Results of a Randomized Phase II Trial of Intense Androgen Deprivation Therapy prior to Radical Prostatectomy in Men with High-Risk Localized Prostate Cancer

Abstract

Purpose: This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).

Materials and methods: Eligible patients had a Gleason score ≥4+3=7, prostate specific antigen >20 ng/mL or T3 disease and lymph nodes <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide (AAPL) or abiraterone, prednisone, leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by radical prostatectomy. Surgical specimens underwent central review. The primary end point was the rate of pathologic complete response or minimum residual disease (minimum residual disease, tumor ≤5 mm). Secondary end points included prostate specific antigen response, positive margin rate and safety. Magnetic resonance imaging and tissue biomarkers of pathologic outcomes were explored.

Results: The study enrolled 118 patients at 4 sites. Median age was 61 years and 94% of patients had high-risk disease. The combined pathologic complete response or minimum residual disease rate was 22% in the AAPL arm and 20% in the APL arm (difference: 1.5%; 1-sided 95% CI -11%, 14%; 1-sided p=0.4). No new safety signals were observed. There was low concordance and correlation between posttherapy magnetic resonance imaging assessed and pathologically assessed tumor volume. PTEN-loss, ERG positivity and presence of intraductal carcinoma were associated with extensive residual tumor.

Conclusions: Intense neoadjuvant hormone therapy in high-risk prostate cancer resulted in favorable pathologic responses (tumor <5 mm) in 21% of patients. Pathologic responses were similar between treatment arms. Part 2 of this study will investigate the impact of adjuvant hormone therapy on biochemical recurrence.

Keywords: abiraterone acetate; neoadjuvant therapy; prostatectomy.

Figure 1.

Consort diagram. Newly diagnosed unfavorable intermediate and high-risk patients with prostate cancer were randomly assigned 1:1 to abiraterone, apalutamide, leuprolide, and prednisone versus abiraterone acetate, leuprolide, and prednisone for 24 weeks followed by radical prostatectomy. *Three patients discontinued treatment due to toxicity after 1, 2, and 4 cycles of therapy.

Figure 2.

A: Representative images of multiparametric prostate MRI pre- and post-neoadjuvant therapy on patient 20. The patient was a 67 year old male at baseline with intermediate-risk disease (Gleason 4+3, PSA 8.3 ng/mL, cT2). Prior to neoadjuvant therapy, on T2 weighted imaging (T2WI) the tumor is seen as a large grey area with corresponding black area detected on Apparent Diffusion Coefficient (ADC) and white signal on Diffusion Weighted Imaging (DWI). There is enhancement post-contrast on subtraction Dynamic Contrast Enhanced (DCE) imaging. Following neoadjuvant therapy with abiraterone, prednisone, and leuprolide the tumor is no longer visible on T2WI and there is less apparent ADC, DWI, and subtraction DCE, though not totally resolved. B: Representative images from a RP specimen show invasive carcinoma (IC) and intraductal carcinoma (IDC) on hematoxylin and eosin (HE) staining. Immunohistochemistry staining of IC and IDC components is weakly positive for androgen receptor (AR), negative for PTEN, and positive for ERG. This patient at RP had ypT3aN0 disease with negative margins. The residual tumor measured 1.8 × 1.0 cm with total tumor volume of 1.73 cm³ and 10% cellularity.

Figure 2.

A: Representative images of multiparametric prostate MRI pre- and post-neoadjuvant therapy on patient 20. The patient was a 67 year old male at baseline with intermediate-risk disease (Gleason 4+3, PSA 8.3 ng/mL, cT2). Prior to neoadjuvant therapy, on T2 weighted imaging (T2WI) the tumor is seen as a large grey area with corresponding black area detected on Apparent Diffusion Coefficient (ADC) and white signal on Diffusion Weighted Imaging (DWI). There is enhancement post-contrast on subtraction Dynamic Contrast Enhanced (DCE) imaging. Following neoadjuvant therapy with abiraterone, prednisone, and leuprolide the tumor is no longer visible on T2WI and there is less apparent ADC, DWI, and subtraction DCE, though not totally resolved. B: Representative images from a RP specimen show invasive carcinoma (IC) and intraductal carcinoma (IDC) on hematoxylin and eosin (HE) staining. Immunohistochemistry staining of IC and IDC components is weakly positive for androgen receptor (AR), negative for PTEN, and positive for ERG. This patient at RP had ypT3aN0 disease with negative margins. The residual tumor measured 1.8 × 1.0 cm with total tumor volume of 1.73 cm³ and 10% cellularity.