Triplet Delays Further Therapy Versus Doublet in Metastatic HSPC - Neal Shore

February 28, 2024

Neal Shore discusses the ARASENS trial's post hoc analysis, emphasizing the benefits of triplet therapy in advanced hormone-sensitive prostate cancer. This study adds to the evidence that combining ADT, docetaxel, and darolutamide significantly delays resistant disease development and extends survival. Dr. Shore highlights the shift away from monotherapy ADT towards comprehensive treatment strategies, including AR pathway inhibitors and chemotherapy, for better patient outcomes. With upcoming studies like ARANOTE and ARASEC set to read out, Dr. Shore underscores the importance of multidisciplinary approaches and ensuring patients progress to each evidence-based therapy line. This analysis reinforces the necessity of intensifying treatment to tackle the disease's heterogeneity and improve survival rates in metastatic hormone-sensitive prostate cancer.


Neal D. Shore, MD, FACS, Medical Director, GenesisCare, Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, SC

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

Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to be here at GU ASCO 2024, where I have the opportunity to speak with Dr. Neal Shore, who is a urologist at the Carolina Urologic Research Center. Thank you so much for being here with me today.

Neal Shore: Great. Thanks for having me.

Alicia Morgans: Well, it's always so nice to talk to you. And today, I really wanted to discuss a poster that you presented at the meeting that was reviewing the ARASENS data, but trying to look at it from different perspectives, really focusing on subsequent therapies. Can you tell me a little bit about it?

Neal Shore: Yeah, I'd be happy to. So, as everybody knows, who was involved in advanced hormone-sensitive prostate cancer, ARASENS was a really important trial because it set the stage now for triplet therapy, in addition to previous data from PEACE-1.

But in ARASENS, we looked at a combination for low- and high-volume patients, de novo recurrence, synchronous, metachronous, to get in one arm, ADT plus six cycles of docetaxel and darolutamide, the approved dose at nmCRPC, 600 milligrams twice a day, versus ADT/docetaxel. And the trial was overwhelmingly positive, both in delaying the development of resistant disease and also next antineoplastic therapy, and then most importantly, survival.

So in this post hoc analysis based upon EMA criteria, we essentially looked at really two things. The methodology is a lot more complicated, and I encourage folks to look at the poster, and we'll have a publication coming out, not in, fairly soon. But we looked at the uncensored patients and the numbers of deaths, as well as the censored patients who went on to get additional antineoplastic therapies.

The bottom line was that they still had the same robust P value and the statistically significant advantage of triplet ADT/doce/daro versus ADT/doce. And so, I think that in the concept of intensification for the right patient who is chemo eligible, that ADT/docetaxel/darolutamide is clearly a part of the shared decision-making conversation and a standard of care.

Alicia Morgans: Great. I think it's so important, as we think about our options for these patients, to really think about the history here, and ADT/docetaxel has been a combination that has been approved and has been really recommended for patients. Especially to really deal with the heterogeneous disease that we have, that may respond best to hormonal suppression, may also respond and require that chemotherapeutic. One of the things that I think is so important, and that came after the ARASENS data and PEACE-1, is that it's actually no longer recommended, in the NCCN guidelines at least, for us to give ADT and docetaxel without then giving an AR signaling inhibitor, either darolutamide or abiraterone.

I'd love to hear what you think about that, and how this kind of analysis, thinking about the next therapies, really comes into play as you're thinking about really intensifying using these multiple approaches to really get at that disease heterogeneity.

Neal Shore: Yeah, I think that's a great point. A very interesting observation that came forward by NCCN. I guess I think to myself where you don't have accessibility issues in terms of getting, whether it's ADT plus abiraterone, or ADT and enzalutamide, or ADT and apalutamide, there's still a lot of folks who may have that in other parts of the world. And docetaxel is still fairly ubiquitous, based upon its approval in 2004 for resistant disease. But I think as we start to see more biosimilars and generics, I understand why that recommendation was made by NCCN.

I'm really excited about the combination of also to add to that, our proverbial embarrassment of riches, ADT and daro without the docetaxel. And so, there are two really important studies that are going to read out in 2024, this year, probably within the next six to eight months. One is a global trial called ARANOTE, which is looking at ADT/daro versus ADT/placebo, conducted outside of the US for equipoise purposes. We'll have that readout sometime this year.

And then another study that was done, a big open-label study that I had the pleasure and the privilege to lead, called ARASEC. And that is a 200-patient open-label study, single-arm, ADT/daro for mHSPC patients. And we're doing a propensity-matched scoring with the control arm from the CHAARTED study, which compared ADT/doce to just ADT monotherapy.

So there's a lot of great opportunities and new things that are coming out. I think the really key thing is, monotherapy ADT is clearly not a standard of care for the overwhelming majority of our patients with low or high volume mHSPC, de novo or recurrent.

Alicia Morgans: Absolutely. And I always think it's important for us to emphasize that message.

And then as we wrap this up, I think this analysis is really thinking about getting patients to that next line of therapy. And there is some data that suggests that between each line of treatment, patients really fall out of the treated population. Up to half of patients may actually not move from one line to the next. How important is it in your practice to really get to that next line of therapy? How do you think about that? And I know you're thinking about it a lot, because you're thinking about subsequent therapies in this particular poster.

Neal Shore: Yeah. I think that's a very important point you raise. And I think there's a lot of learnings that I've seen over the course of my career. One is the importance of really amplifying the multidisciplinary team. And that keeps expanding. We historically just talked about the urologists, the medical oncologist, the radiation oncologist, but we're incorporating so many more people now to think about next lines of therapy. Getting genetic testing, involving the pharmacy folks for DDIs, nuclear medicine radiation, radiologists. Of course, all the allied healthcare personnel, which are so important.

But truly making sure patients don't fall through from getting everything that is level one evidence to optimize their care. We do have this incredible embarrassment of riches now. I think it's 13 or 14 life-prolonging therapies for advanced prostate cancer. But we still have some data that suggests that the overwhelming majority of patients in North America, the US, and Canada, will still have prostate cancer-specific mortality and only receive one therapy. Less than 50% receiving two. So there's work to be done, I think, at organizations like NCCN, and ASCO, and AUA, and SUO, and ESMO. These meetings, ASCO GU, AUA, ASCO, ESMO, they're really the cornerstones for getting that education out there.

Alicia Morgans: Absolutely. So as you think about this data that you've presented, which really again just solidifies the initial findings that adding darolutamide to ADT/docetaxel certainly is associated with a survival benefit. What would your message be to the listeners?

Neal Shore: My message would be, look, this is really important to have this sort of full-throated conversation that, okay, I just got diagnosed. I just got hit across the forehead. I've got metastatic cancer. My wife is very upset right now. My family's upset. I'm upset. How can I optimize care? And of course, we have to look at comorbidities. We have to look at concomitant medications and performance status, but what are all of my options? And it's no longer just, "I'm going to lower your testosterone." We've got to think about adding an AR pathway inhibitor as well as docetaxel, which is for the right patient. So it's just having that conversation and making sure that it's out there.

Alicia Morgans: Absolutely. Well, thank you so much for the work that you continue to do, and certainly for talking it through with me today. I really appreciate your time.

Neal Shore: Thanks.