Marker for Prostate Cancer That Needs Aggressive Therapy

Pam Harrison

January 17, 2017

A new marker can identify men with prostate cancer who would benefit from more aggressive therapy, researchers report. They found that men with prostatic-specific antigen (PSA) levels that exceed 0.5 ng/mL after they have undergone 6 months of radiotherapy with or without androgen-deprivation therapy (ADT) are at high risk for all-cause mortality and should be entered into a clinical trial prior to overt PSA failure to receive more aggressive therapy.

"If the PSA nadir does not get below this point, then that signifies this is a man at risk who needs more treatment," lead author Trevor Royce, MD, senior resident, Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts, told Medcape Medical News.

"And the way we would do that is enroll him in a clinical trial which would be exploring standard of care vs more aggressive treatment, because he is at risk of dying and needs more aggressive treatment," Dr Royce added.

The study was published online January 12 in JAMA Oncology.

The finding comes from a secondary analysis of a randomized clinical trial in which 206 men with unfavorable-risk prostate cancer were evaluated every 3 months for 2 years and less frequently thereafter. A total of 157 of the men were selected for the current analysis.

Investigators looked at the performance of four surrogate endpoints: PSA nadir > 0.5/mL; PSA failure; a doubling of the PSA in less than 9 months; and less than 30 months to PSA failure. Each marker was analyzed in relation to the risk for all-cause mortality using the proportion of treatment effects (PTEs) metric, a statistical tool used to identify which surrogate is superior to others.

"After a median follow-up of 16.49 years, among the 157 men in the study cohort, 110 died (70%)," Dr Royce reports.

Because a PSA nadir of less than 0.5/ng/mL had a PTE value closest to 100%, "it was selected as the optimal surrogate," he adds.

In contrast, PSA failure did not emerge as a surrogate for all-cause mortality despite the fact that the patients in this particular cohort had minimal or no comorbidities on study entry.

Window of Opportunity

Dr Royce and colleagues point out that their observation that men who do not reach a PSA nadir of less than 0.5 ng/mL are at higher risk for all-cause mortality provides a window of opportunity for physicians to refer patients for enrollment into a clinical trial when they are still responding to treatment but are at high risk for eventual treatment failure.

"These men would not yet have metastatic or castrate-resistant prostate cancer," Dr Royce explained. "And the advantage of this is to be able to identify these men before they get to that point in their disease. So while their disease may be incurable, we could make them curable by giving them more treatment," he added.

Senior author Anthony Victor D'Amico, MD, PhD, chief of genitourinary radiation oncology, Brigham and Women's Hospital, Boston, Massachusetts, suggested in a statement that the study's results could have "practice-changing implications" on how future prostate cancer trials are designed.

By enriching study cohorts with men who have clear evidence of a surrogate endpoint for all-cause mortality, "one can enhance the likelihood that the study will be able to answer the question of whether survival is prolonged when novel treatment is added to standard of care as compared with standard of care and over a shorter time period," the investigators note.

Early Prediction Desirable

Asked by Medscape Medical News to comment on the study, Ronald Chen, MD, MPH, associate professor of radiation oncology, University of North Carolina at Chapel Hill, said that all clinicians, including himself, want to be able to predict which patients are unlikely to be cured of their disease as early as possible so that they can offer additional treatment right away and increase patients' chances for a cure.

"What currently happens in clinic is we give patients treatment for prostate cancer ― say, radiation ― and then we wait often many years until they develop signs of recurrence, and then at that time we provide additional treatment," Dr Chen explained. "And that's maybe too late, because we've let the disease grow for many years," he added.

The contribution of the current study, Dr Chen observed, is that Dr Royce and colleagues identified a much earlier marker. This tells physicians that if a patient's PSA does not fall below 0.5 ng/mL with initial treatment, "they are likely to die from their disease," he said. "And therefore providing additional treatment early on to see if we can cure more patients is the real value of this study."

Dr Chen acknowledged that the findings are based on a secondary analysis, so further prospective studies are required to validate the newly identified marker as a signal for high-risk disease.

"However, if indeed this surrogate is validated with further study, then what it says to me is, I probably need to do as much as I can to get a patient's PSA below 0.5 ng/mL to increase my cure rate and the patient's chances of survival," Dr Chen said.

A number of different options are currently available for physicians to try to achieve lower PSA nadirs, including the use of higher radiation doses during initial treatment or one of the newer hormonal agents that may be more potent than the current ADT, Dr Chen noted.

Dr Royce and Dr D'Amico have disclosed no relevant financial relationships. Dr Chen has served as a one-time consultant to Medivation/Astellas.

JAMA Oncol. Published online January 12, 2017. Abstract

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