who are benefiting.”