PARP inhibitors is another example of elegant biology. We know that patients who inherit mutations in BRCA1 and BRCA2 have defects in DNA repair and that predisposes them to getting breast cancer and ovarian cancer. In patients who actually have breast cancers and are known to have mutations in BRCA1 and 2, these tumours, in fact, are also more sensitive to DNA damage. So when we use other drugs that inhibit other pathways of DNA repair we can get what’s called a synthetic lethal effect. That means it makes the drug that is affecting DNA repair work much more efficiently in patients that have BRCA mutations. So these drugs have been developed over the last few years and in the last two years now two drugs have been approved, olaparib and talazoparib. They both now have been shown to improve progression free survival in patients with metastatic breast cancer that are known to have a BRCA1 and 2 mutation. These have now been published and approved and used widely.
However, patients do develop resistance to these PARP inhibitors as well. One interesting way that they develop resistance is the tumours mutate the BRCA receptor back to the wildtype, to the non-mutated. Those patients may then be treated with other drugs and we need to understand what the biology is behind these. There have been a couple of posters at ASCO identifying genes that are upregulated that may be targeted by other drugs. So this work is very early but it perhaps will lead us to making PARP inhibitors better and less susceptible to resistance.
There are also other drugs being combined with PARP inhibitors. Immunotherapy is of interest because it turns out that patients that have BRCA1 and 2 mutations, because it affects DNA repair, they have more mutations in their tumours which make for more mutated proteins and activates the immune system to a greater degree. So now by using checkpoint inhibitors and other immune stimulators you might get a double hit, so to say. So combinations of these types are being explored.
What’s your opinion for the future of this type of therapy?
Well the PARP inhibitors clearly have a role but because of resistance we need to look at other drugs to combine them with so that they can work better. I mentioned immunotherapy is one example but there are other DNA repair drugs that inhibit other aspects of DNA repair that may synergise with PARP inhibitors. So these are also being explored.
There is also a large trial going on in the early stage setting where patients who complete all of their treatment, and these are patients who are potentially cured but still have a risk of recurrence, are being treated with a year of olaparib to see if we can further lower their risk of recurrence. There is also a neoadjuvant trial, that is preoperative treatment, for patients who again have early stage breast cancer in which we are using talazoparib alone to see if we can induce complete pathologic responses. So these are some examples of new avenues for studying where PARP inhibitors may be effective.
