First-Line Cabazitaxel Proves Beneficial in Patients With Metastatic Prostate Cancer

Article

This study tested first-line treatment with cabazitaxel vs hormonal therapy in patients with metastatic castration-resistant prostate cancer with poor prognosis.

CHICAGO-In a cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with poor prognosis, first-line treatment with cabazitaxel yielded a higher clinical benefit rate than treatment with abiraterone or enzalutamide. In addition, elevated circulating tumor DNA and genomic alterations in androgen receptor (AR) and TP53 had prognostic value. The updated results (abstract 5003) from a randomized phase II study were presented by Kim N. Chi, MD, of the BC Cancer Agency in Vancouver, at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31–June 4 in Chicago.

“The optimal management of patients that have poor-prognosis metastatic CRPC has not been well defined,” said Chi.

The investigators aimed to determine if cabazitaxel or novel hormonal agents (abiraterone or enzalutamide) as first-line therapy are most active in these patients. The primary outcome measure was clinical benefit rate, defined as a prostate-specific antigen (PSA) level decline of ≥ 50%, measurable radiological response, or stable disease for ≥ 12 weeks.

Furthermore, Chi explained that molecular biomarkers associated with poor-prognosis metastatic CRPC have been identified, but are not yet validated for use in guiding treatment decisions. Therefore, the researchers tested the prognostic value of circulating tumor DNA (ctDNA) sampled from patient plasma.

A total of 95 patients (median age, 67 years) with poor prognosis (liver metastases, early CRPC, and/or > 3 of 6 poor prognostic criteria) were randomized to receive cabazitaxel (n = 45) or AR-targeted therapy (abiraterone or enzalutamide; n = 50).

The clinical benefit rate was higher for patients who received cabazitaxel (88%) compared with those who received abiraterone or enzalutamide (70%; P = .043). More patients in the cabazitaxel arm had stable disease for ≥ 12 weeks compared with the abiraterone/enzalutamide arm (26% vs 8%, respectively; P = .007). However, no significant differences were seen in the secondary outcome measures of median progression-free survival (PFS; 5.8 vs 3.1 months; hazard ratio [HR], 0.89; 95% CI, 0.57–1.38; P = .59) or overall survival (OS; 37.0 vs 15.5 months; HR, 0.57; 95% CI, 0.31–1.03; P = .06).

“The challenges with the data include [the fact] that 20% fewer patients were enrolled than planned, baseline patient characteristics were not well balanced with the abiraterone/enzalutamide cohort having more liver metastases, higher PSA and LDH [levels], and 40% of the cohort were not treated at progression 1,” said Mary-Ellen Taplin, MD, of Dana-Farber Cancer Institute in Boston, who was the discussant for the study.

“It is possible that if this trial accrued the planned number of patients or if a larger trial was done, or if different eligibility such as molecular selection were used, that perhaps the OS would have been positive,” noted Taplin.

In the biomarker testing, a baseline ctDNA fraction of greater than 15% was associated with shorter PFS (median, 2.8 vs 8.4 months; HR, 2.54; P < .001) and OS (median, 14.0 vs 38.7 months; HR, 2.64; P = .001). Furthermore, ctDNA mutations in the AR, TP53, PI3K pathway, RB1, SPOP, and any DNA damage repair genes were detected in 52%, 45%, 30%, 25%, 4%, and 25% of patients, respectively.

In a multivariate analysis, a high ctDNA fraction (≥ 30%) was the only variable that was independently prognostic for OS (HR, 2.19; 95% CI, 1.16–4.14; P = .015).

More specifically, shorter PFS and OS were associated with increased copy number of the AR (HR, 2.57; 95% CI, 1.63–4.06 and multivariate HR, 2.44; 95% CI, 1.23–4.83; P = .011, respectively) and with defects in TP53 (HR, 2.62; 95% CI, 1.65–4.15 and multivariate HR, 1.96; 95% CI, 1.01–3.79; P = .047 respectively).

Adverse events of grade 3 or higher occurred in 48% and 6% of patients in the cabazitaxel arm and abiraterone/enzalutamide arm, respectively. Neutropenia was the most common adverse event in the cabazitaxel arm (32%), followed by diarrhea (9%), and fatigue and infection (both 7%).

“The role of ctDNA technology remains to be determined,” said “However, this technology holds much promise and may be particularly useful in patients with low PSA-producing tumors or used as part of a strategy to reduce imaging or design trials that apply therapy change at early resistance rather than waiting for radiographic regression.”

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