Andrea Miyahira: Hi. I'm Andrea Miyahira here with the Prostate Cancer Foundation. Here with me today at ASCO 2025 is Dr. Alexandra Sokolova, a medical oncologist from Oregon Health and Science University and also a 2022 PCF Young Investigator. Dr. Sokolova, thanks for joining us.

Alexandra Sokolova: Thank you for having me.

Andrea Miyahira: So Dr. Sokolova, you presented on a clinical trial, TRIPLE-SWITCH. Would you want to tell us about it?

Alexandra Sokolova: TRIPLE-SWITCH is a clinical trial that just recently got activated among multiple United States and Canadian sites. And it's designed to answer the question, how to better treat patients with metastatic hormone-sensitive prostate cancer.

In the last five years, we've learned that treatment densification improves the outcomes. We've learned that the AR pathway inhibitor with ADT (Androgen Deprivation Therapy) is better than ADT alone. We learned that docetaxel plus ADT is better than ADT alone. We now know from ARASENS and PEACE-1 that triple therapy with chemotherapy is better than ADT and docetaxel alone. But what we still don't know is what are the added benefits of docetaxel. Because it hasn't been compared to ADT and AR pathway backbone.

So our trial is trying to close this gap and try to identify which patients would benefit from docetaxel in metastatic hormone-sensitive setting.

Andrea Miyahira: And can you describe the design of the study?

So patients in this trial have metastatic hormone-sensitive prostate cancer. They need to have PSA at least five at the time of diagnosis. They need to be on ADT 6 to 12 months and on AR pathway inhibitor at least four months. And that's any AR pathway inhibitor. And their PSA needs to be 0.2 or higher.

And they get randomized to either continuing ADT and AR pathway inhibitor. The same treatment they were on for standard of care, or docetaxel added to ADT plus AR pathway inhibitor. And they get six cycles of docetaxel, kind of similar to what we do in ARASENS or PEACE-1. And then they continue after they're done with the six cycles of docetaxel. They continue ADT and AR pathway inhibitor.

And we're looking for overall survival as our primary endpoint. We are anticipating that additional docetaxel to those who don't get this undetectable PSA of less than 0.2 response would improve overall survival for those patients who have worse outcomes.

Andrea Miyahira: And what proportion of patients with metastatic hormone-sensitive prostate cancer don't do well on ARSIs and ADT?

Alexandra Sokolova: So the eligibility criteria for our clinical trial is metastatic hormone-sensitive prostate cancer patients who start ADT and AR pathway inhibitor, and any AR pathway inhibitor, is abiraterone, enzalutamide, apalutamide, and darolutamide. 6 to 12 months on ADT and at least four months of AR pathway inhibitor, their PSA should be 0.2 or higher, and they become eligible.

And we chose this PSA threshold because we know that folks who have very low PSA, kind of undetectable PSA, at 9 to 12 months on AR pathway inhibitors do much better versus those who do not achieve this PSA threshold. They have worse outcomes. It started from Hussain data, SWOG 9346, where we show that PSA seven months was a very strong prognostic marker. And we now have multiple randomized clinical trials-- LATITUDE, TITAN, ARCHES-- that show that this kind of PSA response at around six months is very prognostic.

About 50% of patients do not achieve this prognostic, undetectable PSA. And those who don't achieve it, their median overall survival is about three years. And if you look at the curves, they're quite different.

Andrea Miyahira: And where is this trial being conducted, and how many patients have you enrolled so far?

Alexandra Sokolova: So this trial is activated through cooperative group trials. It's SWOG and CCTG combined trial. It activated multiple sites in the United States and Canada, and we just randomized our first patient. So there is still a lot of room to go in the beginning of our journey, but we're really excited about enrolling in our trial.

Andrea Miyahira: OK. Thank you. And tell us more about how PSA functions as a prognostic biomarker in this setting.

Alexandra Sokolova: So as we discussed earlier, the PSA has been proven to be prognostic at a 6- to 12-month. And we've seen it in multiple trials and patients. Basically, the lower your PSA response, the better outcome is. And at this ASCO, Michael Ong is presenting some data from IRONMAN. And he showed that even if you go lower-- PSA 0.2 versus 0.02-- there is still a difference in outcomes. So it does look like the lower your PSA response, the better you do.

So the PSA 0.2 is your biomarker of prognostic response, has been proven in several trials to be-- if you achieve that, a better prognostic marker versus if you don't achieve it, showing early castration resistance, worse overall survival.

Andrea Miyahira: OK. Thank you. And are there any correlative studies planned or other questions that you're seeking to answer in this trial?

Alexandra Sokolova: So we are going to be collecting ctDNA data. And we'll be collecting tissue. And we'll be looking at circulating tumor DNA of those patients at the time of enrollment. Those who don't achieve this undetectable PSA threshold. We'll be looking at the first cycle of docetaxel after completion of treatment and at the time of progression.

So we're hoping to see if there's also earlier ways to know if docetaxel is actually adding benefit. Can we look at circulating tumor DNA? Can we look at molecular signatures to identify those patients who are more likely to respond?

Andrea Miyahira: And so treatment of metastatic hormone-sensitive prostate cancer has been in the news recently because of former President Biden's recent diagnosis. So what should clinicians be informing their patients about when it comes how to diagnose and treat this disease state?

Alexandra Sokolova: Metastatic hormone-sensitive prostate cancer, at this point is not curable, but very treatable. The overall survival to metastatic prostate cancer is a median between five to seven years, and we have now multiple tools to treat it. Most treatment starts with hormone suppression with androgen deprivation treatment plus AR pathway inhibitors.

There is data where using triplet treatment with docetaxel and docetaxel in the beginning, but it's not clear who should be getting the triplet treatment early on versus those who should be just getting doublets. And I think a lot of physicians struggle with these decisions with their patients. And so our trial is asking a question-- can we postpone this decision and, versus asking it early on, use patient response and personalize this decision to the patient?

So we know that some patients are going to have early castration resistance and will progress within the first year and most likely with TP53, RB1, PTEN. We know that there are patients who do well, and they will be undetectable PSA on monotherapy for years and years, and most likely have some sort of mutation or very kind of AR-driven disease. And we want to not treat those who don't need treated, and spare the treatment, improve their quality of life, and intensify treatment for those who likely do worse.

And so the TRIPLE-SWITCH is kind of uniquely positioned because we're using this patient response at six months before the progression to personalize the decision to intensify treatment versus not.

Andrea Miyahira: OK. Thank you. And do you have any final take-home messages for our viewers?

Alexandra Sokolova: We're really excited about the study. This is a very important study that's going to answer a question about intensifying treatment for metastatic hormone-sensitive. Please consider it for your patients. Consider opening for your sites. And I want to say thank you to PCF for supporting me as a Young Investigator.

Andrea Miyahira: Thank you so much also.