Escalation Strategies for Suboptimal PSA Decline in mHSPC - Mary-Ellen Taplin

May 28, 2024

Alicia Morgans speaks with Mary-Ellen Taplin about strategies for managing metastatic hormone-sensitive prostate cancer (mHSPC) patients who do not achieve optimal PSA declines. Dr. Taplin emphasizes that an unfavorable PSA decline is not synonymous with progression and highlights the prognostic value of achieving a PSA nadir below 0.2. She discusses data from various trials, such as SWOG 9346, CHAARTED, and LATITUDE, demonstrating that patients with higher PSA nadirs tend to have poorer outcomes. Dr. Taplin outlines clinical considerations for patients with suboptimal PSA responses, including verifying optimal androgen deprivation therapy, considering radiation or SBRT, and ensuring patients adhere to their prescribed treatments. She also stresses the importance of genetic and somatic testing. Ultimately, recognizing a suboptimal PSA nadir should prompt careful patient monitoring and consideration of additional treatment options to maximize outcomes.


Mary-Ellen Taplin, MD, Oncologist, Chair of Executive Committee for Clinical Research, Director of Clinical Research at Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA

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 today with Professor Mary-Ellen Taplin, who is joining me from Dana-Farber Cancer Institute, actually right down the hall from me, as well as being with me at the APCCC 2024 in Lugano, Switzerland. Thank you so much for being here with me today, Mary-Ellen.

Mary-Ellen Taplin: My pleasure, Alicia.

Alicia Morgans: Well, thank you so much, Mary-Ellen. I really appreciated your talk in Lugano where you talked to us about how we escalate, or consider escalating, our systemic therapy or other treatment options for patients with metastatic hormone-sensitive disease who really don't achieve the PSA decline that we want. So I wonder if you could share your presentation with us and then you and I can chat afterwards.

Mary-Ellen Taplin: Great, thank you. I'm happy to share.

Today I'm going to share my talk from the APCCC meeting in Lugano, Switzerland. I was tasked to discuss what to do with a patient who reaches suboptimal PSA in the context of their initial hormone therapy. And the title of my talk is, Escalation strategies in patients with mHSPC and an unfavorable PSA decline - is more better?

So here are my disclosures, and none of them are relevant to this specific topic. First, we're going to talk about PSA decline and what the data is for this being a prognostic biomarker in metastatic hormone-sensitive prostate cancer. We'll briefly talk about genomics associated with a poor response to androgen deprivation-based therapy. And then I'm going to share with you what I consider some clinical pearls to consider for your patient who has a suboptimal PSA decline.

So first I want to go on record and say that an unfavorable PSA decline does not equal progression. We have clear metrics of progression in the field that include PSA progression, radiographic progression, and clinical progression, and we're all familiar with those. So just to be clear, in this context, an unfavorable PSA decline does not equal progression.

So what is the PSA that should clue us in that a patient is having a suboptimal response to their hormone therapy? Because we've all seen PSA patients who come in with a very high PSA, let's just say a hundred, and their PSA drops to five and they're very happy. But with some of this data that I'm going to share with you now, we would know, as a treating physician, that that is not a good PSA decline and possibly progression trouble would be following shortly. So this is old data, it's from the SWOG trial 9346. These are patients with metastatic hormone-sensitive prostate cancer that were started on standard androgen deprivation therapy, published by Dr. Hussain, as you can see there, in JCO, in '06.

So in this trial, they looked at patients who obtained a PSA nadir of 0.2 or less, and the reason why 0.2 was chosen was because that was the lower limit of the assays that were used at the time. And you can see there that patients who did achieve that 0.2 or less did the best as far as not having progression. Patients between 0.2 and four in the middle there, intermediate. And patients who had a PSA over four did poorly with progression in the short term.

So this evaluation has been brought into our contemporary trials, and this here is the CHAARTED trial which looked at docetaxel combined with androgen deprivation therapy in patients with newly diagnosed metastatic hormone-sensitive disease. And similarly, you can see the blue line is the patients who had the PSA optimal nadir of less than 0.2 doing the best, either with ADT alone, or ADT and docetaxel, and all the patients combined. And they used the same measurements as was used in the SWOG trial. The middle yellow line is 0.2 to four, and the line in gray, where the patients did the least well, is those whose PSA nadir was greater than four.

So the data held up over time with docetaxel, and then we have all the trials listed here looking at the androgen receptor pathway inhibitors such as apalutamide and abiraterone in these trials, and the PSA, I'm not going to go through all of them with you today, but the PSA nadir remained prognostic.

And this is just one of them with the LATITUDE study with abiraterone and prednisone that showed whether they used the PSA of 0.1, because the assays have gone lower in more contemporary times, and looking at time points of PSAs of less than or equal to 0.1 at six months or at 12 months. And whether it was radiographic progression or dying or PSA progression, not achieving an optimal nadir, the patients did more poorly in a statistically significant way.

So these data, as a PSA nadir, or achieving a PSA below 0.2 or 0.1, remains a prognostic biomarker for our contemporary therapies. There are some unanswered questions: which time point is the best to assess? In the SWOG trial, they looked at PSA at seven months because that was the point at which patients were randomized to intermittent therapy or not. Should we look at 12 months like some of the studies did? Should we look at a true nadir? There's really no answer to that, and I don't think there likely ever will be. The important point to know is that not achieving a PSA in a very low range, 0.1 to 0.2, is suboptimal. Should we go even lower? Now we can measure, with a lot of our assays, to 0.02 or even lower, but this is the data we have and this is the data you should have in your mind when you're thinking of patients in the clinic.

One slide to follow: how did genomics factor in the assessment? You want to put all your data together in your mind for your patients as you're assessing them over time. This is some data from the Stand Up To Cancer International Dream Team that we published several years ago. In the context of androgen receptor pathway inhibitors, if the patients had an RB1 mutation or a P53 mutation, their time to progression was shorter on their primary treatment, this is CRPC now, with an AR pathway inhibitor. If you have both of these in play, one of these mutations and a suboptimal PSA nadir, you need to be thinking about how you're going to follow this patient.

What do we consider for the patient who has a suboptimal PSA nadir? No data exists to change the systemic therapy based on the PSA nadir. That was the main point that I was asked to address in this presentation, and we have no randomized or prospective data that says if a patient has not progressed and has a suboptimal PSA nadir, you should change your therapy, so that's not what I'm advocating for. But there are some clinical considerations that should go through your mind if you're at this position with a patient.

Number one is, is the androgen deprivation therapy you have the patient on optimal? In order to assess that, you need to check a testosterone level. If you check a testosterone level and it's measurable, then you can consider changing the primary androgen deprivation agent, such as perhaps changing from an antagonist to an agonist, and then reassessing the testosterone decline. If the patient is on an oral such as Orgovyx, you can assess if the patient is taking it as prescribed, again, by getting a testosterone level. If the patient is on other oral drugs, such as androgen receptor pathway inhibitors, and their dose was reduced, you can give some consideration if their doses can be increased back to therapeutic recommended doses, if that's possible, depending on why they were dose reduced.

To continue this, if a patient was eligible initially for prostate radiation and that hasn't been administered for whatever reason, this would be a good time to consider rediscussing that possibility with the patient. Similarly, if the patient initially had low volume metastatic disease, where we often will consider SBRT to the metastasis, this would be a good time to consider perhaps early restaging and consideration for SBRT to any ongoing active metastatic disease. Additionally, if the patient had high volume metastatic disease when they presented but they were given doublet therapy rather than triplet therapy, you could consider adding the third type of therapy that they didn't receive, such as if they were on an AR pathway inhibitor but didn't get docetaxel, or even vice versa, that could be considered to intensify what would be considered standard recommended therapies.

In addition, this would be a good time to perform germline testing, if that hasn't been done. Similarly, consider somatic testing either from initial biopsy material or from a fresh metastasis biopsy.

Lastly, for my clinical considerations, I think it's important if you have a concern for a patient who's not responding optimally to therapy, that you share that concern with the patient, share what we know about PSA nadir as a biomarker, and should trigger a conversation of how this patient should be followed in terms of interval for PSA or restaging if you know the patient's at risk for early progression.

In conclusion, PSA nadir, or achieving a PSA of less than 0.2, is a prognostic biomarker for both radiographic progression-free survival and overall survival. PSA nadir is not a validated endpoint to change systemic therapy. However, recognition of a suboptimal PSA nadir is an opportunity to evaluate if available standard treatment options are being maximized. And recognition of a suboptimal PSA nadir should prompt careful consideration of patient assessments, following of PSA, and imaging and patient preferences. And I'll end there, and thank you very much.

Alicia Morgans: Thank you so much, Mary-Ellen. That was really so helpful and so practical. And I would love to dig in a little bit into the section where you talked about if you haven't done SBRT, if you haven't done radiation, if you haven't done a triplet, because I think those are really practical strategies. And I wonder, if that's happened to you, have you done that in clinical practice? Have you seen those approaches actually make a difference?

Mary-Ellen Taplin: Yeah, I have. When you initially meet a patient, there's a lot going on and a lot to process in terms of primary androgen deprivation and how to do it now. We have multiple options. There are pathway inhibitors, and of course, there are four to choose from there. And there are all the issues to discuss with patients, including copays, prior authorizations, and the germline testing. A lot of times, patients can only process so much at one time. I have been in the position where it's like, "I'll do doublet therapy, but I really don't want to consider radiation to my prostate right now," and I'll be like, "That's fine, let's see how you're doing, and we will reassess." So I think it really does happen that we tailor our initial therapy to individual patients based on preferences, and then we are given an opportunity to reassess.

Now, of course, if everything is optimal, the patient has a great PSA decline, and they prefer not to get one part of the treatment that's been evaluated in our phase 3 trials and is now considered standard of care, that's certainly their option. You do feel good about how they're doing if everything's optimal. But these patients whose PSA does not drop, especially if it's above four, I really think we need to take a pause and stop and think about it. It's on us to understand that because I have not infrequently been in the situation that I described where a patient walks in the door with a very high PSA, pick the number, be it a thousand. So when their PSA drops to 10 or eight, they're really happy, but we know that that's not the best situation to be in.

Alicia Morgans: And actually, I would love to follow up on that because I agree, if it's not hitting four, that's definitely something that is absolutely concerning. From older data, what do you think about the patient who's between 0.2 and four? Maybe they're 1.5, and they started at a thousand. I know these are all just shades of gray, but these are the things that happen in the clinic, and I'm still worried about them, but I don't always know necessarily what to do. Certainly, more frequent imaging is a great option, and making sure that you understand their genetic profile and their somatic profile. But what do you do in that situation, where it's a little bit lower but not quite where you want it to be?

Mary-Ellen Taplin: Yeah, I think if it's close to 0.2, 0.5 or less, I'm still generally happy. But if it's between one and four, that does get my attention that this is really not an optimal response. I just want to make sure that I understand that the testosterone is castrated and the patient is taking any pills that they're supposed to, and just do a good maintenance check. Checking all the boxes, like you do when you check your car, to ensure that everything you're possibly doing to optimize the therapy has been done. Treating prostate cancer has gotten very difficult in the last few years, and I think even among practitioners like us who do it full-time, there's a lot to think about. When you factor in patients' approach to their disease, the greater patient environment of their family and personalities and other medical problems, other possible cognitive issues, there's a lot to keep track of. Our old friend, PSA, is just a nice guideline to really understand where your patient is in the context of their first hormone therapy-based treatment for metastatic disease.

Alicia Morgans: I could not agree more. I love your comments about making sure that they're actually taking their medicine. It's interesting, in prostate, we haven't had the same data, probably because we just haven't asked the question in such a pointed way. But in breast cancer, patients who are on aromatase inhibitors or long-term therapies that are oral do not always take their therapies. When asked, they admit to not taking their therapies. It might be the side effect burden, it might be the financial challenges, it might be memory, or who knows what it is. But I think that's a great reminder because we don't talk about that enough in prostate cancer, and I love your strategy of just kicking the tires and checking out all of the parts of what's going on to make sure that everything is right. So, final word and recommendation to those practitioners. Where are we going with all of this? Do you anticipate we might see studies that look into these patients who are not reaching the optimal nadir and try to add on therapies in a systematic way?

Mary-Ellen Taplin: Yeah, I think it's a great opportunity for clinical trials. We had a clinical trial here that Dr. D'Amico had written a while ago, that if patients didn't have a low PSA, they would be randomized to an androgen pathway inhibitor. But it accrued very poorly, and it was closed by the company because of too slow accrual. I'm not sure why that wasn't able to get off the ground. Maybe it was the wrong time, this was quite a while ago, definitely before the pandemic. But I think it is a very good potential strategy to evaluate how we can help a group of patients who we expect to have progression in the short term.

Alicia Morgans: Absolutely. Yeah, I actually had some patients on that trial, and I love that strategy. Maybe it was because they were patients getting radiation, maybe it was not the right population, or the pandemic, or whatever it was. But I do really look forward to future trials to help answer this question because I think the way that this landscape has expanded, there are many opportunities for us to do better, and this is clearly selecting a population that is still in need.

Thank you so much for taking the time to go through this with me today. I always appreciate your time and expertise, and it's always nice to see you.

Mary-Ellen Taplin: Yes, likewise. Thank you. Thanks to the team.