ASCO 2018: Novel treatment strategies in prostate cancer therapeutics

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Published: 4 Jun 2018
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Prof Karim Fizazi and Dr Neal Shore

Dr Neal Shore speaks to Prof Karim Fizazi at ASCO 2018 about the changing landscape of treatments for prostate cancer, discussing immunotherapies, PARP inhibitors and PSMA testing as future targets and treatments.

Dr Fizazi highlights that anti-PD1 treatment (pembrolizumab) may provide benefit for metastatic castration resistant patients following antiandrogen treatment (5 of the 28 patients in the trial had a PSA decline of 50%).

Trials building on immune checkpoint therapies with novel combinations to improve response rates have shown promise. Among these, the combination of pembrolizumab and enzalutamide is being explored as a doublet or a triplet with the addition of ADXS-PSA in KEYNOTE-046.

Dr Shore raises PARP inhibitors as an avenue of research, with the recent TOPARP trial confirming the activity of olaparib, and Prof Fizazi considers how different genetic abnormalities will inform selection in upcoming trials and eventual care.

PSMA testing, already providing new insights when used in combination with PET imaging, may also offer new inroads in developing treatments, and Prof Fizazi summarises current clinical interest in targeted or radiologic medicine.

 

Checkpoint immunotherapy for prostate cancers
Heating up immunologically cold tumours
PARP inhibitors for advanced prostate cancer
PSMA testing


This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

 

NS: Hello. Welcome to ecancer.tv.

My name is Neal Shore, I’m the Medical Director of Carolina Urologic Research Center in South Carolina.

We’re here today at ASCO 2018 in Chicago.

It’s a great privilege for me to interview my good friend and esteemed colleague, Professor Karim Fizazi from Gustave Roussey in Paris, France.

It was a year ago, almost to the day, that Karim spoke at the plenary session here and revealed, as the principal investigator, the trial known as the LATITUDE which has now completely revamped how we look at patients with high volume, newly diagnosed metastatic prostate cancer.

It has now been incorporated and approved by both FDA and EMA, so a really remarkable achievement, Karim.

But we’re here today for me to ask you some questions of what’s happened in a year’s time.

Not so much on LATITUDE, we have a separate group that’s going to discuss your work and your outstanding achievement, but I wanted to review with you today some of the work that you’ve been going through in terms of looking at other molecular pathways beyond the traditional androgen–androgen receptor axis, particularly in our patients with advanced prostate cancer or castration resistant prostate cancer, for lack of a better terminology.

So maybe we’ll start with the really sexy topic of the immuno-oncologic agents known as the checkpoint inhibitors. 

What’s some of the work that you’ve been doing and your thoughts on this pathway?

KF: Right, thank you for asking me this question.

Obviously immunotherapy is big thing in oncology at the moment and for some years we thought that perhaps prostate cancer could be an exception, unfortunately.

Although we knew from the past that CTLA-4 targeting can work, at least on the individual level in these men with very long-lasting complete responses seen with ipilimumab, either alone or in combination with local radiation targeted at bone lesions.

But the first experiences that were reported with PD-1 or PD-L1 inhibitors in prostate were not that good and that was based on a very limited number of patients.

So there was no big development urgently in the first part of the 2010s. 

Then all of a sudden we had two reports, two years ago, in patients progressing after enzalutamide indicating that pembrolizumab seems to work with about, say, 20% of patients responding and sometimes responding tremendously.

Actually, some of these patients had MSI high cancers and so this is something we know more and more now, that these patients, regardless of their primary cancer, seem really to benefit from checkpoint inhibitors but actually not all of the patients with prostate cancer do benefit from these drugs.

So the big question now is how to identify those patients but also how to make sure that more patients can benefit from immunotherapy, not just, say, 20% of them.

So one big idea regarding the second question is whether a combination can make a difference.

There are at least two trials trying to marry the drugs with other compounds and I’m talking about PD-1 inhibition together with either chemotherapy, enzalutamide, or PARP inhibitors, depending on what the patient has received and hopefully in the future depending on his own cancer biology.

So these trials are obviously not mature, we don’t know the data, but they are rapidly accruing patients and hopefully we will have data soon.

But the concept is really interesting because in some models you are really able to boost the immune effect of these agents just by combining with something else.

Again, that can be chemotherapy, AR targeting, PARP inhibitor, either to the activity of the drug, PARP inhibitors, or also perhaps because we might select patients with DNA repair defect genes and perhaps those patients are also more likely to benefit from immunotherapy, not only PARP inhibition.

NS: It’s a great point.

I think you’re referencing some of the really nice work done by Julie Graff in that small population but who really responded remarkably who had progressed through multiple lines of therapy and then they received some pembrolizumab.

At this meeting she’s reporting on some additional follow-up.

But I think you really touched on the issue of taking a tumour that may be cold immunologically and perhaps changing it to become more receptive to a checkpoint inhibitor.

Could you maybe expound upon that for our colleagues, how that could happen?

KF: Actually it’s really hypothesis at the moment, to be honest.

It’s true that in most prostate cancers you don’t see too many lymphocytes around the tumour, although there are exceptions obviously.

So the hope is that really using another drug we will generate more, how can I call that?

More activity, in simple words, that will attract the lymphocytes around the tumour and then the lymphocytes will be able to kill cancer cells.

There are several models where that seems to be true.

All these drugs work in totally different ways but, again, a big part of this work is really hypothesis.

We may learn actually more than we expect and perhaps although our hypotheses are not the right ones and we will understand afterwards that these drugs do not exactly work the way we were expecting them to be.

For example, we don’t really know whether the story of patients benefitting just because they had seen enzalutamide is really due to enzalutamide or to the effects enzalutamide is doing to the AR or to something else.

So this is really a brand new field, probably many things to discover, but it’s really exciting because at least at the individual level again we do see responses and sometimes, as you said, in patients who have already exhausted everything.

So that’s really good for patients.

NS: So you touched on, and I think we began by noting, the use of the checkpoint inhibitors as having in a monotherapy approach after multiple lines of traditional approved therapies getting some level of activity.

Then combining, perhaps, a PARP inhibitor with an IO, but what about just the PARP inhibitors just as an additional line of therapy?

There are multiple companies now, just like there are multiple companies that have different IOs, there are multiple PARPs that are approved in other metastatic tumour sites.

What should our colleagues be thinking about now to treat advanced prostate cancer?

KF: The discovery that some prostate cancer men have either germline or somatic DNA repair defects is a really big one.

It’s really hard to know what the exact proportion of these men is and probably there are variations from country to country based on your genetic backgrounds and also the way that you are detecting that.

Also whether you are looking at monoallelic or bi-allelic abnormalities, generally speaking. 

But at least the subject is on the table and we know from the TOPARP phase II trial that at least one PARP inhibitor, olaparib, works also in patients, again, with very advanced disease.

So just that there is intense research at the moment with PARP inhibitors alone, with many, many open questions.

One is really should we select and maybe you don’t need to select actually, like in ovarian cancer where we realised that actually you don’t necessarily need to do that; in prostate it’s really something highly debated.

Another question, obviously, is if we have to select do we go for bi-allelic or monoallelic abnormalities?

Another one is are all these gene mutations or deletions the same, predicting the same?

Most of these patients have BRCA2 mutations but there’s also ATM, CHEK2 and many others; we don’t really know at the moment whether they predict for the same degree of efficacy for these drugs as BRCA2 does, or BRCA1 more rarely.

So all this really needs to be addressed because that’s really important for drug development for patients to benefit.

The good news is that, as you said, there is really currently intense research around that.

I know probably four or five compounds currently under development in phase II but also in phase III trying really to demonstrate their superiority versus standard of care including, mostly actually, in patients failing abiraterone or enzalutamide. 

So we can really expect more and more data, probably every six months or so we will get data to help us for the knowledge.

NS: Yes, it’s such a great time to be in the field, not only doing the research but also enrolling patients in these trials.

It creates a tremendous amount of hope for so many patients.

It’s really interesting when we look at the IOs, the checkpoint inhibitors, we have this ongoing controversy of how important is it to have PD-L1 or PDL ligand positivity or negativity?

Is it an all-comer trial? Do we have selection?

Likewise with the PARP trials, as you say, what is the role of bi-allelic, monoallelic and what are the different genetic mutational changes that could inform therapeutic efficacy?

So it’s a great time, I think, as you’re really masterfully pointing out the precision medicine goals that we all aim for, rather than throwing the kitchen sink at patients.

But let me switch over in the last couple of minutes to an area that’s also very exciting and different from the traditional AR pathway and that is PSMA testing and also theragnostic implications.

Maybe you’d like to talk about that?

KF: Sure.

We knew PSMA for a while in prostate cancer but until recently we were not really able to use this knowledge for either diagnosis or for treatment endpoints or goals.

So this is a protein, a transmembrane protein, that is expressed in most patients with advanced prostate cancer so it’s quite universal.

So that’s important, even if there is heterogeneity interpatient but also intrapatient from one metastasis to another one.

But still it’s quite broadly there.

So one obvious potential application that we can do is PET scanning and this is coming quite fast now.

It’s very, very likely that PET-PSMA is the best imaging for prostate cancer men that we have so far – better than PET-choline, probably at least comparable or maybe better than whole body MRI and for sure much better than the classical couple CT scan plus bone scan.

So this is arriving quite soon and actually this will set a new field because we will see much more than in the past and we will have to adapt all the current treatments according to new images.

For example, if you do bone scan, CT scan or other imaging you see nothing; you do a PET scan, all of a sudden it’s becoming an oligometastatic disease, how do you treat?

So there will be a field for research regarding that.

Perhaps even more important is PSMA as a potential target for treatment.

The first data reported by the Germans who were really probably the first to do that and then the larger trial reported by the Australians is really compelling.

Most patients, even in very advanced stages, when they were selected based on PSMA-PET positive cancers actually benefitted from lutetium PSMA targeting.

So I know that some companies are now running phase III trials but there are also other ways, perhaps, to target PSMA either with a different radioisotope, using an alpha emitter such as actinium, or with something else and this is also ongoing.

So it’s, again, a totally new field which is really exciting.

NS: Yes, you summarised it very well and it’s taking off on sort of an organic basis.

In Germany there are so many centres but you made a very good point that we’ve got to do these phase III trials to really get the level 1 evidence and get some standardisation about interpretation of just the PSMA scans, there are multiple different types.

This whole novel next generation imaging is bringing in our nuclear medicine radiology colleagues along with us so they’re adding a lot of fertile opinion and controversy to the field.

Then, excitingly, this theragnostics by bringing in a targeted alpha therapy, or in some cases even some beta particles, really seeing some dramatic improvements in patients who have blown through multiple lines of approved therapies.

So with that, I wish I had more time.

Thanks for all that you’re doing for advancing the field for patients, for the entire profession of medical oncology, urology, radiation oncology.

Your leadership is essential so thanks a lot, thanks for taking your time out here at ASCO 2018.

KF: Thank you very much Neal.