ASCO 2017: The aggressive variant prostate carcinoma molecular signature (-MS) and platinum-sensitivity in castration resistant prostate cancer

Chicago, IL (UroToday.com) The aggressive variant prostate cancer (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.

AVPC are defined clinically by the presence of at least 1 of 7 criteria (AVPC-C), including:
1. Small cell prostate carcinoma
2. Visceral metastases only
3. Lytic bone metastases
4. Bulky nodes or prostate mass
5. Low PSA relative to volume
6. Neuroendocrine markers & serum CEA or LDH
7. Primary castration-resistance

The AVPC are also uniquely characterized by a molecular signature (MS) of combined tumor suppressor defects (≥ 2 alterations in Tp53, RB1 and/or PTEN by immunohistochemistry or genomic analyses). Dr. Ana Aparicio presented results form a randomized phase II study of cabazitaxel (CABAZ) plus or minus carboplatin (CARB) in men with CRPC to assess whether the AVPC-MS predicted for platinum benefit (Clinical trial information: NCT01505868).  

In this study, 160 men with metastatic CRPC were randomized 1:1 to receive IV CABAZ (25 mg/m2) or CABAZ/CARB (25 mg/m2; AUC4) Q21 days with growth factor support until disease progression, unacceptable toxicity, or for up to 10 cycles. Imaging follow-up was performed every 2 cycles. The primary endpoint was progression free survival (PFS) and secondary objectives were safety, response by RECIST criteria, PSA and bone specific alkaline phosphatase, influence of AVPC and AVPC-MS on response, and overall response (OS). 73 tumor samples obtained within 1 year of registration from 64 of the 160 patients (pts) were stained for Tp53, RB1, and PTEN.  DNA of sufficient quantity for sequencing was extracted from 48 tumors and 66 plasma samples. 

48.5% of the ctDNA samples displayed AVPC-MS. At a median follow up of 21.6 months (mo), median PFS (mPFS) in the overall population (n = 160) was 4.59 mo (95%CI 3.51, 5.81) with CABAZ vs. 7.4 mo (95% CI 5.57, 8.28) with CABAZ/CARB (p = 0.004). Men with AVPC-C positive tumors had a mPFS of 3.75 mo (95%CI 2.84-5.71) with CABAZ [n = 41] vs 5.64 mo (95%CI 4.39-8.04) with CABAZ/CARB [n = 45] (p = 0.012) whereas men with AVPC-c negative tumors had a mPFS of 5.2 mo (95%CI 4.49-6.72) with CABAZ [n = 38] vs 7.8 mo (95%CI 6.08-9.93) with CABAZ/CARB [n = 36] (p = 0.09). Men with AVPC-MS-positive tumors had a mPFS of 1.7 mo (95%CI 1.35, NA) with CABAZ [n = 7] vs 8 mo (95%CI 6.1-9.8) with CABAZ/CARB [n = 20] (p = 0.003) whereas men with AVPC-MS-negative tumors had a mPFS of 6.1 mo (95%CI 5.2-9.2) with CABAZ [n = 15] vs 5.4 mo (95%CI 3.9-8.3) with CABAZ/CARB [n = 36] (p = 0.145). 

In summary, adding CARB to CABAZ is safe and improves mPFS and response among mCRPC men. Men with AVPC-C benefit the most from the CARB/CABAZ combination. The AVPC-MS in tumor biopsies is a better predictor for platinum benefit than AVPC-C. The AVPC-MS identifies a subset of platinum-sensitive CRPC tumors, better than AVPM-C. These findings serve as the basis for a therapeutically relevant classification of prostate cancer. Phase 3 studies evaluating this potential therapeutic benefit are planned.

Presented By: Ana Aparicio, MD, The University of Texas MD Anderson Cancer Center, Houston, TX

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA
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