Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response

Abstract

Purpose: For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT.

Patients and methods: Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response.

Results: Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of <0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology.

Conclusions: Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease.

Trial registration: ClinicalTrials.gov NCT02430480.

Figure 1.. Study schema.

mpMRI: multiparametric MRI; ADT: androgen deprivation therapy; RARP: robot-assisted radical prostatectomy.

Figure 2.. Response to neoadjuvant enzalutamide plus ADT.

(A) 55/59 lesions demonstrated >50% volume reduction. (B) 36/38 patients demonstrated >50% volume reduction. Lesions and patients are color-coded based on pathologic response to treatment at RP. One patient completed baseline and post-enzalutamide plus ADT mpMRI but did not undergo RARP, thus he was included to demonstrate MRI evidence of extreme non-response but was excluded from all analyses involving pathologic response to treatment. (C) Spearman correlation of final imaging volumes per patient with final pathologic residual cancer burden, logarithmically transformed. Values of zero were transformed to nominal values to preserve their rank within the dataset but omitted from the graph.

Figure 3.. Histologic analysis of in situ tissue phenotypes.

Representative micrographs of low, medium, and high histology scores for anti-AR (A) and anti-PSA (B) immunostaining of biopsies (top) and absent, low, medium, and high histology scores for post-treatment surgical RALP or TURP specimens (bottom). There are no examples of absent anti-AR or PSA staining in pre-treatment biopsied tumor tissue. Scale bar: 500 μm. Inset scale bar: 100 μm. Tissue sections immunostained with (C) anti-AR from biopsies (N = 39 cases representing 82 different tissue blocks) and post-treatment surgical specimens (N = 33 cases representing 61 different tissue blocks) or (D) anti-PSA from biopsies (N = 38 cases representing 79 different tissue blocks) and post-treatment surgical specimens (N = 33 cases representing 64 different tissue blocks) were quantified with Definiens to measure stain intensity. Histology scores were reported on a weighted index of 0 to 1, and multiple slides from the same individual were added before computing the index. Each circle represents a single patient. Bars represent median and 95% confidence interval. P < 0.0001 for both AR and PSA staining, by Welch’s t test. (E) Representative micrographs of positive (overexpressed) and negative nuclear ERG immunostaining (left) and reduced or intact PTEN (right) in post-treatment tissue. Scale bar: 500 μm. Inset scale bar: 100 μm. Note that nuclear ERG intensity is reduced relative to endogenous ERG expression in endothelial cells on account of its expression being driven by (reduced) AR activity. (F) Post-treatment tissue sections were immunostained with anti-ERG and anti-PTEN antibodies and the frequency of ERG-positive tumor cells (any percentage positive), or PTEN-reduced or PTEN-deficient (at least 5% of tumor cells) are shown. pCR/MRD vs. NR for PTEN was different at P = 0.0006 by Fisher’s exact test.

Figure 4.. Low relative tumor burden is a statistically significant predictor of final pathologic outcome.

(A) Baseline lesion volumes in cc, based on the final pathology status for each patient. N = 39 for CR/MRD lesions and N = 20 for NR lesions. P < 0.001 by two-sided Mann-Whitney test. (B) Receiver operating characteristic curve for pre-treatment relative tumor burden (RTB) yielding an AUC of 0.89 and optimal threshold of 8.1%. (C) Baseline mpMRI of 2 different patients with high-risk localized prostate cancer and corresponding final pathology. Responder: 72-year-old with a PSA of 5.81 ng/ml had a PI-RADS 5 lesion in the left apical-mid anterior peripheral zone which revealed Gleason 4+4=8 cancer at targeted biopsy. Baseline relative tumor burden was 3.4% of the prostate. Final pathology revealed pathologic complete response. Non-responder: 66-year-old with a PSA of 5.53 ng/ml had a large PI-RADS 5 lesion in the right apical-base peripheral zone which revealed Gleason 4+5=9 cancer at targeted biopsy. Baseline relative tumor burden was 21.5% of the prostate. Final pathology revealed the patient was a non-responder with RCB of 0.24 cc.