Enzalutamide Plus Talazoparib for the Treatment of Hormone Sensitive Prostate Cancer (ZZ-First) - Joaquin Mateo

March 8, 2022

Joining Alicia Morgans is Joaquin Mateo to discuss the ZZFIRST trial, examining enzalutamide and talazoparib for the treatment of metastatic hormone-naïve prostate cancer (mHNPC). Dr. Mateo presented the rationale and design for the ZZFIRST trial during the Trials in Progress Poster Session at the 2022 American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium.


Joaquin Mateo, MD, PhD, Medical Oncologist, Attending Physician, and Principal Investigator, Prostate Cancer Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, Dr. Joaquin Mateo, who's a GU Medical Oncologist at Vall d'Hebron. Thank you so much for being here with me today, Dr. Mateo.

Joaquin Mateo: Thank you. Thank you for inviting me.

Alicia Morgans: So, I wanted to talk with you a little bit about a trial that's ongoing. I think you have just a few more patients to enroll, the ZZ-First trial. Can you tell us a little bit about it?

Joaquin Mateo: Sure. This is an investigator-initiated trial that we've been running across 10 hospitals in Spain. As you say, we are very close to finish the recruitment. We're very excited. Also, I'm very excited because it's the first IAT that I run since I arrived to Barcelona.

This is a phase two trial. It's a randomized phase two trial where patients with metastatic, hormone-naive prostate cancer are getting either enzalutamide, or enzalutamide plus the PARP inhibitor talazoparib.

The trial has been running patients with high volume disease, and we are investigating the antitumor activity of the combination in an [inaudible] population. But at the same time, we are also pursuing an acquisition of serial biopsies for these patients to investigate the mechanics of synergy between AR innovation and PARP innovation.

Alicia Morgans: Wonderful! Now, one of the things that I think is so interesting about this trial is that all patients who have enrolled in the trial, metastatic, hormone-sensitive disease, are starting on ADT plus enzalutamide, and they have a period of treatment before they undergo randomization. Can you tell me why that is part of the design and why that's so important?

Joaquin Mateo: Patients start ADT and then within a month of starting ADT, they get into the trial. That's one of the differences with the other studies. Then, they get a month of enza, and at that point, we repeat the biopsy because one of the things we want to study is how AR innovation interacts with the [inaudible].

We want to look it from the transcriptional perspective, but also from the functional perspective with some masses that we've been developing in the lab. So we wanted to collect a second tumor biopsy after a month of ADT Plus enza.

Of course, we didn't know whether two weeks, four weeks or six weeks was going to represent better the biological effects. So we just made a call to give one month of enza and then patients are randomized to get the talazoparib to continue with a single agent enzalutamide.

Alicia Morgans: And that's so interesting. And really, I think speaks to the attention of this trial on the correlative studies. Can you run through your primary and other secondary and correlative study endpoints so that everyone has a sense of what you and the team are investigating?

Joaquin Mateo: So the primary endpoint relates to the antitumor efficacy of the combination actually is based on achieving a PSA complete response that is maintained after the year of treatment. So it's a similar approach to the definition of PSA, complete responses after seven months in the swap in the regional swap trials of intermittent AVT, correct.

But with a longer period, we know this is not an endpoint that will be valid. For example, for a registration, for a drug, but this is a phase two trial. We are trying to see if there is a signal for antitumor activity with a relatively limited time. We couldn't afford to wait for PFS and three to four years on these patients. But the strength of the study is on the correlatives and looking at a secondary endpoint for RNA signatures before starting the androgen innovation.

And after a month of androgen innovation, we're also looking for liquid biopsies over time, looking at the kinetics of ctDNAs and CTCs just when we started treatment. But also when the patient progresses, we are collecting again, liquid biopsies and also tumor biopsies to study mechanism resistance to this combination.

While this is a relatively small trial, we're talking on 54 patients here. We are randomizing patients with an estratification factor based on whether they do have, or do not have mutations in HR genes. So we aim that we're also going to be able to explore the activity in the two sub groups, even if we know that are going to be small.

There are other trials running in that space, like the telePRO-three trial, there is a global study of the same combination, but this is only in patients with mutations. So we hope to generate some data in the non-mutated patients that can and complement the other trials that are going on in that space.

Alicia Morgans: That's fantastic. I really think that, especially in the setting of the phase three trials that we saw at GU ASCO looking at combinations of an AR targeted agent and a PARP inhibitor, there's just such an eagerness to understand this combination better.

What is your or sense on the landscape? And of course, those were trials that were done in the metastatic CRPC setting, but how might this be applied in settings like this trial in the metastatic hormone sensitive setting?

Joaquin Mateo: Well, clearly if patients are getting novel hormonal therapies upfront in the or naive setting, this is going to affect the potential for synergies between two drugs that are meant to interact based on the capacity of enza [inaudible] or a whatever you're using to inhibit the [inaudible] Right?

So clearly this combination makes sense at the point where androgen innovation is going to be effective on the tumor. If [inaudible] are being used now earlier, we have to move these combinations earlier. The data that we saw last week is really interesting. Clearly there is an important effect in patients with mutations, but even in patients, without these mutations, the PROpel trials seems to suggest there is some efficacy.

What we don't know if these moderated efficacy are moderated efficacy for everyone, or is a big efficacy in certain biological context that maybe we don't understand yet. And this is one of the things that we want to study here by treating patients without these mutations, understand what's going on in the tumor at the transcriptomic, but also protein level. And whether that can help us explain who would be the patients that would benefit the most from these combination of therapies.

Alicia Morgans: Well, I think this is extremely exciting and I know that we will have to wait for probably at least another year and a half or so before we start to see some of this data. But it is so compelling, at least the trial design and the fact that you have nearly enrolled all of these patients already speaks to the excitement around this approach from your colleagues, from the field and certainly from the patients. So I thank you for putting this together and would love to give you a final word on ZZ first.

Joaquin Mateo: Well, so this trial is trying to understand when and in home to use the combination of enzalutamide and PARP innovation. We have invested lots of efforts in trying to collect good quality samples that would provide biological insights into the clinical activity of this combination. And if I may also say that this trial was run as an academic trial by 10 hospitals in Spain, while competing, if we can say that way with the big trials that we're running in parallel. So I'm really grateful for the collaboration of all the investigators and all the sites that were really committed to make this trial happen.

Alicia Morgans: It is a wonderful effort and I commend you. I commend your colleagues at those sites, and I certainly commend the patients of Spain for stepping up and engaging in this really exciting research. Thank you so much for your time and your expertise today.

Joaquin Mateo: Thank you very much, Alicia.