Castration Resistance Without Signs of Metastasis: Points for Patient Discussion
Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rapid prostate-specific antigen (PSA) doubling times are especially at risk for the development of metastatic disease in the near future. Dialogue with patients about the risks and benefits of treatment is a crucial part of the shared decision-making process.
Ken and Donna Derr – Chevron Distinguished Professor
“With the next-generation AR-targeted agents, we are seeing the downward migration of advanced therapeutics into earlier stages of disease, whereas previously we had been thinking of these agents mainly in the context of metastatic CRPC.”
Androgen deprivation therapy is quite effective, but, given enough time, castration resistance will develop. It has been my experience that, at this stage of the disease, patients are knowledgeable about their disease and their options for treatment. Nonetheless, it is important to engage in a dialogue with the patient as part of the shared decision-making process. Advanced imaging and molecular characterization techniques can have a major near-term impact in patients with nmCRPC. The timing and type of imaging can become important, and imaging techniques used in identifying metastatic disease vary in their sensitivity and specificity, as well as in their availability across settings. The indication for imaging is also key. For example, a patient with CRPC who undergoes imaging for bone pain is different from a patient who undergoes imaging as part of routine surveillance. Following the PSA response is a very useful tool that is used across settings. A conspicuously short/rapid PSA doubling time predicts a worse clinical outcome, shorter time to metastasis, and shorter time to mortality.
There are now 3 next-generation androgen receptor (AR)–targeted agents approved by the US Food and Drug Administration for the treatment of nmCRPC: apalutamide, enzalutamide, and darolutamide. Each agent has been shown to delay the onset of metastases by approximately 2 years. Thus, with the next-generation AR-targeted agents, we are seeing the downward migration of advanced therapeutics into earlier stages of disease, whereas previously we had been thinking of these agents mainly in the context of metastatic CRPC. The key question then becomes: Which patients with nmCRPC are likely to benefit from these newer therapies? A vibrant patient with a good performance status, little comorbidity, and a rapid PSA doubling time is at risk for the near-term development of metastasis and may also be an ideal candidate for the addition of a second-generation AR antagonist. In contrast, a patient who is frail, has multiple comorbidities, and has a prolonged PSA doubling time (eg, outside of 10-12 months) may be less likely to obtain benefits from these treatments and may be better treated with continued surveillance or perhaps enrollment in a clinical trial that is a good match for the individual and his or her comorbidities.
American Urological Association. Castration-resistant prostate cancer (2018). https://www.auanet.org/guidelines/prostate-cancer-castration-resistant-guideline. Accessed September 12, 2019.
Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
Howard LE, Moreira DM, De Hoedt A, et al. Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer. BJU Int. 2017;120(5B):E80-E86.
Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474.
Mateo J, Fizazi K, Gillessen S, et al. Managing nonmetastatic castration-resistant prostate cancer. Eur Urol. 2019;75(2):285-293.
Mori K, Kimura T, Ito K, et al. Earlier use of androgen receptor-axis-targeted drugs may improve overall survival in patients with non-metastatic castration-resistant prostate cancer. Prostate. 2018;78(10):766-772.
Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.