The PEARL study: Palbociclib and endocrine therapy vs capecitabine in HR /HER2- metastatic breast cancer

Dr Miguel Martín - Universidad Complutense de Madrid, Madrid, Spain

Moving back to 2013 when we designed the trial we saw that the impact of CDK4/6 inhibitors, palbociclib among them, could be different along the course of the metastatic disease of the patients with hormone receptor positive HER2 negative breast cancer. That means that these patients need to be treated with a pre-planned sequence of therapies, not every therapy could be done at any time. You should design a sequence for each particular patient in which the most appropriate drug for the patient is given first, the second one then, leaving the most toxic therapies for later. So that way you guarantee the best survival for the patients with the best quality of life for a longer time.

At that time palbociclib plus endocrine therapy was approved for patients refractory to aromatase inhibitors, the most commonly used endocrine therapy for this population. But we thought that it might be this is not the best place for that drug, it might be they should be used much earlier because the tumours, the metastatic tumours, particularly when they grow they acquire mutations, they get more and more resistant to endocrine therapies, to targeted therapies. So probably targeted therapies should be administered at the beginning of the disease and we should leave chemo for the last part of the disease.

So we compared palbociclib plus endocrine therapy to chemotherapy given orally, capecitabine. This is important because that chemotherapy is not very toxic, it’s not as toxic as other chemotherapies, IV chemotherapies producing alopecia, nausea, vomiting and other things, myelosuppression and so on. What we saw is that there is no difference in activity between palbociclib plus endocrine therapy and capecitabine. The indirect meaning of that is that probably palbociclib plus endocrine therapy, a combination that performs, to tell the truth, poorly because we expected a better performance in that population, actually should be given earlier because you can give the patients a much better therapy. You can induce disease control lasting for more than two years.

On the other hand, if you use this therapy in third line, second line, the ability to control the disease is only 8-10 months. So it’s much better to use the drugs earlier and leave capecitabine for later.

Do you have any idea as to why there was no difference found?

Yes, the more advanced is the tumour the more resistant it becomes to CDK4/6 blockade. These drugs work very well in first line but they lose their efficacy possibly after several lines. On the other hand, capecitabine probably seems the mechanism of action is different, it’s a chemotherapy, a specific drug, not a targeted drug, probably works well more or less any time. So the reason for the non-superiority of palbociclib is that and the study being negative has a positive comment for the investigators and the patients and the cancer doctors – we should use palbociclib earlier in the course of the disease because it works much better and for much longer. If we leave palbociclib for later lines the drug works much less.

What outcomes did you use to measure the success?

The outcome we measured in the trial was progression free survival. This is the time from the start of therapy until it doesn’t work any longer and it is 8-10 months in both arms in our trial. This is not the best outcome for patients to deal with CDK4/6 inhibitors. If you use the drugs earlier, in first line, you can have a PFS of 24 months, 28 months, more than two years, and this is very important for the patients because the patients receiving these drugs in first line could perceive that they still have some therapy that can benefit them for longer, for a long period of time.

So, in my opinion, reaching a first PFS in the first line long is crucial to improve the morale of the patients and to transmit to the patients the idea that we have things to do treating the disease. If you start with therapies with very poor performance this is not the case. So the best drugs should be used in first line.

We ran the trial because palbociclib was approved for second and third line and we think this is not a good idea, even if it is approved. I think we should move the drug earlier. Today it’s approved for early line which means first line, second line, third line. At the time we did the trial it was only approved for second and third line. But now we should abandon that indication and treat the patients from the beginning with CDK4/6 inhibitors and leave capecitabine for later.

What are the next steps for this research?

There are many, many things to do because luminal breast cancers, this type of breast cancer, is not curable unfortunately. We have improved the prognosis of the patients in terms of overall survival a lot. I remember maybe ten years ago the patients had a median overall survival of 2½ years, now we are moving to 5-6 years median overall survival. This is a significant improvement but to reach the goal of therapy in that population, and the goal for me is to make the disease a chronic condition, we need to have median overall survival times from 15-20 years.

We have a lot of things to do, a long way ahead, until we can reach that. The way we can reach that is we should identify different subpopulations of patients with different prognoses and different sensitivity to therapy. We need to identify new targets, particularly actionable targets, druggable targets, and that means we need new drugs. The idea of sequencing drugs in that population is crucial because since the disease is not curable with any available therapy you have to administer one therapy, then another, another and so on. Using the right sequence could be very relevant for the overall result.

So our study provides additional information in that sense. We should use these very, very effective drugs not in second and third line, as in our study, but earlier, in first line.