Potential of PARP inhibitors for metastatic breast cancer

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Published: 3 Jun 2019
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Dr Alexandra Zimmer - National Cancer Institute, Bethesda, USA

Dr Alexandra Zimmer speaks to ecancer at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about ongoing clinical trials using PARP inhibitors for the treatment of metastatic breast cancer and brain metastases.

She explains that the main challenge with regards to the use of PARP inhibitors is identifying which patient populations responds best to each drug. She also discusses the potential of combination approaches.

Dr Zimmer concludes by speaking about some of the results she looking forward to during the rest of the meeting.

This programme has been supported by an unrestricted educational grant from Pfizer.

We have several different drugs in the PARP inhibitor options, as you know. We have them in the women’s malignancies  world, we have at least three of them approved for ovarian cancer and two of them approved already for the use in breast cancer metastatic disease. The two of them for breast cancer are olaparib and talazoparib, both of them showing efficacy in terms of progression free survival, especially in patients with germline mutation in the BRCA gene in triple negative breast cancer.

The main challenge that has come in with lots of development of new drugs that are developed is to find specifically what’s the population that responds better or that will be the target marker that will make that useful when you use that drug for a group. In triple negatives we have the germinal mutation in the BRCA but we know that there are other patients in the triple negative group that can respond to PARP, we just have to identify them better. Potentially they will be the ones that have alterations in the repair pathway.

Is there an association or relationship with brain metastasis and PARP inhibitors?

There is actually. There is some research in the use of PARP inhibitors in brain metastases ongoing. Some of them don’t penetrate very well the brain but some of them may do that and we are looking into it. There are a couple of pre-clinical studies trying to look into that. So the potential is there.

Could you explain some of the studies that are going on right now?

So for PARP inhibitors we don’t have any specific one. We have other types of trials going on for brain metastases. I think it’s more the investigation of potential penetration in the brain mets that is ongoing.

What main areas should clinicians or researchers focus on in the development of PARP inhibitors?

The main areas are now to use that in combination with other drugs to improve the effectiveness of that. Because we see that we have, for example, the progression free survival when we look at the trials in the triple negative patients with BRCA mutation you see that there are increases in three months, for example, in progression free survival, overall survival is still an open question. But we could have an improvement in those in that progression free survival, maybe in response.

We have data that it could be combined, it’s very well tolerated so it could be combined to other drugs easily. One of the ideas is combining, and we saw some responses on that, with immune therapeutic drugs, PD-L1 inhibitors for example. So that’s one area that could be and is already under development in that sense.

Also the use in other areas, not only metastatic disease but also seeing the effect in the neoadjuvant disease or adjuvant use of that and we have trials going on. Still not reporting in results, final results, but they are ongoing now.

The official recommendation for the PARP inhibitors as we have now which is, as we said, the two approved ones by the FDA, the talazoparib and the olaparib, that generally are well tolerated and the recommendation is triple negative patients with BRCA mutations, when they are metastatic disease if they receive less lines of chemotherapy the better because we even saw the recent results. It’s an exploratory result but the overall survival may be improved with olaparib in patients that received one line or less in the metastatic disease.

Here at ASCO now we have some studies reporting on extra results or extra analyses on the talazoparib and the olaparib that will be presented tomorrow, mainly, and Monday. Not any result in terms of progression free or anything like that but more results in the correlative analysis that they did in those trials. So those are the ones that we are waiting to see in the next two days.

We have at least five agents in the group for PARP inhibitors and all of them have in some way been tested in the breast cancer. As we mentioned before, the more successful ones or the ones that came first are the talazoparib and the olaparib, so we have some data on that as I talked before about when they are used and approved for use. We have other agents that have phase II or initial evaluations or even pre-clinical evaluations like rucaparib, veliparib, that are being evaluated and we still don’t have any analysis or result that is leading to approval. But it could come up with some specific results because these agents, though they are the same type, subtype, of drug or the same target, they have a different profile of side effects and potentially extent of action that could be combined to other drugs.