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Understanding Competing Risks for Mortality Among Men with Nonmetastatic Castration-Resistant Prostate Cancer 

A pressing issue facing men with a rising PSA despite hormone therapy is whether to pursue more potent androgen receptor inhibition. While novel PET imaging such as PSMA scans are reducing the size of this M0 CRPC population, this setting remains fairly common in regions of the world where PSA screening is common and men are treated for initially localized prostate cancer. Relapsed disease is first manifested as a PSA rise, and many urologists and oncologists will utilize androgen deprivation therapy (ADT) prior to the onset of visible metastases on standard CT/MRI or technetium bone scans. We know that most of these men have metastases, but these metastases remain small and below the limit of detection of these scans. We also know that most of these men will likely die of metastatic prostate cancer over the next 4-8 years, and therapies that can delay or prevent prostate cancer-specific mortality are needed.

Recent phase 3 trials suggest that both apalutamide, enzalutamide, and darolutamide can delay metastasis-free survival (MFS) significantly in such men with M0 CRPC who have rapid PSA doubling times (<10 mo) and an elevated PSA of 2.0 or higher. These men may have disease in their prostates or regional nodal involvement but no detection of distant metastases but are at high risk of developing distant metastases andsymptoms within 1-2 years. These trials have not yet demonstrated a significant survival advantage, although the early data suggests that for these selected, healthy men who are trial eligible and have rapid PSA kinetics, overall survival may favor the early use of these AR inhibitors as compared with placebo, and favors early therapy for delays in symptomatic progression. The overall high quality of life and low toxicity burden of these therapies also makes them attractive; however, notable toxicities of fatigue, muscle loss, fracture risk, and cardiovascular risk are real, and individual agents have specific liabilities including seizure risk, rash, and hypertension.

In this setting, a much-needed analysis by Whitney et al retrospectively examines the SEARCH database of VA hospitals from 2000-15 for men with M0 CRPC during the era prior the availability of these novel agents and examines the risk of prostate cancer-specific mortality (PCSM), other cause mortality (OCM), and overall mortality according to PSADT and comorbidity subgroups and age. As expected, they find that as PSADT shortens, PCSM increases relative to OCM, and as age and comorbidity index increases, OCM increases relative to PCSM. The data indicated in their figures and table provides very useful information for patients and providers to help in the decision to pursue more aggressive therapy. For example, an 81-year-old man with M0 CRPC and a PSADT of 12 months and a recent MI, diabetes, and peripheral vascular disease (CCI of 3) has a nearly 3 fold increased risk of dying from other causes besides prostate cancer over the next 5 years, and thus perhaps the focus of care may be in cardiovascular risk reduction, and secondarily in cancer therapy, and avoiding AR therapies for some time may reduce his risk of worsened cardiovascular disease. However, a 53-year-old otherwise healthy male with M0 CRPC and a PSADT of 6 months has a 40-50% risk of death from prostate cancer at 5 years and a less than 10% risk of dying from another cause. Thus, potent AR inhibition is reasonable in this setting provided there is an informed discussion about the risks and benefits of this therapy. Patients in the middle, of course, will have a more complex discussion and decision.

Overall, these data are intended to facilitate medical decision making in this M0 CRPC treatment space. Ultimately, long term survival follow up of these trials for PCSM, OCM, and overall survival are needed, but we will also need updated population-based studies investigating the benefits and risks of these novel agents when accounting for PSA kinetics, age, and comorbidity and perhaps genomic or clinical biomarkers to help better guide these decisions.

Written by: Andrew J. Armstrong, MD ScM FACP, Professor of Medicine, Surgery, Pharmacology and Cancer Biology, Director of Research, the Duke Cancer Institute Center for Prostate and Urologic Cancers, Divisions of Medical Oncology and Urology, Duke University

Reference:
Whitney, C., Howard, L., Freedland, S., DeHoedt, A., Amling, C., & Aronson, W. et al. (2018). Impact of age, comorbidity, and PSA doubling time on long-term competing risks for mortality among men with non-metastatic castration-resistant prostate cancer. Prostate Cancer And Prostatic Diseases, 22(2), 252-260. doi: 10.1038/s41391-018-0095-0 Received: 4 June 2018 / Revised: 31 July 2018 / Accepted: 26 August 2018 / Published online: 2 October 2018 © Springer Nature Limited 2018

Read the Full-Text Article: Impact of Age, Comorbidity, and PSA Doubling Time on Long-Term Competing Risks for Mortality Among Men with Non-Metastatic Castration-Resistant Prostate Cancer