Dr. Maha Hussain is the Genevieve Teuton Professor of Medicine in the Division of Hematology, Department of Medicine, and the Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.
Prostatepedia spoke with her recently about biochemically recurrent prostate cancer.
What is biochemical recurrence?
Dr. Hussain: A biochemical recurrence implies that an individual with prostate cancer who has received therapy now has evidence of disease activity as reflected by their PSA blood test. In the context of negative imaging, the PSA is a flag. It generally indicates a relapse. Generally speaking, when the patient has a rising PSA, they get imaged. If the scans are negative, then this becomes purely biochemical recurrence.
Why is this a disease state that we’re particularly focused on? What are some of the key issues in how we approach treating these men?
Dr. Hussain: There are two settings of biochemical recurrence. One is the non-metastatic hormone sensitive setting. This means a patient has had local therapy with surgery and their prostate was taken out, or they’ve had radiation therapy with or without hormonal treatment, and now they have a PSA that’s going up. This implies there is cancer activity. Generally, imaging is done, and most of the time, conventional imaging such as bone and CAT scan are negative.
While not imminently harmful, non-metastatic hormone sensitive biochemical recurrence has significant psychological implications for the patient because it reminds them that there is cancer activity in their body that’s growing.
With regard to management, salvage radiation plus hormone therapy is the standard of care for patients who developed PSA-only relapse post radical prostatectomy as it reduces risk of mets and improves longevity. While there are options for patients who had radiation therapy plus hormonal therapy, they are not optimal.
For example, while hormone therapy is an option for patients whose PSA started to increase after salvage radiation and hormonal therapy, the totality of the data to date does not suggest significant benefit for early hormone therapy versus waiting until there’s a reason to treat.
This population; non-metastatic hormone sensitive PSA relapse, tends to live quite long, and some may not develop visible mets. The speed by which the PSA starts to go up and how fast it increases—what we call doubling time—can imply earlier versus later development of metastatic disease. Detailed discussion is needed to address options, pros and cons of treatment, and potential options for clinical trials.
The other setting of biochemical recurrence is the non-metastatic but castrate-resistant setting, which differs from the previous setting in that patients were treated with hormone therapy and now their PSA is rising while on therapy; that is the rising PSA is occurring despite the fact that hormone therapy has lowered their testosterone levels to the castration range. This is a different clinical phase of disease where the cancer has shown that it is no longer responsive biologically to the hormonal therapy that they are receiving. We know that, given enough time, cancer will show up. We know also that the speed by which the cancer is growing, as reflected by the PSA rate of increase, has an implication as to how soon the cancer will show up on the scans.
This is an area of an unmet need for decades, until last year when two drugs were FDA-approved for this particular patient population, specifically Erleada (apalutamide) and Xtandi (enzalutamide) based on significantly delaying time to development of metastasis. At this year’s American Society of Clinical Oncology GU (ASCO GU) conference, there was also positive data from another trial with Darolutamide in this disease setting. I believe the drug is in front of the FDA at this moment for review.
These three trials were done in a population of patients who had a worse prognosis as reflected by their fast PSA doubling time—a doubling time of 10 months or less. This is because these patients are likely to show metastases within an average of about two to two and a half years.
The issue is whether there is benefit for people who don’t have that kind of PSA doubling time. What if the doubling time is one or two years? It certainly is an area where we need to think about value to that patient.
For both Erleada (apalutamide) and Xtandi (enzalutamide), the FDA approval did not specify the doubling time requirement. The FDA approved it in all patients who have non-metastatic castrate-resistant disease. Clearly one size does not fit all. It’s critical to make shared decisions between the patient and the treating physician with regard to the value of the treatment, the risks from the cancer, the risks from the treatment, the treatment objectives, and when to initiate therapy.
Some good news about this disease phase is, because it’s invisible cancer, and while this means there’s micrometastatic disease, the patient has some time to think about things and also monitor carefully.
In my experience, probably about 8 to 9 out of 10 patients elect to be on treatment because of the concern over worsening disease and the value based on the clinical trials. There are some patients who feel great, and if they’re not going to have an issue tomorrow, then they want to wait a few months before deciding on treatment. That’s perfectly reasonable.
Isn’t that true for a variety of situations in prostate cancer, that you have time to gather a variety of opinions?
Dr. Hussain: Correct in general, but specially for this disease space because no one is going to die overnight from a PSA that’s not controlled. That’s to put it bluntly. There is that room. Patients should talk with their physician about that and discuss risk-benefit ratios as all therapies have side effects.
For certain patients, those side effects might be more important, especially for those who have significant cardiovascular disease. It becomes important to incorporate risk-benefit and close monitoring, but it doesn’t mean that no treatment should ever be done.
Do you have any other advice for men in this situation?
Dr. Hussain: One thing to remember for men with hormone-sensitive biochemical recurrence who have had salvage therapy or post radiation and hormonal therapy is that if therapy is to be done, it ought to have a good reason. Lowering the PSA alone is not the objective; clinical benefit should be the objective.
There is potential harm from treatment in the absence of proof that giving hormone therapy for a PSA of let’s say 0.5 or 0.6 will have a benefit. One has to balance the risks from the treatment and both physical and monetary risks to the patient and ultimately implement a shared decision.
These conversations with patients can be long and potentially stressful to the patient. Yes, hormone therapy can be given. The issue is not whether it can be given but whether it should be given, and if so, when.
There’s a fair amount of population-based data that suggests there’s no clear advantage, but there’s limited prospective clinical trial data. I would encourage patients to discuss these issues with their physicians, understand the upsides and downsides, and also discuss opportunities for clinical trials. Clinical trials are one space in which we need informative data and partnerships with patients to come up with better answers.
For patients who had radical prostatectomy (surgical removal of the prostate), and then their PSA is going up, their best treatment option is salvage therapy, which involves radiation with hormonal treatment.
Based on the more recent data from Radiation Therapy Oncology Group (RTOG), the radiation involves the prostate bed and the pelvis to include the pelvic lymph nodes with four to six months of hormone treatment. This is something that should be discussed with the care team. Radiation alone is not enough, and certainly the data indicate the combination is better with regard to outcomes. If the patient doesn’t want to do the hormones, that’s fine, but the hormones can reduce risk of progression and potentially add to overall survival.
The other side would be situations where patients have had radiation therapy and have received hormonal treatment as part of their primary treatment. Then they stopped the therapy, and now months or years later, the PSA is rising. That’s a different scenario. The issue is whether to resume hormone therapy or not. That’s when a careful conversation is necessary between patients and their physician because there is no compelling data that say it’s necessary to do the hormone therapy.
So, there are a variety of situations.
Dr. Hussain: Yes and/or access to clinical trials. We know the phases of prostate cancer now. The same disease state now has multiple phases, and it’s becoming complicated. That’s important because this speaks to the importance of personalizing care for the patient at all levels.
We’re becoming more and more personalized about how we categorize the different disease states.
Dr. Hussain: Yes, absolutely, and we do individualize the care. A 50-year-old who comes in with non-metastatic castrate-resistant prostate cancer and no comorbidities has a very different disease than someone who is 85, had a stroke, and is in a wheelchair.
Patients should ask their physicians specifically about the type of biochemical recurrence they have, their expected prognosis based on their PSA doubling time, their risk-benefits ratio, and which scientific information from prospective clinical trials can help guide their decisions. Patients should ask for educational material, and doctors should help patients make a decision that’s not based on being afraid but being informed about the choices, pros, and cons.
Would you give similar recommendations to anyone along any stage of the disease progression?
Dr. Hussain: Absolutely. Informed decisions are critical in every disease setting. But biochemical recurrence is a complicated phase of disease. In the setting of metastatic disease, it’s relatively easy in that there is no question regarding the disease risks. Earlier therapy, before symptoms or before the disease worsens, is better generally. This a disease setting that is likely to cause harm if therapy is delayed significantly.
But with non-metastatic hormone sensitive biochemical relapse, a patient can go for years without having any visible metastasis. It’s more complicated when there’s no imminent danger. At the end of the day, I tell patients with non-metastatic hormone sensitive disease in whom there is no clear data to support benefit from systemic therapy, that this is a gray area where we don’t have compelling data to say that giving hormone treatment is going to give a meaningful benefit. Therefore, one option is we monitor closely with interval PSA checks and periodic imaging. Based on doubling times and trends, what new evidence that comes up, and patient comfort we can watch. Once the patient is informed about the specifics, it is fascinating that the majority tends to be comfortable with watching and about a third are not comfortable with not getting therapy. There is not a one-size-fits-all approach. Personalized shared decision is critical.