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Let’s revisit our case of the patient with nonmetastatic castrate-resistant prostate cancer (nmCRPC) and rising PSA from the Presurvey. The patient has a history of Parkinson’s disease, and his prostate cancer has been managed with ADT. His current PSA is 7.2 ng/mL and his PSADT is 5.5 months. Imaging revealed no evidence of metastases. His PS is 1 and he is expected to live 5 years or more. Entering these data into our tool finds that all 5 experts recommend continued ADT with the addition of darolutamide. One expert suggested that enzalutamide or apalutamide would be equally acceptable.
The treatment recommendations for a similar patient without a history of a neurological disorder are more variable, with 3 experts recommending ADT plus either darolutamide, apalutamide, or enzalutamide, all equally acceptable; 1 recommendation for ADT plus darolutamide and 1 for ADT plus observation.
Now, let’s take a look at the data that support these treatment recommendations from our tool.
Nonmetastatic castrate-resistant prostate cancer is a clinically important disease state. In patients with nmCRPC receiving ADT alone, the median time to metastasis in 1 study was < 30 months, and median OS was 45 months, which is comparable to the survival in high-risk/high-volume mHSPC.
In men with nmCRPC, a shorter PSADT is associated with greater risk for metastasis or death. Results from an exploratory analysis of a prospective clinical trial showed a clear stepwise increase in the risk for metastasis or death with each tertile of PSADT, with the greatest risk in patients with a PSADT of less than 6 months.
There are now 3 next-generation AR inhibitors approved for the treatment of nmCRPC: apalutamide, enzalutamide, and darolutamide. Apalutamide and enzalutamide have similar structures. By contrast, darolutamide is structurally distinct from the other 2 drugs and is characterized by low blood-brain barrier penetration. Those attributes of darolutamide may confer improved tolerability.[15,16]
The approval of each next-generation AR inhibitor in nmCRPC was based on a prospective, randomized, placebo-controlled phase III trial of similar design. Each study included patients with nmCRPC who were at greater risk for metastasis or death, based on a PSADT of < 10 months. Patients were randomized 2:1 to an AR inhibitor or placebo, and patients in both arms continued ADT as the standard of care. The primary endpoint was metastasis-free survival (MFS), and key secondary endpoints included OS.
In each of the 3 pivotal trials, treatment with an AR inhibitor was associated with a marked improvement in MFS, with HRs varying from 0.28 to 0.41 and highly significant P values in each case.[17-19] The improvement in median MFS was approximately 2 years, and this improvement was consistent across all 3 trials.
The primary analysis of the 3 trials was event-driven. Although the OS data were immature at that time, there was a trend toward improved OS in each case. With longer follow-up, each study has reported a significant improvement and clinically meaningful improvement in OS, with HRs ranging from 0.7 to approximately 0.8 and significant P values.[20-22] Two of the studies have recorded a median OS improvement of approximately 1 year.
While the efficacy data from each of the 3 trials are remarkably consistent, there are some differences in safety profiles that are worth noting. In the SPARTAN study of apalutamide, fatigue was the most commonly reported adverse event (AE), with other AEs of interest including falls and fractures that occurred at a greater rate with apalutamide than placebo. Similar safety results were observed in the PROSPER study of enzalutamide, with fatigue the most commonly reported AE; falls were also more common with enzalutamide compared with placebo. The safety data from the ARAMIS study of darolutamide were somewhat different. Fatigue was the most commonly reported AE, although the rate is more similar to that of placebo than what is seen with either apalutamide or enzalutamide. Also in contrast with the SPARTAN and PROSPER studies, rates of falls and fractures were similar between the darolutamide and placebo groups.
Bone health is an important consideration for patients with prostate cancer. First, patients diagnosed with prostate cancer are older and at risk of age-related bone loss. Second, the fundamental therapy for prostate cancer is ADT, especially in earlier stage disease, yet ADT increases the risk of fractures.
For patients with a limited life expectancy due to their prostate cancer, such as patients with mHSPC, bone health is a minor concern. Two studies have examined the use of zoledronic acid in hormone-sensitive disease. One study found no reduction in risk of skeletal-related events, while the other study concluded there was no survival benefit associated with zoledronic acid.[24,25]
In contrast, bone health is more of an issue for patients who are diagnosed with early disease who need long-term hormone therapy. They are likely to live for a very long time, and you might actually cause them harm with more treatment and increase their risk of fractures. The other concern is disease-related skeletal complications or symptomatic skeletal events. There are bone-targeted therapies, or osteoclast-targeted therapies, more specifically, that reduce the risk of skeletal-related events, and zoledronic acid and denosumab are both approved in mCRPC and recommended for patients with mCRPC.[26,27]
An issue relevant to nmCRPC is that more sensitive imaging techniques are increasingly available, and the consequence of more sensitive imaging is that patients will be reclassified from having nmCRPC to having metastatic disease. If you perform a prostate-specific membrane antigen (PSMA) PET scan of a patient with nmCRPC, you are likely to find metastatic disease, reclassify the disease as metastatic, and perhaps treat the patient accordingly. But reclassification does not change the evidence. In the SPARTAN, ARAMIS, and PROSPER trials, only patients without detectable metastases by conventional imaging were included. However, we now know from other studies that most of those patients would have been found to have metastases by PSMA PET, so we have indirect evidence for managing these patients as having nmCRPC rather than as mCRPC.
For patients with nmCRPC, we routinely recommend the addition of one of the approved AR-targeted drugs to ADT. In the specific patient case presented here, where the patient has a history of Parkinson and occasional falls, we favor darolutamide over the other 2 agents, based on evidence of better tolerability, including lower rates of falls and fractures. That does not mean that darolutamide is the right choice for every patient, or that it is better than the other drugs for every patient, but I would suggest it would be better for that patient in this case.
In selecting therapy, we always need to consider the evidence. All treatments have risks, some understood and some not understood or identified yet. For instance, with cardiovascular risk, patients bring a level of risk with them to the clinic. Therapy may affect that risk, but I think there is a misunderstanding in the field that the risks of ADT and cardiovascular disease are quite high, when in fact it appears to be a pretty small effect. Without adequate head-to-head data, we do not know how the cardiovascular safety compares between these drugs. In the setting of nmCRPC, we have 3 studies of very similar design, follow-up, and patient population where there do appear to be differences in tolerability, but whether these differences really provide a major benefit to the typical patient is unclear.
Now let’s revisit the polling question regarding one of our earlier patient cases.