The aggressive variant prostate carcinoma (AVPC) molecular signature (-MS) and platinum-sensitivity in castration resistant prostate cancer (CRPC).

Abstract

5013 Background: The AVPC are a subset of prostate cancers that share the clinical, therapy response and molecular profiles of the small cell prostate carcinomas, a histological variant of the disease that responds poorly to androgen receptor directed therapies. The AVPC are characterized by a molecular signature of combined tumor suppressor defects (≥ 2 alterations in Tp53, RB1 and/or PTEN by immunohistochemistry or genomic analyses). We conducted a randomized phase II study of cabazitaxel (CAB) plus or minus carboplatin (CARB) in men with CRPC and asked whether the AVPC-MS predicted for platinum benefit. Methods: 160 men with metastatic CRPC were randomized 1:1 to receive IV CAB (25 mg/m2) or CAB/CARB (25 mg/m2; AUC4) Q21 days with growth factor support until disease progression, unacceptable toxicity or for up to 10 cycles. Imaging occurred every 2 cycles. The primary endpoint was progression free survival (PFS). 73 tumor samples obtained within 1 year of registration from 65 of the 160 patients (pts) were stained for Tp53, RB1, PTEN, AR-N terminus, AR-C terminus and Ki67. DNA of sufficient quantity for sequencing was extracted from 27 tumors and 70 plasma samples. Results: At a median follow up of 21.6 months (mo), median PFS (mPFS) in the overall population (n = 160) is 4.6 mo (95%CI 3.5, 5.8) with CAB vs 7.4 mo (95% CI 5.6, 8.3) with CAB/CARB (p = 0.004). Men with AVPC-MS-positive tumors had a mPFS of 4.5 mo (95%CI 1.5, NA) with CAB [n = 9] vs 8.0mo (95%CI 6.11-9.7) with CAB/CARB [n = 23] (p = 0.0036) whereas men with AVPC-MS-negative tumors had a mPFS of 6.8mo (95%CI 5.2, NA) with CAB [n = 12] vs 5.4mo (95%CI 3.72, NA) with CAB/CARB [n = 12] (p = 0.1445). Analysis of plasma DNA samples is ongoing and will be presented at the meeting. Conclusions: The AVPC-MS identifies a subset of men platinum-sensitive CRPC tumors. These findings should serve as the foundation for a therapeutically relevant classification of prostate cancer. Clinical trial information: NCT01505868.