Transcript:
Alicia Morgans, MD, MPH: Sandy, what are your thoughts are on the trial design, safety, and end points? Which of these is the most compelling to you? Or is there more than 1? What do you think is important about this study design that may set it apart from other trials that lead to treatment options in this space?

Sandy Srinivas, MD: One of the biggest questions in this field is who is docetaxel appropriate for? We’ve come to adopt ADT [androgen deprivation therapy] plus 1 of the AR [androgen receptor]–targeted drugs as the standard. But you’re still grappling with who would be best served with the addition of docetaxel. This trial, unlike other trials, looked at triplet therapy rather than dual therapy. That’s the first thing. As Matthew eloquently pointed out, this is the first trial where we don’t have rPFS [radiographic progression-free survival] as an end point; it’s overall survival.

We’re used to thinking about prostate cancer as high volume vs low volume. We didn’t see that in this trial. Instead, there was a surrogate about the division into M1a, M1b, and M1c. Visceral disease represented about 17%, so we have to tease that out to see how that’s applicable to patients we see today. Nevertheless, it reinforces the question: is there a group of patients for whom triplet therapy is appropriate? We’ve seen that with PEACE1 trial with abiraterone, ADT, and docetaxel. For a patient in my clinic, if they’re fit for docetaxel, the ARASENS trial becomes extremely relevant. Clearly, the hazard ratio for overall survival was so impressive. It’s another option. We can use either abiraterone or darolutamide in patients we think are chemotherapy fit.

Alicia Morgans, MD, MPH: That makes a lot of sense. I’m curious to hear from you, Scott. When you see patients in clinic, who are the patients you’re thinking of applying the ARASENS data or a triplet approach to?

Scott T. Tagawa, MD, MS, FACP: I agree with Sandy. The key part of it is docetaxel, and the comment I made before, that everyone should get more than 1 drug, is the main message. Some will benefit from 3 drugs vs 2, even though we have more of an indirect comparison when the 2 are ADT and an AR pathway inhibitor rather than ADT and docetaxel. Karim Fizazi showed the stepwise change in the hazard ratios in his presentation [of PEACE1]. They’re data but not direct level 1 data.

This is a patient population that wants to have the most aggressive therapy possible. I hope we have additional biomarkers—there may be some out there, but they’re not validated—on those who are more likely to benefit from a taxane chemotherapy than AR, or at least not AR alone. We’ve used them for CRPC [castration-resistant prostate cancer]. CRPC was simple: we had docetaxel alone. Then it became more complex, and we had multiple drugs. Now it’s like that here, but we always thought there was a subset where line 1 should be chemotherapy, generically maybe less AR driven, more visceral disease, etc. Certainly, I see those patients sometimes, and some patients warrant having the high escalation therapy. We have 2 data sets, but it’s clear that 3 are better than 2 when we look at ARASENS plus PEACE1. We’ll see, with longer follow-up and hopefully some meta-analyses, when we put the data together, that maybe we’ll be able to tease out who might benefit from different combinations.

Alicia Morgans, MD, MPH: That’s certainly a hope of mine as well. Evan, I assume you’re waiting for some biomarker-driven decision-making too. In the absence of that, how do you incorporate the ARASENS data into your clinical decision-making?

Evan Y. Yu, MD: That’s a great question. Obviously, we’re doing more next-generation sequencing. To your first part about the biomarkers, if we see DNA repair gene alterations, we’re considering PARP inhibitors. If we see mismatch repair alterations, microsatellite instability, or hypermutation, we might be considering I/O [immuno-oncology] therapies like pembrolizumab. But in the absence of that, the whole field of treatment intensification for metastatic castration-sensitive disease has made first-line metastatic castration-resistant prostate cancer a disease state where we need to work hard on new therapies.

We all recognize that sequencing novel hormonal therapies, like abiraterone, enzalutamide, etc, 1 right after the next generally doesn’t work for most patients. With that being said, changing the mechanism of action makes sense. With the likely upcoming availability of lutetium-177–PSMA-617, that may become an excellent therapy in that situation in patients who’ve already received androgen deprivation therapy, docetaxel, and either abiraterone or darolutamide. That’s something to look for. There’s obviously development of novel immunotherapeutics and bispecific antibodies. It’s a fruitful area, first-line metastatic castration-resistant prostate cancer disease state, and these new data will change how we sequence our agents for these patients.

Alicia Morgans, MD, MPH: I don’t think anyone will disagree with that. That’s for sure. Matthew, final words. How do you put the ARASENS data into the context of the PEACE1 and ENZAMET trials? Give us a message as we try to put it all together.

Matthew R. Smith, MD, PhD: Based on the data from ARASENS and the subgroup analysis of PEACE1, of those patients who received docetaxel, which is about half the patients in PEACE1, we have compelling evidence that the triplet of ADT-docetaxel plus an AR pathway inhibitor is at least superior to ADT-docetaxel. That’s unequivocal. We need not wait for data from the other trials. In fact, I’d be very loath to even try to interpret that data because, remember, in the trials other than ARASENS, docetaxel was not mandated. I guess for PEACE1 it was mandated in the latter group that were enrolled. But in the other trials, it wasn’t mandated. It was clinician choice.

That creates all kinds of challenges in interpreting that data, so I wouldn’t look to the maturation of ENZAMET or other trials to be either necessary or sufficient to provide confirmation because it’s a potentially flawed type of analysis. We have sufficient information that triplet therapy is better than the doublet, as described. The question that neither study was designed to answer is whether you need docetaxel if you’re giving ADT and an AR pathway inhibitor. Whether the field collectively has the will to take on such a randomized controlled trial remains to be seen, but it will be important.

Alicia Morgans, MD, MPH: That question remains to be answered, but the question that has been answered is that ADT alone is not the standard of care for treatment of these patients. Combinations—doublets or triplets—are the way to go. The data are there, and it’s time to make sure we get the patients the treatments they deserve. Thank you all for talking that through.

Transcript edited for clarity.