Signature for Aggressive-Variant CRPC Predicts Platinum Sensitivity

A molecular signature for aggressive-variant prostate carcinoma (AVPC-MS) can predict which men with castration-resistant prostate cancer (CRPC) will benefit from cabazitaxel with or without carboplatin, and does so better than clinically defined AVPC, according to findings from a randomized phase II study (abstract 5013) presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.

“The AVPC-MS identifies a subset of men platinum-sensitive CRPC tumors,” reported lead study author Ana M. Aparicio, MD, of The University of Texas MD Anderson Cancer Center, Houston. “These findings should serve as the foundation for a therapeutically relevant classification of prostate cancer.”

AVPC represents 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,” Dr. Aparicio explained.

AVPC have a molecular signature (AVPC-MS) defined as ≥ 2 tumor suppressor mutations in Tp53, RB1 and/or PTEN as determined using immunohistochemistry or genomic sequencing analyses. The researchers sought to evaluate whether or not this AVPC-MS predicted outcomes for patients treated with platinum-based chemotherapy.

They randomly assigned 160 men with metastatic castration-resistant prostate cancer to receive intravenous cabazitaxel (25 mg/m²) with or without carboplatin (AUC 4) every 21 days with growth factor, until patients reached 10 cycles or experienced unacceptable toxicity or disease progression. Patients underwent imaging examinations every other cycle. Tumor samples were obtained from 65 of the study participants and these were tested for Tp53, RB1, PTEN, AR-N terminus, AR-C terminus, and Ki67. Tumor DNA was also retrieved for sequencing from 27 tumor biopsies and 70 patient plasma samples.

Adding carboplatin to cabazitaxel therapy was safe and improved progression-free survival (PFS) and response rates among study participants overall, the researchers confirmed.

At a median follow-up of 21.6 months, median PFS in the overall population (n = 160) was 4.6 months (95% CI, 3.5–5.8) with cabazitaxel vs 7.4 months (95% CI, 5.6–8.3) with cabazitaxel/carboplatin (P = .004).

The AVPC-MS was predictive of treatment outcome. Men with AVPC-MS tumors saw a median PFS of 4.5 months on cabazitaxel and 8 months with cabazitaxel and carboplatin (P = .0036), compared with 6.8 months and 5.4 months, respectively, among men with AVPC-MS-negative tumors.