The AFT-19 Study: A Comprehensive Look at High-Risk Prostate Cancer Treatment - Rahul Aggarwal

November 17, 2022

Rahul Aggarwal speaks with Alicia Morgans about the completed phase III trial AFT-19 for high-risk biochemically relapsed prostate cancer patients. The trial explored three arms: ADT alone, ADT plus apalutamide, and a triplet of ADT, apalutamide, and abiraterone, with a primary endpoint of PSA progression-free survival. Results showed significant prolongation of PSA progression-free survival in both experimental arms, with more toxicity observed in the triplet arm. Dr. Aggarwal emphasizes the clinical significance of these results and indicates that doublet therapy, rather than triplet, appears preferable in this context. The interview also touches on challenges such as the COVID pandemic's impact on accrual, the importance of testosterone recovery, and the evolving role of imaging. The conversation concludes with the potential for intensified hormonal therapy for a finite duration in high-risk patients.


Rahul Aggarwal, MD, Assistant Professor of Hematology/Oncology, Director of STAND Clinic, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA

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

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Rahul Aggarwal of the University of California San Francisco. We are talking this morning about AFT-19, which is a phenomenal endeavor that you and the team at Alliance and the other cooperative groups who contributed really did such great work in. Can you please let us know what was the study design in this recently completed phase III trial?

Rahul Aggarwal: Well, it's great to be here and to be able to discuss the trial. This was a trial in patients with high-risk biochemically relapsed prostate cancer with a rising PSA after prior radical prostatectomy, and the majority had had prior salvage radiation. They were high risk based on their PSA doubling time, which had to be nine months or shorter for this study, and we know that's the patient population that's at higher risk for distant metastases and prostate cancer-related mortality.

And so we enrolled on the basis of that, and then patients were randomized to one of three arms, either ADT alone, ADT plus apalutamide or a triplet of ADT apalutamide and abiraterone with prednisone. In all three arms, patients were treated for a finite duration of 12 months and then stopped as part of an intermittent therapeutic framework that we often utilize for these patients. Primary endpoint was PSA progression-free survival, which we reported on ESMO, and then follow-up is ongoing to look at longer term endpoints such as metastasis-free survival.

Alicia Morgans: So just to start, this is a tough population, tough study design, tough to figure out the endpoints. What are your thoughts, how did you come to this design with the 12 months on, then the PSA endpoint, MFS? These are really hard conversations.

Rahul Aggarwal: Yeah, and it's been evolving. The imaging has evolved during the course of the study where you're seeing a lot more metabolic imaging, and that impacts how often do we detect distant metastases. It is challenging. There's always going to be a high screen failure rate for patients who have detectable metastases. We had about 25, 23, 25% screen fail rate, which is pretty consistent with the prior studies in this space, definitely makes it challenging when you're sort of thinking about the sample size that's going to be a valuable.

We chose a PSA-based endpoint just really for pragmatic reasons. How can we get a study done in a timely fashion without a sample size of over 1000 patients, so how can we accrue that? I'm  proud of the team. During the course of the study, we had the COVID pandemic hit and that certainly had an impact on accrual, but we were able to push forward and get the study fully accrued. And we are going to have follow-up ongoing to really capture that metastasis-free survival endpoint.

Alicia Morgans: And, again, just congratulations, no small feat to get a study done in this space, particularly during a pandemic. So what did you find?

Rahul Aggarwal: Yeah. The primary study results we report on ESMO were really the prolongation, statistically significant prolongation of PSA progression-free survival in both experimental arms compared to control. So we compared ADT plus apa versus ADT alone and then the triplet versus ADT alone. In both arms, we saw prolongation with a hazard ratio in the 0.5, 0.55 range for prolongation of PSA progression-free survival, which in the context of intermittent therapy and we're often making decisions based on drops and rises in PSA, I think can be argued that that's clinically significant.

Alicia Morgans: I would agree with that, and wonder, you had these two arms of the intensified strategy. It sounds like they both had a hazard ratio that was around 0.5 when compared to ADT alone. What do you take away from that?

Rahul Aggarwal: Yeah. I think the effect size was relatively similar and yet we saw more toxicity in the triplet arm, especially with hypertension. Nothing unexpected, but certainly just saw more toxicity with the triplet without really a significant impact on effect size. The study wasn't powered to compare between the two experimental alarms, but when you take the data we have coupled with the other triplet data that we've seen in the CSPC setting, I think it sort of lends support to the idea that triplet therapy doesn't really have a role here and really think about intensification in the form of a doublet, so ADT plus apalutamide in the case of this study.

Alicia Morgans: Okay. And that's helpful for patients to know too, I think, rather than taking 10 pills a day or whatever the combination would've been, to have one and one prescription is kind of nice.

Rahul Aggarwal: Absolutely, both from a toxicity and a financial toxicity standpoint; I think that's important.

Alicia Morgans: Yes. So can you tell me a little bit about how testosterone recovery was assessed and how important was that as you think through these PSA endpoints?

Rahul Aggarwal: Yeah, thanks for asking about that. That was really a key secondary endpoint, was looking at the time to testosterone recovery, as well as the PSA progression-free survival in the testosterone of valuable population, so how many patients recover their testosterone. We're pleased to say that majority recovered, and the time to recovery is actually similar across all three arms so that when we look at the population of patients who recover testosterone, the PSA progression-free survival was also prolonged in the experimental arms versus control, meaning that if you intensify ADT, give it for a finite period of time, you delay time to PSA progression without negatively impacting that testosterone recovery.

Alicia Morgans: I think that's so important and that actually leads to me is one of the key factors that means that, hopefully, fingers crossed, we're going to see that MFS endpoint really pushed back in this intensified group.

Rahul Aggarwal: Absolutely. I think we're aiming to see that. We're going to be following long enough so that we can capture those events. Obviously, the study's not powered around MFS, but I do think with long enough follow-up, we can hopefully have enough events to hit that. And the other thing I'd highlight is the patient-reported outcomes. We're going to be looking at that data both on treatment, as well as long-term follow-up, and that really gets a sense of that testosterone recovery and hopefully seeing that improvement in quality of life over time.

Alicia Morgans: Wonderful. Well, final question and then I'll let you sum it up. But the last question is, how does newer imaging come into play here? Are you capturing that on your case report forms? Is there a way to kind of at least think that through, because this has evolved, as you said, during the study?

Rahul Aggarwal: It absolutely evolved during the course of the study; most patients were enrolled on the basis of conventional imaging. We did from the outside allow PSMA PET imaging and other metabolic imaging modalities, and patients that had metastasis on those, but not on conventional imaging, were actually still allowed to enroll. And then during follow-up, we are capturing what imaging modality is basically being used to detect metastases. So it is being captured. We don't have it prospectively embedded in the study. What I would say is that with the metabolic imaging as we detect micrometastatic disease, we still need to think about that systemic therapy overlay. Even as we might think about metastasis-directed therapy for some of these patients, we still think that systemic therapy is important. We want to know what's the right ADT combination to use.

Alicia Morgans: I could not agree more. And I guess I lied, I have one more question.

Rahul Aggarwal: Sure.

Alicia Morgans: If they get another treatment, metastasis-directed therapy, start of systemic therapy, are you capturing that in event-free survival type of an endpoint?

Rahul Aggarwal: Yeah, absolutely. We are capturing time to subsequent therapy, and I think that'll be important in terms of that overall clinical benefit. If you can intensify therapy, give it for a finite period of time, can you delay the subsequent systemic therapy? I think that's what we think about in the context of intermittent therapy in this population, so that'll be a key secondary endpoint to look at.

Alicia Morgans: Great. So what is your final take home point, that final message on AFT-19?

Rahul Aggarwal: So, I think that intensification of ADT may have a role to play in biochemically relapsed patients who are at higher risk, who have a shorter doubling time. I think with longer follow-up and capturing metastasis-free survival, as well as reporting the patient-reported outcomes, I think we can build a strong case around intensification of hormonal therapy for a finite duration of time in these patients.

Alicia Morgans: Well, thank you so much for your time. Congratulations again to you, the team, and, of course, thank you to the patients who participated. Phenomenal work. Thank you.

Rahul Aggarwal: Thank you so much.