Study Addresses Appropriate Clinical Use of PSA Trial Data in Prostate Cancer

Nicholas J. Giacalone, MD

A treatment recommendation based on reduced prostate-specific antigen (PSA) failure observed from early results of randomized controlled trials is not likely to prolong survival in men with moderate-to-severe comorbidities, according to a recently published report in the Journal of Clinical Oncology.

Although PSA failure was more common in men with no or minimal comorbidity, PSA failure was shown to be associated with an increased all-cause mortality (ACM) among men with no or minimal comorbidity (adjusted HR, 1.59; 95% CI, 1.03 to 2.46; P = .04), but not among those with moderate or severe comorbidity (adjusted HR, 1.75; 95% CI, 0.76-3.99; P = 0.19).

“The reason why this is important is because right now, today, there are several large, randomized prostate cancer trials that have reported preliminary results demonstrating a reduction in relapse-free survival (primarily driven by a reduction in PSA failure), but no difference in overall survival,” said lead author Nicholas J. Giacalone, MD, a senior resident in Radiation Oncology at Brigham and Women’s Hospital.

The study examined 206 men with localized intermediate- and high-risk prostate cancer, who were randomly assigned to receive radiation therapy or radiation therapy plus 6 months of androgen deprivation therapy (ADT).

The current standard of care in this space calls for a combination of external-beam radiation therapy (EBRT) and ADT; however, a recent post-random assignment analysis stratified by comorbidity status found that the addition of 6 months of ADT to EBRT was associated with a survival benefit, but only in men with no or minimal comorbidity. The same analysis demonstrated a shortened survival in men with moderate-to-severe comorbidity. Therefore, the current study aimed to answer the question of whether PSA failure—an endpoint that often occurs many years before metastasis and death from prostate cancer—is a clinically relevant endpoint only in men who have no or minimal comorbidity.

A comorbidity score was assigned at the time of random assignment using the ACE-27, a 27-item comorbidity index validated in patients with cancer. For the current study, patients were separated into 2 different subgroups: men with no or minimal comorbidity and men with moderate-to-severe comorbidity.

Follow-up began on the day of random assignment and concluded on the date the patient was last observed or on the date of death, whichever came first. Lifelong ADT administration for PSA failure was recommended when the PSA level reached 10 ng/mL. The decision to administer salvage ADT was left to the discretion of the treating physician and was dependent on how quickly the PSA was rising, as well as whether it exceeded 10 ng/mL.

Approximately half of men who experienced PSA failure initiated salvage ADT because the remaining patients had slow increases in PSA with long doubling times, and their PSA levels had not yet reached 10 ng/mL at the time of this analysis. Once a patient became refractory to first-line salvage ADT, he was given second- and third-line hormonal treatment, usually followed by cytotoxic chemotherapy.

To record a death as being caused by prostate cancer, there had to be documented castration-resistant metastatic prostate cancer and evidence that the PSA level was increasing at the time of the last follow-up visit despite the use of second-line hormonal maneuvers, and, in most cases, cytotoxic chemotherapy before death.

After a median follow-up of 16.62 years, 156 men (76%) died, of whom 29 (19%) died as a result of prostate cancer. Among men with moderate to severe comorbidity, 46 of 49 (94%) died, compared with 110 of 157 men (70%) with no or minimal comorbidity.

The results of the study showed that men with no or minimal—as compared with moderate-to-severe—comorbidity were significantly less likely (P = .006) to have died overall, or to have died as a result of cardiovascular disease (11.5% vs 42.9%). However, men with no or minimal comorbidity were more likely to have died as a result of prostate cancer (15.9% vs 8.2%).

Among men with no or minimal comorbidity at random assignment, the risk of ACM was significantly increased in men who were observed to have PSA failure compared with those who were not. There was no significant increase in risk of ACM in men with moderate-to-severe comorbidity, irrespective of PSA failure status.

Although PSA failure was more common in men with no or minimal comorbidity compared with men with moderate-to-severe comorbidity, the occurrence of PSA failure was associated with a significantly increased risk of ACM only in men with no or minimal, but not moderate-to-severe, comorbidity.

The discordance in association between the occurrence of PSA failure and the subsequent risk of ACM provides evidence to support the possibility that competing risks—and not prostate cancer death—are the reason for a lack of translation of PSA failure into an increased risk of ACM in men with moderate-to-severe comorbidity.

These results also provide evidence to support an ongoing discussion of treatment approaches that have been shown in early results of randomized controlled trials to provide a PSA failure-free survival benefit in men who have unfavorable-risk prostate cancer and no or minimal comorbidity.

“Men with minimal or no comorbidities should have the preliminary results of these studies discussed with them, as a reduction in PSA failure may translate into improved overall survival,” said Giacalone.

However, because of the low likelihood that a PSA failure-free survival benefit will translate into a reduction in the risk of death from ACM in men with moderate-to-severe comorbidity, such a discussion may not be appropriate for this subgroup of patients.

“Our study suggests that men with more significant comorbidities—such as a history of coronary artery disease or stroke—are unlikely to benefit from such treatment shown only to reduce PSA failure, because our study suggests that this is unlikely to transfer into improved overall survival in these men,” explained Giacalone.

The authors of this study emphasize that the current evidence suggests that PSA failure in men with no or minimal comorbidity is a prognostic factor and not a surrogate for prostate cancer death. Therefore, having a negative prognostic factor (PSA failure, in this case) does not necessarily dictate that a patient will subsequently die as a result of prostate cancer.

In order to validate that PSA failure is a surrogate for prostate cancer death in men with no or minimal comorbidity, a randomized trial would have to be conducted, in which men are stratified by comorbidity status before random assignment, and in whom results documented a prostate cancer-specific survival benefit in the experimental arm. RTOG 0815 (NCT00936390) is an ongoing trial in which men were stratified before random assignment using the ACE-27 index, and were then randomly assigned to receive high-dose radiation with or without 6 months of ADT.

If this study shows both a prostate cancer—specific survival and an overall survival benefit in the subgroup of men with no or minimal comorbidity with the addition of ADT to high-dose radiation, then formal testing of PSA failure as a surrogate for prostate cancer–specific mortality and ACM could be performed. Until then, practice-changing measures should only be carried out on the basis of improved overall survival results.

Giacalone NJ, Wu J, Chen MH, et al. Prostate-specific antigen failure and risk of death within comorbidity subgroups among men with unfavorable-risk prostate cancer treated in a randomized trial [published online September 6, 2016]. J Clin Oncol. doi:10.1200/JCO.2016.68.4530.