Carrie Tompkins Stricker, PhD, RN, ANP-BC:
Let's actually progress this case a bit now then, and take it to the scenario you just mentioned. Let's consider this alternative scenario where at the end of 2020, let's say his PSA doubling time has accelerated, maybe even to 3 months. His PSA is 6.8. Testosterone is still less than 20 on androgen deprivation therapy. But in this case, imaging now shows limited axial bone mets, but he has no pain in the sites of bony mets. I'm going to toss it back to you to talk about just what you were saying. What might you do in the presence of limited bone mets, and why you're doing that? Either you, or one of the other panel members, we've mentioned PSMA a couple of times now. Let's just make sure we orient the audience to what that is and the importance of that in a diagnosis.
Saneese Stephen, MPAS, PA-C:
Okay. So you have patients with bone mets who may have still hormone sensitive disease, and you may have as this patient, he may be developing or has developed already castrate resistant disease and subsequent bone mets. So there's two different buckets here. We have two different patients that we treat very differently. So there are some recommendations from some groups.
Patient starting with bone mets, with some type of bone agent that they've also noted, not necessarily for castrate sensitive disease. And that's based on a couple of different trials. We have actually a STAMPEDE trial that led to the approval of docetaxel as upfront therapy. And they looked at over 2,900 patients and put them in different arms. One of the arms with Zometa, a bisphosphonate with standard of care. Also, Zometa/docetaxel and standard of care by self. Overall, studies showed that Zometa with standard of care, or Zometa with chemotherapy had no improvement in survival skeletal risk factor development, or progression failure free survival in terms of a disease in bone, in patients who had bone metastases, or were high risk at developing bone metastases.
So this is the hormone-sensitive group. There's also a trial from JCO by Matthew and group and they looked at about 600 patients. And they also looked at patients on ADT and bone mets and compared a Zometa group versus a non-Zometa placebo group. And they also found no benefit in survival, SRE, or failure-free survival in these patients, in hormone sensitive disease with bone mets.
So we're very cautious about starting people on continuous therapy. Once they start these agents they generally continue on indefinitely in some cases on the right setting. So in the hormone sensitive setting bone mets we still do not start a bone targeted agent. But if they become castrate resistant, which this patient is also at this point developing, we would start medications to further minimize the risk of bone related injuries or falls and complications.
But I think based on these trials important to look at the patient separately in context, and not all patients fit the trial patient. So everybody's situation is different. If they have a family history of fractures and advancing age and other risk factors that we know put them more at risk, we may want to start something more and more frequently. So it takes a discussion with the physician, with the pharmacist, with the patient of course, and the family, before we come to a decision-making point.
Carrie Tompkins Stricker, PhD, RN, ANP-BC:
Thank you. So I'm going to open this up to the panel. Any key points you want to make in terms of management of this gentleman now that he is castration resistant and still has the same report in context, in terms of bone loss, that we talked extensively about earlier?
Paul Sieber, MD:
I think this guy highlights, hey, he needs bone targeted treatment for his osteoporosis, or significant bone loss, but maybe not for his cancer. Then we move to the fact that he's got limited metastasis. And as Saneese says, we worry a little bit about cumulative toxicity to these drugs. So if we look at the original trials, the old trials, the ones that I was involved with 20 years ago, those guys had significant burden of disease. And with better imaging we're finding limited disease. So does this guy justify--and it's never ever been risk stratified--does he justify a high dose of treatment now? Monthly zoledronic acid, or at least quarterly, or monthly denosumab? That's a question mark that goes back to what we've talked about earlier. The art of the game.
And I might take a guy like this who has limited actually metastasis who's on treatment, and let's just say, he's on denosumab every six months, and I'll look at a bone turnover marker. And it's easy for me to do because we use urine N-telopeptide, and I'm a urologist. So guess what? Everyone that walks in my office, the first thing they do is they go to the bathroom and give us a urine sample. So I use that frequently. So if this guy doesn't normalize, I'm looking for a below 50 in my lab for N-telopeptide. I may think about, maybe his cancer is more progressive than I thought was otherwise happening, and I'm going to adjust my course for this guy.
That's probably not a likely scenario, but it does occasionally happen. Or even if you're watching him and he doesn't seem to be progressing otherwise, I will occasionally look at serial N-telopeptide to see if this guy's going up on his N-telopeptide that I may want to introduce the idea of, we need more of an SRE bone treatment versus an osteoporosis treatment. So I think it's kind of, it's a little catchy there because the prostate world, and again as Saneese said, there's a difference between castrate resistant and castrate sensitive. And in the castrate-sensitive state now, especially with our newer agents, we can keep people non-metastatic for some years, these days, especially with traditional imaging.
Carrie Tompkins Stricker, PhD, RN, ANP-BC:
Thank you. Again, the context of how improved survival with all the primary agents we have to treat the primary cancer itself, how that affects the context of supportive care decisions is so crucial in this case of bone health. How does that play out in your world, Christine, with your role as an oncology pharmacist? And is there anything you want to add to management of this case as well?
Christine Cambareri, PharmD, BCPS, BCOP, CSP:
So to your point exactly, Carrie, we are blessed to be in situations now where patients are living so much longer, and it may not even be on a lot of active treatment, or very intensive treatment for their cancers, but we are managing some of these long-term effects, bone health being one of them. Within the prostate cancer population there are other comorbidities that kind of pop up because of what we do to them to manage their disease, bone health being one of the bigger ones and kind of making sure that patients continue to get the appropriate imaging and measuring of appropriate biomarkers if that's what's being followed. And continuing on therapies, I think we often see this in breast as well, which I know we're going to talk about. If patients are feeling good a lot of the time it's easy for some of those other long-term supportive care things to fall off.
As we're learning, as we have longer and longer survivors of metastatic disease, that some of these other non cancer-related symptoms and management of it has long-term impacts that we're finding are impacting overall survival as well. So I think it's important to not minimize that and important to begin that conversation early in someone's diagnosis and be on top of it. Kind of like we've been talking throughout this case, that it is the conversation about minimizing fall risks and optimizing nutrition, diet and exercise as a patient is able. And so that's kind of honed in and zeroed in from day one, and continued for these patients that we are having as long-term survivors with advanced disease.
Carrie Tompkins Stricker, PhD, RN, ANP-BC:
Well, that brings us to really closing out this case with a discussion of duration. As we are stating here, patients with prostate cancer, including castration resistant, and patients with metastatic breast cancer, are projected to live significantly longer than what we used to quote as 2 or so years due to novel treatments. So making the importance of this duration discussion of bone modifying agents is a crucial discussion point. A recent study just published in 2021 is the first systematic review summarizing the available data on efficacy and toxicity of bone modifying agents after two or more years of exposure. And that'll be in your references, audience listening today. This included three prospective and nine retrospective studies that looked at side effects and adverse events. We're going to get into these in our next breast cancer case.
So reported incidence of ONJ was 1% to 2% in the first two years, but then rose after that. So it rose a bit after two years ranging from 5.3, to in some series as high as 20 over 20% of ONJ, which is osteonecrosis of the jaw. Rates of hypocalcemia were as high as 14.4% in denosumab, but clinically significant hypocalcemia was much, much, much less. Highly uncommon ranging from one to 2%. Nonetheless, we're going to integrate these concepts into our next case in breast cancer.
And incidents of severe decline in renal function was 3% or less. These all emphasize the importance of having discussions of duration. So as Moe says that BMA should normally continue indefinitely including into the hospice setting. Although they do note that treatment may be interrupted for folks with good prognostic features such as oligometastatic disease, a perceived risk of bone complications and durable response to their primary cancer treatment, their systemic treatment.
Some other things that are important to consider, denosumab in particular, when discontinued, you'll have rebound. We've seen bone resorption. And recent evidence suggests that vertebral fracture risks could quickly return to pre-treatment levels. And so that has led to ESMO guidelines recommending that if denosumab is stopped for more than 6 months, we should be suppressing that rebound bone breakdown or osteolysis with this phosphonate treatment during that period of time. Now some of the limitations of the studies are that they were in a non-cancer population in terms of this bone resorption, but we often, in clinical practice, have to apply learnings from outside our very particularized domain of clinical decision-making, to make informed decisions in our patient population.
