Dr. Smith: Welcome to The ASCO Post Roundtable Series on Updates in Prostate Cancer. I'm Dr. Matthew Smith from the Massachusetts General Hospital Cancer Center in Boston. Joining me today are two of my colleagues.
Dr. Gao: Thank you, Matthew. My name is Xin Gao. I'm an instructor in medicine at Harvard Medical School and a medical oncologist at Massachusetts General Hospital.
Dr. Morgans: Thank you, Matthew. My name is Alicia Morgans. I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago.
Dr. Smith: Today we'll be discussing recent updates in prostate cancer, including data presented at the 2021 ASCO annual meeting, and integrating these new developments into four patient case studies. Our second installment will focus on management of metastatic castration-sensitive prostate cancer, including data from the phase III PEACE-1 trial.
In this case, we have a 61-year-old man with de novo metastatic prostate cancer. He presented with pain and was found to have an abnormal digital rectal examination, PSA was markedly elevated at 781, TRUS biopsies demonstrated Gleason 4+4 in multiple cores. Imaging included a bone scan showing extensive bone metastasis and that he has an abdominal pelvic CT scan showing an enlarged prostate and large pelvic nodes and multiple osteoblastic metastasis. His past medical history is otherwise unremarkable.
What do you recommend in this case? ADT alone, ADT plus docetaxel, or ADT plus abiraterone acetate plus prednisone? Dr. Gao, how would you manage such a patient?
Dr. Gao: Thanks, Matthew. It sounds like this is a patient with presentation of de novo metastatic high-volume prostate cancer, based on the CHAARTED criteria. For this particular patient, I would lean towards ADT plus early intensification of therapy with docetaxel. He's got quite a lot of metastatic disease, I would assume fairly symptomatic in that sense, and I would add on docetaxel in this situation.
Dr. Smith: Dr. Morgans, do you agree?
Dr. Morgans: I think that's a phenomenal answer and a great choice, because as you said, this is a de novo metastatic patient, which we saw in STAMPEDE is a patient that's going to benefit from ADT plus docetaxel as compared to ADT alone and then intensification strategy. Actually, in that assessment, both in high-volume and low-volume for those patients who have de novo metastatic disease, in this case, though I think I would also consider ADT plus abiraterone.
There are several reasons for that. Of course, we know that ADT plus abiraterone certainly seem to improve survival for patients who have metastatic hormone-sensitive disease, in the high-risk population tested in LATITUDE as well as across the board in the STAMPEDE trial. There was a really interesting contemporaneous randomization that allowed comparison of patients who were treated with ADT plus docetaxel versus ADT plus abiraterone in the STAMPEDE trial that I also would consider in this context.
In that contemporaneous randomization, there was actually a quality of life assessment that compared patients treated with ADT/[abiraterone] to ADT/[docetaxel], and found that in the first year and a half to 2 years, there was a pretty clear advantage to treatment with ADT and abiraterone in terms of quality of life that never really seemed to make up for itself in terms of that docetaxel quality of life for ADT and docetaxel–treated patients. It was interesting, of course, that in the CHAARTED trial, the quality of life for patients seemed to recover at 12 months, but it did not seem to do the same in the metastatic hormone-sensitive population in STAMPEDE. Although we haven't seen this data for quality of life actually formally published in a paper yet, it was presented and is something that comes into conversations that I have with patients.
Dr. Smith: I think those are all excellent points. I think the priority is really going to be to intensify therapy, particularly in this patient with high-volume, high-risk disease. In my practice, I tend to use abiraterone acetate plus prednisone, patient acceptance of that appears to be better than docetaxel. I am moved by the quality of life and other data from the STAMPEDE contemporaneous comparison.
We're going to move on to a more complicated question, which is, are there patients where we should be giving really triplet therapy: ADT, docetaxel, and [abiraterone/prednisone]? We got an update at the 2021 ASCO Annual Meeting with the first report from PEACE-1 presented by Karim Fizazi. This is a rather complicated phase III trial that has four arms: patients with de novo metastatic castration-sensitive prostate cancer and distant metastasis with at least one bone scan lesion and/or a CT scan metastasis were randomized to standard of care, which is ADT/docetaxel for the most part or one of three other arms: standard of care plus abiraterone acetate/[prednisone], standard of care plus radiation therapy, or standard of care plus [abiraterone/prednisone] and radiation therapy to the primary tumor.
We're going to focus on the data as it relates to the addition of abiraterone acetate to standard of care. What was reported from PEACE-1 is that there is a meaningful improvement in progression-free survival in the overall population with a hazard ratio of 0.54 on an absolute improvement in rPFS of about 2.3 years or about 27 months—quite a large absolute improvement in rPFS. At the time of this analysis, the overall survival data are immature, and we're going to have to await longer follow-up to see if this translates into an OS benefit.
Karim Fizazi at the meeting concluded that regardless of the OS results, he asked the question, should we deny patients an approximately 2.5-year improvement in rPFS? Meaning not add [abiraterone] to ADT/docetaxel, or do we have a new standard of care with the triplet?
Xin, what do you think of this data? Is this intermediate endpoint of rPFS sufficiently compelling that we should now view the triplet therapy as the new standard of care, at least in patients who would have met inclusion criteria for PEACE-1?
Dr. Gao: I think this is a really interesting question. I think this is a question that's been asked for several years now, really ever since upfront docetaxel became the standard of care. People have looked at it and other trials with the question of immediately starting an antiandrogen like enzalutamide or apalutamide after completion of upfront docetaxel and certain subsets of patients in those trials.
With this trial in PEACE-1, they used concurrent therapy with abiraterone and docetaxel upfront. For me personally, I would still like to see an overall survival benefit or at least some overall survival data. Certainly, regardless of OS results, the assumption is that it's at least going to be as good and that it's not going to be detrimental to add on abiraterone upfront.
Certainly I think the data on toxicities and the AE profile was fairly good. I think there was some increase in grade 3 or higher hepatic toxicity with adding abiraterone in PEACE-1 as well as a slight increase in hypertension, so not totally surprising. I would like to see some OS data or at least some sort of PFS2 type of data. To me it's not altogether surprising that there's going to be a PFS benefit and there's going to be a pretty significant PFS benefit with people getting abiraterone upfront and continuing that compared to patients who finish six cycles of docetaxel and then just continue on ADT alone.
I think it is very intriguing data and certainly this rPFS benefit may end up translating into an overall survival benefit. I think I'd still like to see more data. I'd still have to consider some of these toxicities that we see with abiraterone and continuing abiraterone and also the financial toxicities involved.
Dr. Smith: Dr. Morgans, do you agree? What is your take on the PEACE-1 data?
Dr. Morgans: Yeah, I think very similarly, but I also think that I would make this option known to patients. I would probably talk to them about the data. What I think is compelling is that it is a radiographic progression-free survival, this is a time to progression on imaging, which is certainly something that can be really meaningful to patients. Again, it's always a trade-off whether patients want to, as I alluded to, pay for abiraterone for that duration of time is not clear and certainly it's going to be an individual decision.
What I also thought was somewhat compelling was that this is actually similar to the ENZAMET trial in that the radiographic progression-free survival appeared as somewhat longer in ENZAMET as well with the triplet therapy. Certainly the toxicity was actually greater with the triplet therapy in that trial, particularly in things like fatigue and nail discoloration. This was a less compelling story because in PEACE-1, there did not seem to be a safety signal that really suggested that there was a significantly increased toxicity associated with the triplet.
There are always reasons why people want to do things or not do things. I think that the overall survival data is certainly going to be most compelling to everyone, but I do think it's worth mentioning it to patients because 2.5 years is a long time to live without any growth or change on your imaging.
Dr. Smith: It is a big benefit. What PEACE-1 and the other trials won't tell us is whether addition of docetaxel to ADT plus an NHT improves outcomes, and that is one of the advantages of priority being reported first.
Let me conclude with a few clinical takeaways from this case, the data, and the thoughtful comments of my faculty. I think we need to think of this in a new way for patients with mCSPC. The new standard of care is intensification of systemic treatment by addition of another agent to androgen deprivation therapy. There's strong level one evidence that the addition of docetaxel or a novel hormonal therapy, specifically abiraterone acetate, enzalutamide, or apalutamide, improves progression-free and overall survival compared to ADT alone.
Based on the PEACE-1 data for patients with de novo mCSPC, the addition of abiraterone acetate plus [prednisone] to ADT and docetaxel appears to improve progression-free survival compared to ADT and docetaxel but will require longer follow-up to understand the impact of that intervention on survival.
This brings us to the end of the case. Please see the other segments for further discussion about the latest data in prostate cancer or visit ascopost.com.