The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. We used a quantitative reverse-transcriptase–polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression–free survival), clinical or radiographic progression–free survival, and overall survival. A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7–positive patients had lower PSA response rates than AR-V7–negative patients (0% vs. 53%, P=0.004) and shorter PSA progression–free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression–free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7–positive patients had lower PSA response rates than AR-V7–negative patients (0% vs. 68%, P=0.004) and shorter PSA progression–free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression–free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA. Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.)

There are currently 6 available therapies for the treatment of castration-resistant prostate cancer (CRPC), all of which have produced survival improvements.¹ These therapies fall into 4 classes: androgen receptor (AR)-directed therapies (abiraterone acetate,² enzalutamide³), taxane chemotherapies (docetaxel,⁴ cabazitaxel⁵), immunotherapies (sipuleucel-T⁶), and bone-targeting radiopharmaceuticals (radium-223).⁷ Of these, the most widely used are the AR-targeting therapies and the chemotherapies. However, mechanisms of response and resistance to these therapies remain poorly understood.^8,9 Furthermore, predictive biomarkers aiding in treatment selection (ie, selecting for or against a particular therapy) are still lacking, although prognostic markers are abundant.¹⁰

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/ 2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

Study Type – Prognosis (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Patients with biochemical recurrence after prostatectomy often develop subsequent metastases. However, the natural history of metastatic progression in men who have not received subsequent therapies before developing metastases has been understudied. Here, we describe the largest known cohort of men with PSA‐recurrent prostate cancer after prostatectomy who have not received additional treatments before metastasis. We characterize metastatic risk based on clinical variables, and we show that Gleason score and PSA doubling time are the strongest predictors of metastasis‐free survival. We present tables stratifying metastatic risk by these two variables. OBJECTIVE: To describe metastasis‐free survival (MFS) in men with prostate‐specific antigen (PSA) recurrence following radical prostatectomy, and to define clinical prognostic factors modifying metastatic risk. PATIENTS AND METHODS: We conducted a retrospective analysis of 450 men treated with prostatectomy at a tertiary hospital between July 1981 and July 2010 who developed PSA recurrence (≥0.2 ng/mL) and never received adjuvant or salvage therapy before the development of metastatic disease. We estimated MFS using the Kaplan–Meier method, and investigated factors influencing the risk of metastasis using Cox proportional hazards regression. RESULTS: Median follow‐up after prostatectomy was 8.0 years, and after biochemical recurrence was 4.0 years. At last follow‐up, 134 of 450 patients (29.8%) had developed metastases, while median MFS was 10.0 years. Using multivariable regressions, two variables emerged as independently predictive of MFS: PSA doubling time (<3.0 vs 3.0–8.9 vs 9.0–14.9 vs ≥15.0 months) and Gleason score (≤6 vs 7 vs 8–10). Using these stratifications of Gleason score and PSA doubling time, tables were constructed to predict median, 5‐ and 10‐year MFS after PSA recurrence. In different patient subsets, median MFS ranged from 1 to 15 years. CONCLUSIONS: In men undergoing prostatectomy, MFS after PSA recurrence is variable and is most strongly influenced by PSA doubling time and Gleason score. These parameters serve to stratify men into different risk groups with respect to metastatic progression. Our findings may provide the background for appropriate selection of patients, treatments and endpoints for clinical trials.