Welcome to the second installment of the three- part CARE™ nmCRPC Case Series!
This series aims to provide context and guidance on how to navigate the evolving treatment landscape and some of the challenges that specialists face in routine practice.
A 69-year-old patient is on continuous ADT for a rising PSA post-prostatectomy and adjuvant RT. He was lost to follow-up and represented with a PSA of 12. Imaging studies (CT chest/abdomen/pelvis and bone scans) were negative for metastatic disease. He was started on ADT which controlled his PSA for 3.5 years (PSA nadir 0.7). His PSA and testosterone levels are being monitored every 3-6 months. His most recent testosterone level was < 0.2 nmol/l and PSA was 4.5 ng/mL. His calculated PSADT is 8 months. Recent CT chest/abdomen/pelvis and bone scans were negative for metastatic disease. He is ECOG 0-1, has no symptoms from his cancer, is not working but still active, and has a ≥ 5-year life expectancy. He has high anxiety about his rising PSA.
This patient meets the definition for high-risk nmCRPC based on his rising PSA, PSA doubling time of less than 10 months, and with conventional imaging (CT and bone scan) showing no evidence of metastatic disease.
It should be noted this is a relatively young, healthy patient with a good ECOG performance status and no symptoms from his cancer.
This is a patient who would benefit from oral treatment when looking at the data that’s out there (ARAMIS- Darolutamide, SPARTAN- Apalutamide, PROSPER- Enzalutamide; See part 1 for more information and data from these trials)
What are your thoughts on the similar MFS benefits seen across trials in this setting?
All three trials looked at similar patient populations and we know that the three drugs are relatively similar in terms of their molecular structure and mechanism of action.
The similarity in these outcomes increases our confidence in treating patients in this setting that is not based on a single study.
Additionally, these trials are really interesting because they have shown that MFS can act as a surrogate endpoint for OS, which is especially important in settings where reaching this endpoint can take several years.
How do you choose what option to use for each patient in clinical practice?
The choice of treatment should be made together with the patient. With MFS and OS benefits being so hard to distinguish between, it really boils down to tolerability, adverse effects, contraindications (i.e. seizure history), and drug-drug interactions. Looking at these patient characteristics helps us to fine-tune and tailor treatment.
Treatment that has no detriment to QoL is particularly critical this setting where many patients are asymptomatic.
The CUA calculator for determining drug-drug interactions helps us to administer these drugs more safely, taking into account things like risk of seizures with enzalutamide.
Studies looking at how the 3 options compare have suggested that there may be a less blood brain penetration with darolutamide making it a good option for patients with many comorbidities, and/or are on a number of other medications.
“Treatment that has no detriment to QoL is particularly critical this setting where many patients are asymptomatic.”
Are there any patients that you would not treat in this setting?
Those patients are few and far between now. Perhaps just patients who are at an advanced age (i.e. over 90) with multiple comorbidities and who do not have a five- or greater-year life expectancy.
Until we had access to darolutamide, patients with a history of- or high-risk features for seizures would typically not have been treated in this setting.
How will the integration of novel imaging approaches (i.e. PSMA PET) impact the management of nmCRPC?
Eventually it will have a major impact, but right now there’s fairly limited access to PSMA PET across the country.
We have to make sure that we don’t forget about what we’ve been using for a long time in terms of the conventional imaging, and it will be nice to see trials going forwards incorporating both.
PSMA PET has the potential to make us think about metastases-directed therapy (i.e. SBRT). When considering how to optimize treatment for patients going forwards it may be interesting for patients to be treated as per conventional imaging in nmCRPC and then as time goes on, utilize newer imaging in the metastatic setting.
As these novel agents move into earlier settings, what is the impact on later lines of therapy?
Sequencing is always an issue, but we know from most of the trials in advanced prostate cancer that treatment earlier is better overall.
The other question is how a patient who’s been treated with a one of the three drugs in the nmCRPC space going to respond to subsequent therapy. We know that there’s a lot of cross resistance between these agents.
Many of studies show that sequencing hormonal therapy is likely not the best way to go, so it’s going to bring chemotherapy back in some ways and also re-emphasize the need to get molecular profiling of our patients to know if they’re candidates for a PARP inhibitor or other new treatments coming down the line.
It’s been a very exciting time and there is more to come. The future is very bright in the field of prostate cancer.
“Sequencing is always an issue, but we know from most of the trials in advanced prostate cancer that treatment earlier is better overall.”
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