Role of PSA response as a marker for efficacy of patients with castration-resistant prostate cancer treated with novel hormonal therapies

Dear Editor,

Recently, novel hormonal therapies (NHTs) such as abiraterone acetate and enzalutamide have changed the therapeutic scenario for castration-resistant prostate cancer (CRPC) (1). Unfortunately, except for androgen receptor splice variant-7 (AR-V7) (2), no other biomarker can predict the outcome of patients exposed to NHTs; consequently, the optimal sequence of these therapies remains unknown (3).

The identification of a more easily available surrogate marker for survival or efficacy in patients with CRPC treated with either abiraterone acetate or enzalutamide represents an important advance toward finding an active therapy early, particularly with the increase in alternative available therapeutic options. In this context, prostate-specific antigen (PSA) response rate (RR; defined as an improvement of ≥50% in the PSA concentration from the pretreatment baseline value (4)) may represent an early and rapid biomarker.

Recently, from a literature-based analysis involving the largest number of trials of docetaxel-based first-line chemotherapy for patients with CRPC, we found a correlation between PSA RR and overall survival (OS) (5, 6). On the basis of these findings, it would seem reasonable to extend our previous analysis to NHTs in patients with CRPC.

In this letter, we present preliminary results of an ongoing review performed by our group. We reviewed the literature describing controlled or randomized studies of NHTs for CRPC; the complete methodology of search strategies and the inclusion and exclusion criteria were previously reported (1).

Nine studies were chosen. The characteristics of the studies included and the definitions of PSA response are reported in Table I. A total of 8,713 participants were evaluated (4,934 cases in the NHT group and 3,779 cases in the control group). Among these studies, there were 4 postchemotherapy studies and 5 prechemotherapy studies, 4 studies investigated enzalutamide, 3 studies abiraterone acetate and 2 studies orteronel as experimental drug; while a placebo was the control arm of most of the studies.

Table I

Trials included in the analysis

Study and drugs compared	Patients	Median OS (months)	Median PFS (months)	PSA response rate >50% (%)	Definition of PSA response rate
AFFIRM E vs. PL	800 vs. 399	18.4 vs. 13.6 Δ4.8	8.3 vs. 2.9 Δ5.4	54 vs. 2 Δ52	Reduction in the PSA level from baseline by 50% or more, as confirmed in an additional PSA evaluation performed 3 or more weeks later.
COU-AA-301 AA + P vs.PL + P	797 vs. 398	15.8 vs. 11.2 Δ4.6	5.6 vs. 3.6 Δ2	29 vs. 5 Δ24	The proportion of patients with a decrease of ≥50% in the PSA concentration from the pretreatment baseline PSA value, which was confirmed after ≥4 weeks by an additional PSA evaluation.
COU-AA-302 AA + P vs. PL + P	546 vs. 542	34.7 vs. 30.3 Δ4.4	16.5 vs. 8.2 Δ8.3	68 vs. 29 Δ39	≥50% decline in PSA level from baseline.
ELM-PC 4 O + P vs. P L+ P	781 vs. 789	31.4 vs. 29.5 Δ1.9	13.8 vs. 8.7 Δ5.1	53 vs. 32 Δ25	Patients with a 50% or greater decrease in PSA from baseline at 12 weeks.
ELM-PC 5 O + P vs. PL + P	734 vs. 365	17 vs. 15.2 Δ1.8	8.3 vs. 5.7 Δ2.4	25 vs. 10 Δ15	Patients with a 50% or greater decrease in PSA at 12 weeks.
PREVAIL E vs. PL	872 vs. 875	35.3 vs. 31.3 Δ4	20 vs. 5.4 Δ16.6	78 vs. 3 Δ75	A ≥50% reduction in PSA from baseline to the lowest postbaseline PSA result. A consecutive assessment conducted at least 3 weeks later was required to confirm the PSA response.
TERRAIN E vs. BIC	183 vs. 189	NR	15.7 vs. 5.8 Δ9.9	82 vs. 21 Δ61	A ≥50% PSA decline from baseline.
STRIVE E vs. BIC	198 vs. 198	NR	19.5 vs. 5.7 Δ13.8	81 vs. 31 Δ50	Confirmed PSA responses, defined as >50% from baseline at any postbaseline assessment. Confirmation of these PSA responses was required at a consecutive assessment obtained at least 3 weeks later.
SAKK 08/11 O vs. PL	23 vs. 24	NR	8.5 vs. 2.8 Δ3.2	57 vs. 4 Δ53	PSA decline ≥50%.

Δ = delta; AA = abiraterone acetate; BIC = bicalutamide; E = enzalutamide; NR = not reported; O = orteronel; OS = overall survival; P = prednisone; PFS = progression-free survival; PL = placebo; PSA = prostate-specific antigen.

The nonparametric Spearman’s rank correlation test (ρ) was used to assess relationships between PSA RR and OS or progression-free survival (PFS). We also derived ΔPSA RR, ΔOS and ΔPFS by subtracting the value in the control arm from the value in the experimental arm. StatIC software, version 2012, was used for the analysis.

Although using the literature rather than patient data analysis does not allow definitive conclusions, our preliminary results showed a good relationship between PSA RR and OS (ρ = 0.71; p = 0.01) and a strong correlation between PSA RR and PFS (ρ = 0.91; p = 0.00). However, with regard to any correlation between ΔPSA RR and ΔOS, ρ decreased to 0.42 and showed a nonsignificant result (p = 0.39), while regarding any correlation between ΔPSA RR and ΔPFS, ρ showed a similar decrease (from 0.91 to 0.71) but the result was significant (p = 0.03).

In conclusion, although the issue of any correlation between PSA RR and survival or efficacy for patients with CRPC treated with NHTs remains unresolved, the present analysis suggests that the role of PSA RR as a surrogate marker for median OS and PFS should be reassessed and should not be ignored for early identification of patients who will not respond to NHTs.