Current and Future Applications of PSA Nadir

“To determine a treatment failure or recurrence, you have to watch the PSA drop and rise. This is novel because it provides the opportunity to identify men much, much earlier, even years earlier who have failed treatment and who are very likely to die of prostate cancer by watching how low the PSA goes and where it nadirs,” Dr D’Amico said.

Typically, men who are treated with RT and ADT will experience PSA nadir within about 6 months of initiating therapy. Dr D’Amico said that for men who nadir above 0.5 ng/mL, “you can then enroll them right then and there on clinical trials that would allow you to give them medicines like enzalutamide, abiraterone, sipuleucel-T, docetaxel, radium-223—all of the things shown to prolong survival among men with castrate-resistant metastatic disease.”

Exploring the possibility of cure for men whose PSA has not nadired below 0.5 ng/mL and therefore are at high risk of dying from prostate cancer is worth investigating in clinical trials, according to Dr D’Amico. Specifically, the use of PSA nadir above 0.5 ng/mL will identify men at high-risk of death much earlier, allowing for earlier novel treatment initiation on clinical trials.

“It gives you a window that you didn’t have before, this lead-time that you get that could be crucial,” he said.

Neal D. Shore, MD, FACS, director of the Carolina Urologic Research Center of the Atlantic Urology Clinics in Myrtle Beach, South Carolina, who was not affiliated with the study, agreed with the authors, and told Cancer Therapy Advisor that these results are clinically relevant now, though further studies are needed to validate the findings.

Dr Shore commented that he felt “the most interesting aspect of the study is the potential for future enrichment of populations for randomized clinical trials; that would be very important for the research community.”

More broadly, Dr Shore stated that, “For the larger, clinical community for your patients who don’t nadir below 0.5 ng/mL as opposed to PSA failure by the traditional ASTRO [American Society for Radiation Oncology] definitions, this would inform urologists, radiation oncologists, and medical oncologists that these patients who are at high-risk, as defined by the criteria they used, should potentially be subjected to further intensity of monitoring and/or at least a patient-physician discussion regarding clinical trial enrollment or consideration of earlier initiation of ADT.”

Remaining Questions

Dr Shore noted that the analysis included men with a Gleason score of 7 under the unfavorable risk umbrella, but there is a considerable difference in terms of risk between a Gleason 7 score and scores above 8. In the analysis, 22% of men had a Gleason score of 8 to 10. A Gleason 7 score can be divided based on the number of positive cores with a potentially more aggressive or high-risk biology with a 4+3 vs a 3+4.

“It would be interesting to better understand how this PSA cut-point would relate to those stratifications of the high-risk populations,” he said.

Another consideration that Dr Shore noted is that the current National Comprehensive Cancer Network (NCCN) treatment guideline for prostate cancer recommends 2 to 3 years of ADT plus RT in men with high-risk (Gleason 8 or greater) disease.2 Men with intermediate-risk disease (Gleason 7, 4+3 or 3+4) may consider 4 to 6 months of ADT plus RT. In contrast, the men in this trial—who were treated between 1995 and 2001—received 6 months of ADT. How this may affect the findings of this trial is unknown.

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Dr D’Amico noted, however, that if this early marker of PSA nadir greater than 0.5 ng/mL works to identify men at risk of early death who receive only 70 Gy of RT and 6 months of ADT, it would also be expected to apply to men who receive higher doses of radiation and/or longer duration of hormonal therapy, or who were treated with surgery.

References

  1. Royce TJ, Chen MH, Wu J, et al. Surrogate end points for all-cause mortality in men with localized unfavorable-risk prostate cancer treated with radiation therapy vs radiation therapy plus androgen deprivation therapy. A secondary analysis of a randomized clinical trial. JAMA Oncol. 2017 Jan 12. doi: 10.1001/jamaoncol.2016.5983 [Epub ahead of print]
  2. Mohler JL, Antonarakis ES, Armstrong AJ, et al; National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 1.2017. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Published December 16, 2016. Accessed January, 2017.