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BACKGROUND AND OBJECTIVE: Docetaxel has become a standard component of care for advanced prostate cancer (PC); however, its benefits are not universal among patients. A subset of PC cases exhibit TMPRSS2-ERG gene fusion, resulting in ERG overexpression in tumors. Our aim was to assess biomarkers for docetaxel efficacy in men with hormone-sensitive PC (HSPC). METHODS: Pretreatment prostate biopsies were obtained from participants in two randomized phase 3 clinical trials investigating docetaxel in high-risk localized PC (GETUG 12) and metastatic HSPC (GETUG 15). Immunohistochemistry staining for Ki67, PTEN, RB, and phosphorylated RB was conducted for GETUG 12 samples, and ERG staining for GETUG 12 and GETUG 15 samples. We examined biomarker association with outcomes using univariate and multivariable analyses adjusted for other validated prognostic factors. KEY FINDINGS AND LIMITATIONS: Among GETUG 12 patients, Ki67 was associated with a worse relapse-free survival (RFS; hazard ratio [HR] 1.72; p = 0.0092). A pooled analysis for the two trials (pinteraction = 0.056) revealed that docetaxel-based chemotherapy improved failure-free survival for patients with ERG-positive cancer (HR 0.58; p = 0.03), but not patients with ERG-negative cancer (HR 1.08; p = 0.72). In the ERG-positive subgroup in GETUG 12 (high-risk localized PC), median RFS was 7.79 yr with androgen deprivation therapy (ADT) alone, and was not reached with ADT + docetaxel. In the ERG-negative subgroup, median progression-free survival (mPFS) was 7.79 yr with ADT alone versus 7.08 yr with ADT + docetaxel. In the ERG-positive subgroup in GETUG 15 (metastatic HSPC), mPFS was 10.7 mo with ADT alone versus 18.8 mo with ADT + docetaxel. In the ERG-negative subgroup, mPFS was 10.6 mo with ADT alone versus 13.2 mo with ADT + docetaxel. CONCLUSIONS AND CLINICAL IMPLICATIONS: Ki67 may serve as a prognostic factor in HSPC, while ERG expression appears to predict a response to docetaxel in both high-risk localized and metastatic HSPC. PATIENT SUMMARY: We assessed factors that could predict outcomes after docetaxel chemotherapy in patients with advanced prostate cancer. We found that expression of a protein called ERG can predict a good response to docetaxel in these patients.
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This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.