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PRESTO Trial Final Results for High-Risk Biochemically Recurrent Prostate Cancer - Rahul Aggarwal

November 21, 2025

Zachary Klaassen is joined by Rahul Aggarwal to discuss final results from the PRESTO trial evaluating treatment intensification for high-risk biochemically recurrent prostate cancer. The trial randomized approximately 500 patients with PSA doubling time under nine months to ADT monotherapy, ADT plus apalutamide, or ADT plus apalutamide plus abiraterone for 52 weeks. Dr. Aggarwal presents long-term follow-up data demonstrating that both experimental arms prolonged PSA progression-free survival and metastasis-free survival compared to ADT alone, though the triplet regimen did not meaningfully improve outcomes over the doublet while adding toxicity. The conversation contextualizes PRESTO alongside EMBARK, noting important differences. Dr. Aggarwal emphasizes that both trials support combination therapy as standard of care for high-risk biochemical recurrence, with the caveat that PSMA PET imaging now identifies low-volume metastatic disease in many patients who would have enrolled in these conventional imaging-based trials.

Biographies:

Rahul Aggarwal, MD, Medical Oncologist, Associate Professor, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA



Related Content:

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ESMO 2025: Discussant – EMBARK and PRESTO Trials

ASCO 2024: HRQoL Results from PRESTO (AFT-19), a Phase 3 Randomized Trial of Intensification of Androgen Blockade in Patients with High-Risk Biochemically Relapsed Castration Sensitive Prostate Cancer

ASCO 2024: Discussion: Living Your Best Life on Treatment

Read the Full Video Transcript

Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. Delighted to be joined on UroToday by Dr. Rahul Aggarwal, who is a medical oncologist at UCSF. Rahul, thanks so much for joining us on UroToday.

Rahul Aggarwal: Yeah, my pleasure to be here.

Zachary Klaassen: So you presented some great data at ESMO looking at PRESTO. This was a late breaking abstract and we've heard a lot about PRESTO over the last little bit, but before we get into the trial, maybe just tell us why we should be treatment intensifying high-risk biochemical prostate cancer.

Rahul Aggarwal: Yeah, absolutely. I mean, I think that when you look at patients with biochemical recurrence, it's really important to risk stratify. And those patients with a short PSA doubling time, nine months or less is sort of our typical cutoff. They're certainly at higher risk for distant metastasis and prostate cancer related mortality, hence the desire to ask that question, does treatment intensification improve outcomes?

Zachary Klaassen: Yeah, absolutely. I think I always thought too, this is not the 82 year old guy with a PSA doubling time of 36 months, this is that tight, high risk patient. So on that background, maybe tell us about the PRESTO trial design.

Rahul Aggarwal: Absolutely. So this was a randomized open label study. There are three arms. So the control arm was ADT monotherapy. The first experimental arm was ADT plus apalutamide, one of our AR antagonists. And then the third arm was really testing that triplet question of ADT plus apalutamide plus abiraterone given with prednisone. In all three arms, patients treated for a finite period of 52 weeks. And then in the absence of progression, treatment was stopped, patients were followed until PSA progression, which was the primary endpoint.

Zachary Klaassen: Excellent. And what were the key results? I know we've had some previous data, but this was the final results presented at ESMO for the trial.

Rahul Aggarwal: That's right. So previously we presented the primary analysis, which was PSA progression-free survival, both experimental arms prolonged compared to control. Didn't look like the triplet did much better than the doublet, although the study was underpowered. This ESMO, we presented the secondary endpoint analysis. This is the long-term follow-up for metastasis-free survival, time to castration resistance, as well as time to subsequent therapy we looked at as a post-hoc analysis.

Zachary Klaassen: Awesome. And what were the key findings from those endpoints?

Rahul Aggarwal: Yeah, absolutely. So we looked at metastasis-free survival. We did a pragmatic definition of looking at either conventional or PET-based detection of distant metastasis, just reflecting the changing standard of care. We found that both experimental arms did seem to prolong MFS compared to the control arm of ADT monotherapy, but the study was relatively underpowered to really detect that difference. There was still less than 50% of events amongst the patients randomized, but nevertheless showed a benefit there. And then we also saw a prolongation in time to castration resistance and time to subsequent therapy. Similar to the primary analysis of PSA PFS, the triplet didn't seem to really improve outcomes compared to the doublet and added toxicity.

Zachary Klaassen: Excellent. So we take this all into context, we were talking off camera a bit about some of the differences between EMBARK and PRESTO. I want to get you to highlight that because I think it's important for our listeners, but also just, we saw EMBARK OS data now at ESMO as well. How does PRESTO fit into that landscape?

Rahul Aggarwal: Yeah. I mean, thinking EMBARK is a really impressive phase three study. Some important differences there.

Zachary Klaassen: Sure.

Rahul Aggarwal: With EMBARK, this was placebo controlled. Metastasis-free survival was the primary endpoint. It was a larger study. It was about 1,100 patients. PRESTO was about 500 patients. EMBARK used retreatment at the time of progression. And I think all those factors really enhanced the treatment effect and really impressive overall survival data that Steve Freedland presented. That being said, I think both studies really provide good data that in this high risk biochemically relapse population, combination therapy should be the standard of care. And then if you have two clinical trials, now really supporting that.

Zachary Klaassen: Do you make any difference between your population of just radical prostatectomy recurrence and then EMBARK at RP and XRT? Is there any difference where you just basically take them as the same?

Rahul Aggarwal: Yeah. I think for the context of thinking about biochemical recurrence, we sort of think about maximal prior pelvic therapy. And about 90% of our patients had salvage or adjuvant radiation treatment. So actually, the vast majority had had prior radiation. I really think about once you've gone past that salvage setting, past pelvic therapy in the higher risk biochemical relapse, you're really talking about similar patient populations, short doubling times.

Zachary Klaassen: Fair enough. Before we finish up, I want to get your take on a lot of these trials started occurring before PSMA PET was kind of ubiquitous. And I liked you leaned on the fact that some of these patients were having PSMA PETs. Now everybody's getting a PSMA PET. So how do we take both PRESTO and EMBARK into context of what we're seeing in the clinic on Monday?

Rahul Aggarwal: Yeah, absolutely. I think that's the key question because I mean, both studies enrolled patients based on no distant metastasis on conventional imaging. And now of course we use PSMA PET on pretty much every patient with biochemical relapse. I think if you think about recurrent prostate cancer as a spectrum in terms of the volume of disease, the median PSA at entry of PRESTO was 1.8, above five in EMBARK. Undoubtedly, a lot of these patients would've had lesions on PET. And what it tells us is even in that low volume setting, when you're going to start systemic therapy, it should really be combination therapy. What neither trial really tells us is what's the role of metastasis-directed treatment. I think that's a key question. And then are there non-ADT treatment approaches that we can use? Also, an important question.

Zachary Klaassen: I think, and this isn't a thing, but I think about it this way, is that there's maybe a PSMA ultra low volume hormone sensitive metastatic prostate cancer. And like you said, we would probably find lesions on these patients, but the drugs clearly work in that disease space.

Rahul Aggarwal: Absolutely. Absolutely. There are still patients that really fit that M0 biochemical relapse setting.

Zachary Klaassen: Great conversation. Thanks for highlighting PRESTO. Any quick take home messages, conclusions, anything we haven't hit on?

Rahul Aggarwal: I think those are the key things. Combination hormone therapy works in this setting.

Zachary Klaassen: Awesome. Thanks so much for joining us.

Rahul Aggarwal: Yeah, my pleasure.