Neeraj Agarwal: Hi. My name is Dr. Neeraj Agarwal. I am here to welcome the PIs of a new, exciting phase III trial in metastatic hormone-sensitive prostate cancer. In my view, this is probably the first treatment escalation trial based on the PSA response, which is great for our patients.

So here we have the PIs-- Doctor Sasha Sokolova, assistant professor at the University of Oregon, Doctor Michael Ong, associate professor at the University of Ottawa, and Dr. Tanya Dorff, professor of medicine and oncology at the City of Hope. Welcome to all of you.

Michael Ong: Thanks for having us.

Alexandra Sokolova: Thank you. Thank you, Doctor Agarwal, for having us today. I'm really excited to discuss our clinical trial today, which is titled TRIPLE-SWITCH, a randomized clinical trial for the addition of docetaxel to androgen receptor pathway inhibitors in patients with metastatic hormone-sensitive prostate cancer with suboptimal PSA response.

This is a joint CCTG and SWOG trial through the CTAB group. So we have a lot of advancement in how we treat metastatic prostate cancer. We now know that AR pathway inhibitor and ADT is better than ADT alone.

We know that AR pathway inhibitors and ADT and docetaxel is better than docetaxel plus ADT. However, we're lacking a phase III trial randomizing metastatic hormone-sensitive patients to ADT plus AR pathway inhibitor versus ADT plus AR pathway inhibitor and docetaxel.

So I think the question remains, who should get docetaxel upfront and what is the benefit of added docetaxel to ADT and AR pathway inhibitor? And that's the question our clinical trial will be addressing.

We know that patients with metastatic hormone-sensitive prostate cancer have heterogeneous outcomes. There are cancers that have bad biology, often with PTEN, RB1, or TP53 alterations, that have quick resistance and have poor outcomes. There's also patients that have cancer that's AR dependent. For example, patients with tumors with SPOP mutations, and they have very prolonged and durable responses.

On the bottom, you see a graph from a STAMPEDE control arm on patients on ADT. And you see that there is a subgroup of patients that were highly sensitive to hormonal treatment, and they developed no resistance for over seven years.

There is also a cohort of patients that develop resistance within a year. And so those tumors are more aggressive. They're faster to develop resistance. And those are likely the ones that will have the most benefit from early intensification and early use of docetaxel.

So TRIPLE-SWITCH uses PSA response as our biomarker to choose the patients that are eligible for intensification with docetaxel. Why did we choose this biomarker? PSA is a cheap and widely available biomarker. We also know that detectable PSA while on ADT and pathway inhibitors is evidence of early castration resistance and a poor prognostic marker.

On the bottom, you see overall survival curves for TITAN trial that used apalutamide, ARCHES that used enzalutamide, LATITUDE that used abiraterone, and real-world data. And you see the top curve is overall survival of patients who had PSA response of less than 0.2 at six months, and the bottom curve is those who did not achieve the PSA response.

So patients who did not have a PSA response of 0.2 or lower had worse overall survival, worse outcomes, and the median overall survival was around 36 months. So those are patients that could potentially benefit from intensification with docetaxel.

On the other hand, those from the kind of top curve population, those who had this PSA response are likely the ones that would do good without chemotherapy and might not need intensification with chemotherapy and could avoid those additional side effects.

So TRIPLE-SWITCH is uniquely positioned in our disease space. When we think about our metastatic hormone-sensitive cancer patients, when we see them for the first time, we think of what treatment we're going to start them on. Are we doing a doublet, are we doing a triplet, and which AR pathway inhibitor we're using?

We start them on treatment. And then the next time we're thinking about treatment change is when we see evidence of castration resistance. Well, TRIPLE-SWITCH is going to enroll patients before the signs of castration resistance. We can enroll the patient between 6 to 12 months after start of ADT, and at least four months of AR pathway inhibitors, for those who do not have this PSA response of 0.2.

So we're using this treatment response data to identify patients with this worse prognosis, the ones that are likely to develop castration-resistant earlier, to randomize them to additional docetaxel or not.

So this is the TRIPLE-SWITCH CCTG-PR26 design. Our study population is metastatic hormone-sensitive prostate cancer. Any volume, any risk. They need to be on ADT for at least six months, no longer than 12 months. They need to be receiving AR pathway inhibitors for at least four months. And any AR pathway inhibitor is allowed-- abiraterone, enzalutamide, apalutamide, or darolutamide.

They need to have a PSA at least five at the time of ADT start and PSA of at least 0.2 at the time of trial enrollment. They need to be docetaxel-naïve and docetaxel eligible. So at that point, the patient will be randomized to continuous standard of care, which is ADT and AR pathway inhibitors, or be randomized to intensification with docetaxel.

They will continue ADT, continue the AR pathway inhibitor that they were on before the start of the trial, plus they will get six cycles of docetaxel. Patients will be stratified based on their PSA at the time of enrollment, 0.2 to 4 versus above 4, AR pathway class, presence of liver metastasis, de novo or recurrent disease, and time on ADT—six to nine months versus nine to 12 months.

As far as the metastatic hormone-sensitive eligibility criteria, patients need to have evidence of metastasis on conventional imaging at the time of enrollment. So at the time of enrolling patients, we'll be doing standard imaging, and as long as they have evidence of metastasis at that time point, they would be eligible.

Our primary objective is overall survival. We'll also be looking at secondary objectives such as PSA progression, PSA response, PSA kinetics, PSA 90 decline, PSA less than 0.2, PSA less than 0.02, clinical progression-free survival. And we'll be collecting and analyzing circulating tumor DNA and archival tissue. And this phase III trial will be enrolling a total of 830 patients.

This is the treatment evaluation schedule. And when we designed the clinical trial, we had a pragmatic design in mind. We really wanted to utilize standard-of-care treatments and wanted to minimize any additional visits or study assessments to make it easier for both patients and sites.

So if you see, patients are seen every three weeks at the time of docetaxel administration. So for the first 18 weeks, we have every-three-week visits. But after that, the visits are only every 12 weeks, with the only study-required assessments being survival status, PSA, and some circulating tumor DNA sample collections.

The rest of the patient care is the standard of care. We do not have any imaging that is required by the study. So the imaging will be based on physician assessment.

So in summary, TRIPLE-SWITCH is a pragmatic study answering an important clinical question of which patients will benefit from docetaxel intensification.

It addresses a patient population with poor outcomes and worse overall survival. It uses standard-of-care treatment. And I would love for you to consider offering this trial for your patients. If you need any information, please feel free to reach out to myself, Dr. Ong, or the SWOG general email. Thank you.

Neeraj Agarwal: So this is a great design based on PSA responses. So Tanya, let me ask you first why it is important to intensify the treatment further in those patients who do not achieve a PSA level of less than 0.2.

Tanya Dorff: So what we've seen across all the studies in metastatic castration-sensitive prostate cancer is that this is a very powerful biomarker that tells us which patients are not going to do well. So we can debate about doublets and triplets right up front, but we know we would be over-treating some patients who actually do respond very, very well to doublet therapy. And there are serious potential toxicities of docetaxel.

It's a great drug, but we only want to use it in people who really need it and can benefit from it. So this study is going to ask a very important question that we've already been debating in a very rational way, by using not just some predictive or prognostic marker, but truly a phenotype.

This patient's cancer is exhibiting inadequate response and it's showing us that the survival will be shorter. And so right now, we don't have anything to offer those patients. We just continue their therapy even though we know they're not going to do as well.

This study, if it's positive, could open the door to having a different conversation with the patient. We're six months in and I'm just seeing that your cancer isn't responding as well, and now I can say that adding chemotherapy here versus just waiting for the cancer to grow and spread will extend life or delay the time to symptoms. And I think those are all really worthwhile goals for patients.

Neeraj Agarwal: Absolutely. I agree. So Michael, when should we be looking at those PSA levels? Say I have a patient who I start on ADT plus, say, abiraterone, and I want to know whether my patient may be eligible for this trial. So what are the PSA values? After how many months after starting them on ADT plus, say, abiraterone?

Michael Ong: Yes. So we know that a lot of our decisions for our patients are made in those first six months of their androgen deprivation therapy. They're put on androgen deprivation therapy and then there's a talk about intensifying agents, and there are so many to choose from. And there's even talk of whether a patient could benefit from triplet.

But once those decisions are made in our trial, patients that get ADT and ARPI, they should have received at least six months of ADT to be considered and at least four months of ARPI to be considered.

We wanted a minimum exposure to really understand, like, OK, if there's still a detectable PSA, that they've had enough exposure to those drugs to say there's some evidence of potential resistance. We'll be highlighting some data actually at ASCO about how the PSA kinetics are, when they get to under 0.2 or over 0.2 between 6 to 12 months, because that is an important point.

But I think that when you're thinking about this trial, right when you're intensifying them with the ARPI, you should be thinking about, has my patient achieved an optimal response or is it suboptimal? And if they've had four months of ARPI, their PSA is still high, somewhere between 6 to 12 months after ADT, they're eligible for this trial.

And I think it's an important discussion for a patient. Docetaxel is something that is going to be offered sometime during the disease course of this patient anyways. So again, like Doctor Dorff has said, why are we waiting until there's obvious resistance? Why not tackle this earlier on? And we think that there's going to be patient buy-in for that approach.

Neeraj Agarwal: So six months of ADT and at least four months of an ARPI, and if PSA is not dropping to the undetectable levels, then this trial may be applicable to those patients.

Michael Ong: The nice thing is that it's any of the agents, right? Abi, darolutamide, enzalutamide, and apalutamide. So it's pragmatic and there's a lot of choice there.

Neeraj Agarwal: Thank you. Sasha, thank you for-- thank you to all of you for keeping the design so simple and the calendar. Whenever I look at the study calendars and see hundreds of tests, that discourages me.

I see here it's a very pragmatic, very real-world-like clinical trial where there are minimal requirements for extra testing, and patients are going to be followed the way they would have been followed if they were not on the trial.

For our patients and clinicians out there in the real world and in cancer centers like us, can you please summarize the eligibility criteria? Two most important eligibility criteria beyond PSA levels?

Alexandra Sokolova: Sure. So we commented briefly on the requirement for metastatic disease. And the question has come up, what if a patient had only PSMA-PET at the time of metastatic disease diagnosis? And that's OK, as long as patients still have metastases on conventional imaging at the time of enrollment.

They need to have a PSA of at least five at the time of ADT start and a PSA of 0.2 at the time of enrollment. We want to make sure that they have castration levels of testosterone, testosterone less than 50, and that they are candidates for docetaxel chemotherapy.

It's also important to highlight that we allow ECOG performance 0 to 2. Patients need to have adequate bone marrow and organ function to be allowed to receive docetaxel. We are looking for patients who are likely to develop castration resistance early, but we don't want to see any evidence of disease progression at the time of enrollment.

So the trial does not allow any clinical, radiographic, or PSA progression on current ADT and AR pathway inhibitor treatment. Protocol allows for a little bit of PSA fluctuation. But if we see the PSA is rising or there is evidence of some sort of progression on imaging or clinically, we don't want to enroll those patients because they likely do need a change of treatment, and randomizing them to the standard arm would not be a fair thing to the patient.

So the most important parts of the trial are the timeline of the treatment, 6 to 12 months of ADT, at least four months of AR pathway inhibitor. We want a PSA of 0.2 or higher, and we want evidence of metastasis on conventional imaging and no signs of progression.

Neeraj Agarwal: Thank you, Sasha, for outlining the criteria so simply and so well. So Tanya, if I have a patient and if I'm not a SWOG site or a CCTG site in Canada, who should I be contacting to allow my patients to go on this clinical trial?

Tanya Dorff: We hope that this study will be available broadly. SWOG has an extensive network of community oncology sites through NCORP, but also our partners at ALLIANCE and ECOG-ACRIN will have access to this study. So it's hoped that really almost every oncology practice would have access to a study location relatively near them.

Neeraj Agarwal: That's great. So just to summarize, we have a trial for the first time which allows our patients to further intensify the treatment with a drug which is widely available and is quite inexpensive if they do not achieve an optimal response to ADT plus an ARPI. Congratulations to you all for starting this trial, and I really hope you all the best.

Michael Ong: Thank you so much, Neeraj.

Alexandra Sokolova: Thank you so much for having us. We're really excited about different sites and patients joining our trial.