We have now two agents, two PARP inhibitors, that are now FDA approved for the treatment of patients with germline BRCA mutations in the metastatic setting. These two agents are olaparib and talazoparib. They have been investigated in two very similar randomised trials, olaparib in the OlympiA-AD and talazoparib in the EMBRACA trial. Both trials showed very similar results – approximately 3 months’ improvement in progression free survival with single agent PARP inhibitor versus single agent chemotherapy – and almost a doubling in the number of responses observed – approximately 30% with chemotherapy that went up to 60% with PARP inhibitors – with a good toxicity profile, mostly anaemia and nausea that appeared to be superior for the PARP inhibitor. So these are now important treatment options for patients with metastatic HER2 negative disease and carrying a germline BRCA mutation.
How would a clinician decide on which one to use?
Among olaparib and talazoparib we don’t have a lot of tools to decide which one of the two drugs is superior. Both of them are available treatment options and they show very similar results in terms of efficacy and also in terms of safety. So it’s a matter of probably reimbursement and approval in the different countries more than the agent itself.
Even though there are preclinical data that probably talazoparib is more effective as a drug than olaparib, however, it does not appear to be confirmed by looking at this trial, even though comparing indirectly two different trials is not easy. But we can say that we have preclinical data that probably talazoparib is a more potent PARP inhibitor.
What are the main challenges that remain to be addressed?
There are two main issues that should be addressed. The first one is the role of these agents in the early setting. Now they are approved for patients with metastatic disease so the question is can we move these agents for patients receiving neoadjuvant or adjuvant treatment? We have several trials ongoing, probably the most important is the OlympiA trial in which the investigators included BRCA mutated patients that finished neoadjuvant or adjuvant standard chemotherapy. They randomised patients to receive one year of olaparib as adjuvant treatment or not. The trial has already completed accrual so we are looking forward to have the results and to see if these agents can be moved also to the early setting. So this is the first question that we have to address.
The second one, and very important, is the possibility, going back to the metastatic setting, of improving the efficacy of these agents. So we have signal, we have data that these are effective drugs but can we do something more than what has been shown in these two trials that I have just discussed? There are several possibilities of combining these agents with other types of drugs. The combination with chemotherapy has not proven to be a very successful approach so far, however, we have several ongoing trials in which these agents are combined on the one hand with targeted agents, for example, angiogenic inhibitors, androgen receptor inhibitors, MEK inhibitors, PI3K inhibitors, but on the other side, and this is very interesting and very promising, the combination with immune checkpoint inhibitors. There’s a strong preclinical rationale to think that combining a PARP inhibitor with an immune checkpoint inhibitor can have a synergistic effect, so can increase the efficacy of both treatment options. Indeed, we already have some clinical data suggesting that indeed these are a very active combination. We have already an ongoing randomised trial randomising patients to receive single agent PARP inhibitors or PARP inhibitor combined with immune checkpoint inhibitor.
Are there other PARP inhibitors that in the future could be used in the breast cancer setting?
This is a challenging question. There are other PARP inhibitors that have already shown to be effective in other types of cancer, for example rucaparib is one example in patients with ovarian cancer. Of course it will be important to test these agents also for breast cancer patients before considering the possibility to use them in daily clinical practice. So far we don’t have large randomised trials with other agents than talazoparib and olaparib in this setting.