Prostate cancer agent evaluated by PSA progression status

Post-hoc analyses of data collected in PROSPER, the prospective phase III randomized placebo-controlled trial of enzalutamide (XTANDI) treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC), show that a significant proportion of men who progress radiologically while on the androgen receptor inhibitor do not meet standard criteria for PSA progression, reported Fred Saad, MD at the AUA annual meeting in Chicago.

“Many clinicians rely on PSA along with physical examination to monitor prostate cancer patients for therapeutic response and disease progression,” said Dr. Saad.

“The findings from the post-hoc analyses indicate that this practice may risk delay in detection of progression, and they also suggest the need to consider redefining PSA progression criteria for use in clinical trials in men who are being treated with a potent androgen receptor inhibitor.”

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PROSPER enrolled men who developed nmCRPC while on androgen deprivation therapy (ADT). Eligible patients had a rising PSA despite having a castrate testosterone level, baseline PSA ≥2 ng/mL, and PSA doubling time ≤10 months. A total of 1,401 men were randomized 2:1 to treatment with enzalutamide, 160 mg (n=933) or placebo (n=468) and continued on ADT.

The primary endpoint analysis for PROSPER showed that enzalutamide reduced the risk of a metastasis-free survival (MFS) event (defined as radiographic progression or death) by 71% (p<.0001). Subgroup analyses showed that enzalutamide maintained its statistically significant benefit for reducing the risk of radiographic progression or death in both men with and without PSA progression (p<.0001 for both subgroups), as defined by Prostate Cancer Working Group 2 (PCWG2) guidelines (≥25% increase and an absolute increase of ≥2 μg/L above the nadir confirmed by a second consecutive value obtained at least 3 weeks later).

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At the data cut-off date, 22% of patients being treated with enzalutamide and 69% of patients in the placebo group met the criteria for PSA progression. In both the enzalutamide and placebo treatment arms, the proportion of men with an MFS event was higher within the subgroup of patients who had PSA progression than in those who did not. Compared to the placebo group, treatment with enzalutamide reduced the risk of an MFS event by 43% within the subgroup of men with PSA progression and by 81% in the subgroup without PSA progression, Dr. Saad reported.

Comparisons between the two treatment arms also showed that at the time of an MFS event, men in the placebo group had a higher median maximum PSA than men being treated with enzalutamide (38.5 ng/mL vs. 6.0 ng/mL), a higher median maximum increase from nadir (193.2 vs. 81.3%), and a higher median maximum absolute increase from nadir (25.6 ng/mL vs. 1.4 ng/mL).

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In addition, among men who experienced an MFS event, PSA was unchanged or decreased from nadir in 29% of those being treated with enzalutamide compared with just 3% of those in the placebo group.

Dr. Saad reiterated that the PCWG2 criteria for PSA progression require a median maximum absolute increase from nadir of 2 ng/mL. He added, “Most patients in the study who had a radiographic progression event in the absence of PCWG2-defined PSA progression still showed some increase from nadir PSA.”

The study was sponsored by Pfizer and Astellas. Dr. Saad receives honoraria, consulting fees, and research funding from Astellas and from other companies that market products used for treating prostate cancer.