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Doublet or Triplet Androgen-Deprivation Therapy Options for Metastatic Prostate Cancer

This is Part 2 of Updates in Prostate Cancer, a four-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

In this video, Drs. Celestia (Tia) Higano, Julie Graff, and Neal Shore discuss doublet and triplet androgen-deprivation therapy options for metastatic prostate cancer. The patient is a 71-year-old man with metastatic prostate cancer, a PSA of 275, and a positive bone scan, who has begun to receive androgen-deprivation therapy. The faculty discuss what, if any, additional therapy they might add to this patient’s treatment regimen, weighing the current doublet and triplet combination options for metastatic hormone-sensitive prostate cancer. They review the results of the recent PEACE-1 and ARASENS trials and emphasize the importance of assessing bone mineral density and of encouraging genetic counseling for these patients.


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Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.
Dr. Higano: Hello, welcome to The ASCO Post Roundtable Series on Updates in Prostate Cancer. My name is Tia Higano. I'm an adjunct professor at the Department of Urologic Sciences at University of British Columbia, formerly University of Washington, and joining me today are two of my colleagues and they'll introduce themselves. Ladies first. Dr. Graff: Thank you, Tia. My name's Julie Graff. I'm a medical oncologist at the Knight Cancer Institute at OHSU as well as the VA Portland. Thank you. Dr. Shore: Yeah. Hi everybody. I'm Neal Shore. I'm the chief medical officer for urology and surgical oncology for GenesisCare US, and the medical director for Carolina Urologic Research Center in Myrtle Beach, South Carolina. It's a great pleasure to participate on this roundtable today with both Tia and Julie. Dr. Higano: Thanks, Neal. Today, we're going to be discussing recent updates in prostate cancer and integrating these new developments in four patient case studies. Our second case will focus on a patient with metastatic prostate cancer receiving androgen deprivation therapy. This is a case of 71-year-old man, who presents with a PSA of 275 and a positive bone scan. He has no prior history of prostate cancer. ADT, androgen deprivation therapy, is started. So now the question is, what should we do next? Do we offer this patient ADT alone, intermittent ADT, ADT and docetaxel, ADT and abiraterone, ADT and apalutamide, or ADT and enzalutamide? Any of those phase 3 trials that have shown survival advantage. And then I guess, let me just ask, where you would start, Neal? Dr. Shore: Well, there's just abundant level I evidence now, that combination therapy since 2017 to now for high-volume patients -- I'm going to assume this patient's high-volume -- defined by four or more bone lesions or visceral metastases, would benefit from six cycles of docetaxel in combination with ADT or one of the oral androgen receptor access drugs: the abiraterone, apalutamide, enzalutamide. There's just wonderful global phase 3 trials that have demonstrated the value of these oral therapies. I think that I would clearly have that discussion with this patient unless he was just so frail and had such poor performance status, because the data is overwhelming. And I think the sad part is, despite this overwhelming abundance of great trials and in all the guidelines -- I don't think there's a guideline that doesn't incorporate it, NCCN, ASCO, for sure, AUA, ESMO, EAU -- that we still see a tremendous amount of our colleagues who just give monotherapy ADT, watch the PSA go down, and declare victory, which is a false victory. So I would say absolutely, it is the standard of care to offer this patient combination therapy in 2022. It certainly was really since 2018 onward. Dr. Higano: Right, I want to ask you Julie, because I think you see primarily a population of veterans, right? And I was in the VA for eight years, myself, these guys are hard to crack sometimes. What kind of discussions do you have with them? You can understand they'd maybe push back discussion about chemo and then other drugs that can add insult to injury in terms of side effects. Do you have men who actually refuse to do a double therapy and why? I'm just curious. Dr. Graff: Thanks, Tia. This is a very timely question because I met a new patient yesterday who has active CLL on ibrutinib, and apparently there's a drug-drug interaction between enzalutamide and ibrutinib. So he went on abiraterone/prednisone plus ADT. And he has very brittle diabetes, refuses to take treatment for that. So his blood sugar is in the 500s, even with 5 mg of prednisone. And then he refused chemotherapy. Fortunately, darolutamide doesn't have a drug-drug interaction, so we're going to apply for that. But I guess what I do is, I think people who are newly diagnosed with metastatic disease are pretty overwhelmed. And so I try to just break it down and just start with the ADT and make another appointment for them to come back. And we talk about the second treatment. There are still a lot of questions about -- I think I agree with Neal that the only wrong answer is ADT monotherapy, unless there's a real compelling reason for it. I think that the data, and we're probably going to talk about it, we are going to talk about it, is even leaning toward not just ADT plus a hormonal agent or chemo, but maybe all three. So we know that more powerful therapies upfront help people live maybe a year longer than when they're given in a much later prostate cancer setting. Dr. Higano: Yes. And that's exactly where I was going to go next because at ASCO GU and at ESMO last fall, we heard data about two triplet combinations with ADT/docetaxel. And in the sense of the ESMO trial, we heard PEACE-1 from Karim Fizazi. And then the ARASENS trial more recently at ASCO GU looking at the combination with darolutamide. So, we know that in the PEACE trial, they were actually able to report overall survival, whereas ARASENS hasn't quite reached that yet, yet there's very impressive radiographic progression-free survival advantage at four years. Julie, how do you think your patient would take to talking about triplet therapy? Dr. Graff: That person would not be interested because the triplet, I think it's good to say that the triplet means chemo plus another hormonal pill. Dr. Higano: Yes. It does right now. Exactly. To my knowledge, those are the only triplets that had any readout from phase 3 trial. Dr. Graff: Yeah, I agree. Dr. Higano: What are your thoughts or what kind of conversation do you have with your patients in the situation doublet versus triplet versus mono? I think you crossed that one off the list. Dr. Graff: Well, thinking about someone who's maybe 88, maybe monotherapy is just fine. Maybe life expectancy supports that, but yeah, outside of that, I usually just recommend doublet therapy. Although I offer six cycles of chemotherapy followed by abiraterone or another oral hormonal therapy. And again, I just take it step by step. Dr. Higano: Right. And Neal, you were mentioning, you assumed this case had high-volume disease and that's exactly the setting where PEACE-1 has a readout for improved overall survival. Does the fact this person has high-volume disease push you more towards the triplet, or you haven't made that decision yet? Dr. Shore: Oh, I've absolutely made the decision. And I think Matthew Smith has said in the presentation that about 85% probably were high volume in ARASENS. They used a sort of an antiquated M1a, M1b, M1c, but I think this is the sweet spot for these patients. Patients who get newly diagnosed with de novo mCSPC are younger by and large. They're not like our mCRPC patients which are in their mid 70s. These patients are in their, typically in these studies, they're in their mid 60s. They're just getting that frontal assault to their frontal lobe that, "Oh my gosh, I got cancer." And not only do you have cancer, but it's metastasized and you're high-volume. So I think they're a different mindset in terms of our mCRPC patients who are a little bit, they've been through it. And then when you say to them, "Oh, now I'm going to give you chemotherapy." I have to really sell it. And I'm a big believer in chemo for taxane-based therapy for mCRPC. My experience with mCSPC patients, it is not hard to convince them; they're younger, they're more fit, they're more frightened, they're more desperate, but more importantly, the data is now PEACE-1 and ARASENS is overwhelmingly compelling for high-volume patients, as long as they're chemo-fit, to get ADT docetaxel and an ARPI. And I think whether you want to give abiraterone or an ARPI -- and clearly the ARASENS is a brilliant trial because it's really game changing. And that was the conclusion from the presentation at ASCO GU, and it was the discussant Elizabeth Heath's conclusion. I agree with it. As long as you're chemo-fit and you're high-volume, why wouldn't you take advantage of the novel mechanism of action of a taxane and an ARPI, because this is a life-ending illness. And you see the curves, they separate really nicely over time and fairly quickly. So it's been my standard of care frankly before this trial came out, and I'm really happy to see there's now level I evidence to support triplet with therapy for these patients. Dr. Higano: Great. So another thing that we've lived with for many years now is the fact that we don't usually use antiresorptive therapies in metastatic hormone-sensitive disease. And did either of you see the abstract about the PEACE-1 data and use of, or loss of bone mineral density? Dr. Shore: We give testosterone suppression to elderly men who are already at risk for bone demineralization. It starts happening in healthy men over the age of 30. It's a natural evolution, it's a pathophysiology of aging. And then we lower their T, which is a dramatic way of also lowering their estradiol much like post-menopausal osteoporosis. And I think it's been incredibly important to make sure that these patients who we give T suppression to, whether it's in an adjuvant-neoadjuvant strategy for high-risk patients getting radiation therapy or intermittent or continuous ADT for biochemical relapse patients, that we have had to be very, very careful about monitoring for bone mineral density, starting on an antiresorptive, whether it's a bisphosphonate or a RANKL ligand monoclonal antibody. So this is incredibly compelling, in addition to exercise, some supplemental D and calcium, because these fragility fractures are horrific. But even now in the mCSPC patients who have bone metastases, they can really suffer from skeletal-related events. The approval of zoledronic acid and denosumab were all based on mCRPC trials. So there may sometimes be label issues and reimbursement issues for our mCSPC patients with bone metastases. And that can times get in the way of starting a more aggressive antiresorptive or bone health agent regimen. But nonetheless, something needs to be started always in these patients. Dr. Higano: Yeah, I think there was extra concern especially in PEACE because not only was there ADT and six cycles docetaxel, but also the abiraterone and prednisone. And I think that's what spurred them to look at bone mineral density. And I think it was interesting that even though there's a smaller number of patients with those readouts from the PEACE trial and the follow-up is a bit limited, but I think that they were surprised and I'm sure happy that there wasn't as much loss of bone mineral density as they anticipated. And so, the recommendation is still obviously to assess baseline bone mineral density prior to starting ADT with or without these other therapies, and if appropriate, to add antiresorptive therapy. But not for the bone mets indication, but for the therapy-induced bone loss. So either once or twice a year, depending on which agent you use. So, I thought that was interesting because that abstract could have changed standard of care for use of bone agents in metastatic hormone-sensitive disease, but in fact, it did not. Anyway, let, I think we could go on and on, on this case, I think, but let me just try to put together some takeaways for the audience. I think we made the point that doublets results in improved overall survival compared to ADT alone, there's no question there. And the triplet studies compared a standard of care doublet of ADT and docetaxel. There's no comparative trials between the doublet combination, so we can't really say one is better it and the other. We are going to choose based on different things with each patient. So, in PEACE-1, I think it's important to remember that at the moment, the benefit of triplet therapy in low-volume disease has not really been demonstrated, and that the median survival in ARASENS, the study with docetaxel and darolutamide, has not yet been reached. So we're still awaiting some final data to come out of both of those trials. And then when deciding on treatment, disease volume, patient comorbidities, and preferences obviously should always be taken into account. BMD in metastatic hormone-sensitive disease should be assessed and use drugs to treat therapy-induced bone loss, if it's indicated. Any other takeaways you guys would like to point out for patient with new metastatic bone sensitive disease? Dr. Graff: I think your points are really well taken. I guess I would just say I'm giving some empathy to my colleagues that it's really hard to remember the DEXA scan when you're, this person's coming in and maybe going to get triple therapy. And it's just like, they want to hear about all the side effects, etc. So I've actually put it in my note template. So I don't forget. But yeah, I really like your points, and I guess I would also add that we would probably get them genetic screening to genetic counseling. Dr. Higano: For sure. 100% agree. Neal, do you have anything to add? Dr. Shore: No, I think that was a great addition by Julie. Absolutely. Genomic profiling for anybody, or 100% of patients regardless of their family history, do a good family history, but anybody with metastatic disease should absolutely have germline testing, hereditary cancer risk. There are many who would do somatic testing as well. Clearly it's highly recommended once they develop resistant disease, but great point by Julie. I agree with all the earlier ones as well. Dr. Higano: Good. Well, thank you. This brings us to the end of this case. Please see the other segments for further discussion about the latest data in prostate cancer or visit ascopost.com.
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