Alicia Morgans and Joaquin Mateo discuss mapping the genomic landscape of advanced prostate cancer, and the realization that many patients with advanced forms of prostate cancer have tumors with defects in the repair of DNA damage. And what we observed for the first time is actually that a drug like olaparib, a PARP inhibitor, that has been used in breast or ovarian cancer, were associated to these same defects and that it works in men with prostate cancer that have this type of mutation. Based on the data we have acquired over the last few years in breast and ovarian cancer and what we now know in prostate cancer, it seems clear that patients with mutations in BRCA1 and BRCA2 are very likely to benefit, but there is another big group of genes that are altered in some prostate cancers that may confer different degrees of sensitivity to this treatment. So the work now is to first fine-tune who are the patients who will benefit the most, and second, try to understand when is the optimal time to add these therapies to the course of management of prostate cancer.

Biographies:

Joaquin Mateo, MD, Ph.D., Vall d’Hebron Institute of Oncology (VHIO), Barcelona. Joaquin joined the Vall d´Hebron Institute of Oncology in November 2017 as Principal Investigator of its newly established Prostate Cancer Translational Research Group to lead research aimed at translating prostate cancer genotypes into phenotypes and a clinically-relevant classification of the disease. He and his team will also seek to build a precision medicine core fo prostate cancer patients.

Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Read the full video transcript:

Dr. Alicia Morgans: I'm delighted to have here with me today Dr. Joaquin Mateo, who is the prostate cancer team lead at the Vall d'Hebron Institute of Oncology at Barcelona, Spain. Thank you so much for taking the time to come all this way and talk to us.

Dr. Joaquin Mateo: No, thank you, thank you for having me. It's a pleasure.

Dr. Alicia Morgans: Wonderful. Well, you've done so much work in the PARP inhibitor space, and I'm just wondering if you can tell us a little bit about how that part of our field in prostate cancer has evolved over the last few years, and where your work really fits into that.

Dr. Joaquin Mateo: Over the last few years of my work in the UK, we work together with many sites here in the US to develop a true map of the genomic landscape of advanced prostate cancer, and we realized that many patients with advanced forms of prostate cancer have tumors with defects in the repair of DNA damage. And this is normally shown by a series of mutations in some particular genes.

So what we did, basically, and building from some preliminary data we were developing in my formal group with Johann de Bono in the UK, was to launch a trial where we were trying to exploit these defects in the benefit of the patient by giving them therapies that target particularly these problems to repair the damage in the cell. And what we observed for the first time is actually that a drug like olaparib, a PARP inhibitor that has been used in breast or ovarian cancer, were associated to these same defects. Also, works in prostate cancer in men that have this type of mutation.

So, that was a first study, a pilot phase in 50 patients that basically was for us raising a flag, saying, "Well there is something here. We have to look into that." 

I think we still have to learn a lot more about who are the patients that would benefit the most from these therapies.

Based on the data we have acquired over the last few years in breast and ovarian cancer and what we know now in prostate cancer seems clear that patients with mutations in BRCA1 and BRCA2 are very likely to benefit, but there is another big group of genes that are altered in some prostate cancers that may confer different degrees of sensitivity to this treatment. So the work now is to first fine tune who are the patients who will benefit the most, and second, try to understand when is the optimal time to add these therapies to the course of management of prostate cancer.

Dr. Alicia Morgans: So that's a huge question, I think. And I'm so glad you're tackling it, because we're often thinking in prostate cancer that finding a treatment that works in the very advanced setting is potentially an attractive thing to move into an earlier stage of disease. And so we'd want to, of course, be sure that it worked, but also make sure that we understand the side effects and potential complications.

So what are the things that you think about in terms of potential complications of these treatments as we move them earlier on in a stage of treatment?

Dr. Joaquin Mateo: So, PARP inhibitors are treatments that are normally well tolerated. The main side effects are fatigue, which is not very severe, normally. Gastrointestinal effects like nausea and vomiting and diarrhea are commonly mild. They were more relevant in the ovarian cancer trials, but in the prostate cancer trials, we have not seen much gastrointestinal toxicity so far.

The main issue we are seeing is hematological toxicities. So anemia, thrombocytopenia. And that's probably in part due to the fact we are testing these drugs in patients at very late stages that have a lot of bone metastasis, and probably their bone marrow function is already impaired.

In that sense, it's probable that if we can move these drugs earlier when patients may be more fit, and may not have done much infiltration of the bone marrow, we could even see better tolerance, and I would anticipate seeing less toxicities earlier in the disease.

Dr. Alicia Morgans: Absolutely. I think you make a great point, because exposure to chemotherapy or even radium can certainly predispose a bone marrow to be much less able to take something like olaparib or any of the PARP inhibitors. So, wonderful.

You'll have to please let us know how your work evolves in the space. Patient selection, I think, is going to be so critical. What kind of things are you doing to help sort out all of these other genes that might be involved? Besides BRCA2.

Dr. Joaquin Mateo: So, one of the first questions we wanted to address was actually whether these mutations appear as a course of tumor evolution. And then we have to wait until the patient is in a very late stage disease to treat them. Or actually, it's something carried to the tumor from the very beginning, which would basically make us feel more comfortable in testing the drug earlier.

This week at ASCO we're going to be presenting some data in a group of patients that develop late-stage disease. But we went back to their original diagnostic samples and we were able to find these mutations at the similar rate to what we would expect in a later stage disease.

And even for some of them, we have several samples at different points of the disease, and we actually were able to identify those mutations in a pretty stable fashion all the way through the treatment.

So in that sense, we believe that this is something that the tumor develops from the very beginning in the prostate, and therefore it would not be a reaction to the exposure to other treatment. That's first of all.

The second thing we have to do is to get more data in terms of bigger number of patients, because for some of these mutations, right now, we have experienced maybe one, two, three patients. That's not enough to make a call on whether they are relevant or not. We think they may be, but we need more data.

So we just finished a second part of the two-part study, which we hope we will be reporting by the end of this year, or beginning of 2019, in a much bigger group of patients of almost 100 patients, all with mutations in different genes of the DNA repair pathway. There are phase 3 trials now ongoing.

The next thing we want to do is to actually try to provide farther evidence of the functional impact of these mutations. And I'm currently working in my laboratory in different ways of addressing this, either through transcriptional analysis, but also through protein analysis and trying to see if proteins that are effectors of the repair are present or not in the patients that have these mutations.

Dr. Alicia Morgans: That's fantastic. Are there things at ASCO that you think that are going to be presented in the next few days that are going to contribute to your work and to our knowledge overall in this area?

Dr. Joaquin Mateo: Well, definitely. Actually, the PARP inhibitor work in prostate cancer is now a very hot topic, and there are several studies that are going to be presented here at ASCO that are of relevance. Among them on Monday, there's a presentation on a trial combining olaparib and abiraterone, I'm really looking forward to seeing this data, because it may actually provide evidence to actually treat patients beyond those that have these specific mutations. If this drug is synergistic when combined with standard treatments of prostate cancer.

And there are also other studies more in the field of fine-tuning the biomarkers we use to select these patients being presented over the next few days that we really should look at.

Dr. Alicia Morgans: Fantastic.

So if you had to kind of sum it all up, and give the listeners some final thoughts, what is your take on PARP inhibitors in the rest of the prostate cancer landscape and what can we look forward to?

Dr. Joaquin Mateo: I think that until now in prostate cancer, we have been developing drugs that have provided a big benefit to lots of patients, and that has changed dramatically the outcome of prostate cancer in the last decade. And now, probably we are in a stage in which we are going to develop drugs that provide great benefit, but only to some patients. And I think that PARP inhibitors are the first of a new wave of drugs in prostate cancer that may provide great opportunities for a group of patients. That also means we have to change the way we do research and clinical trials, not only to develop the drugs, but in parallel to understand how do we find these patients. So we treat the ones that are going to benefit, because we want to benefit them, but we also don't want to waste opportunities for patients that should get other therapies that will work best.

Dr. Alicia Morgans: Absolutely. It all goes back to patient selection. Understanding the mechanism of what's driving their tumor, and attacking that directly if we can. And I commend you for your work in this area, and really look forward to hearing about your studies over time.

Dr. Joaquin Mateo: Thank you.

Dr. Alicia Morgans: Alright. Thank you so much.