Adding Value to Clinical Decision-Making in Nonmetastatic Castration-Resistant Prostate Cancer

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Several recent investigations have led to the U.S. Food and Drug Administration (FDA) approval of novel antiandrogens to treat nonmetastatic castration-resistant prostate cancer. Yet, this work has not addressed the treatment of nonmetastatic hormone-sensitive biochemically recurrent prostate cancer.

To shed some light on this important issue, The ASCO Post spoke with Catherine H. Marshall, MD, MPH, lead author on a study that looked at the timing of androgen-deprivation treatment for men with biochemically recurrent prostate cancer in the context of novel therapies. Dr. ­Marshall is Assistant Professor in the Department of Oncology at the Johns Hopkins University School of Medicine, with a special interest in prostate cancer. Most of her current research focuses on the overlap between cardiovascular disease risk factors and cancer.

Catherine H. Marshall, MD, MPH

Catherine H. Marshall, MD, MPH

Study Background, Goal, and Methods

You were lead author on an investigation looking at the timing of androgen-deprivation treatment for men with biochemically recurrent prostate cancer. Please describe the purpose of the study and its method.

The study was prompted by three recent FDA approvals for drugs that are used to treat nonmetastatic castration-resistant prostate cancer. However, the trials lacked a component of when to initiate continuous hormone therapy in the first place.

We know that some men with biochemical recurrence, even those who do not receive hormone-deprivation therapy, will have long periods of survival. In thinking about that, we wanted to estimate what the overall survival was from the time of radical prostatectomy in men who delay hormone therapy until the development of metastases.

Our study was a retrospective review of two prospective clinical cohorts of men with localized prostate cancer who underwent radical prostatectomy at Johns Hopkins University and Walter Reed National Military Medical Center.1 All men who had a radical prostatectomy from 1983 to 2014 and developed biochemically recurrent prostate cancer with a prostate-specific antigen (PSA) doubling time of less than or equal to 10 months were included. Men who received adjuvant or salvage androgen-deprivation therapy with radiotherapy were excluded. Our goal was to estimate metastasis-free and overall survival of men with biochemically recurrent prostate cancer.

Clinical Relevance of Biochemical Recurrence

Before discussing the results of your study, perhaps you could shed some light on the clinical relevance of biochemical recurrence in the context of survival outcomes among men diagnosed with prostate cancer. Other than the finding of rising PSA levels, how do we determine biochemically recurrent prostate cancer?

Biochemical recurrence is a rising PSA level after local treatment with either surgery or radiation and no evidence of metastatic disease, at least as determined by conventional scanning. According to the literature, the optimal treatment in this setting is still very much a gray area. For instance, the natural history of biochemical recurrence after radical prostatectomy can be long but variable.

We certainly need better risk-assessment models to identify men who are at high risk for early prostate cancer death early as well as those men who may benefit from aggressive salvage treatment. Equally important, we need to find more effective ways to identify men at low risk for prostate cancer death, so they can be safely observed.

Considerations for Androgen-Deprivation Therapy

Please tell our readers what you found and how the findings might affect the clinical management of men who might be considering androgen-deprivation therapy.

We found that men with biochemically recurrent prostate cancer, who put off having hormone therapy until metastasis, tend to have overall survival that is quite long; thus, the early initiation of continuous androgen-deprivation therapy for biochemical relapse may not meaningfully improve overall survival for these patients. The median time to metastatic disease measured from the time of local treatment in patients with a PSA doubling time of 6 months or less was 144 months, which is quite long.

It is important to note, ­however, that adequately designed prospectively ­randomized studies in patients with biochemical ­recurrence that test the role of early vs deferred ­androgen-deprivation therapy remain critical to inform treatment decisions in this population as well as enhance patients’ and physicians’ understanding of the clinical ­significance of the ­pivotal nonmetastatic castration-resistant prostate cancer studies.

The way that we think about this information being used is to inform the clinical decision as to whether or not to employ continuous hormone therapy or to initiate alternative therapies (including observation, delaying hormone therapy, or initiating intermittent hormone therapy). So, this study has added another layer of information that can be used when patients and physicians are discussing such decisions.

We know that some men with biochemical recurrence, even those who do not receive hormone-deprivation therapy, will have long periods of survival.
— Catherine H. Marshall, MD, MPH

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Clinical Factors Predictive of Biochemical Recurrence

Please discuss the relationship between positive margins or extracapsular extension and biochemical recurrence.

Many clinical factors are associated with the likelihood of developing biochemical recurrence, with positive surgical margins being one of them. In our study, we did examine a number of these factors, among men who already had biochemical recurrence. We found that older age, higher pathologic tumor staging (which would be with extracapsular extension outside of the prostate capsule), higher Gleason scores, and quicker PSA doubling time were associated with a higher risk of adverse outcomes.

Closing Thoughts

Please share some closing thoughts on this important issue in prostate cancer.

The big caveat when you’re putting biochemical recurrence into the clinical prostate cancer scenario is that it is still a very active area of research. However, what is changing this space is the advent of novel imaging techniques, which will affect treatment paradigms in this setting as research continues in this area on whether and how treatment should change. Finally, it is important to note, that these retrospective studies were performed prior to this new generation of imaging. 

DISCLOSURE: Dr. Marshall has served as a consultant to Bayer Pharmaceuticals and McGraw Hill and has been reimbursed for travel expenses by Dava Oncology.


1. Marshall CH, Chen Y, Kuo C, et al: Timing of androgen deprivation therapy for men with biochemical recurrent prostate cancer in the context of novel therapies. J Urol 206:623-629, 2021.