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Men with poor-prognosis metastatic castration-resistant prostate cancer (mCRPC) had better outcomes with cabazitaxel (Jevtana) as initial therapy instead of an androgen-receptor inhibitor, a phase II randomized trial showed.

First-line taxane therapy led to a clinical benefit rate (CBR, response plus stable disease) of 80% as compared with 62% for patients treated with either enzalutamide (Xtandi) or abiraterone (Zytiga). Patients treated with cabazitaxel lived more than twice as long, although the difference did not reach statistical significance because of a small patient population.

Patients treated with cabazitaxel had higher rates of grade ≥3 neutropenia, diarrhea, and infection, reported Kim N. Chi, MD, of BC Cancer in Vancouver, and colleagues, in .

"Cabazitaxel was associated with a modestly higher clinical benefit rate compared to ARPI [androgen receptor-pathway inhibitor]," the authors concluded. "However, both treatments should remain important options for patients with ARPI-naive mCRPC. CtDNA [circulating tumor DNA] abundance was prognostic, independent of clinical features, and holds promise as a stratification biomarker."

Disease progression despite castrate testosterone levels defines mCRPC. Clinical trials of first-line treatment with ARPIs led to median overall survival (OS) of approximately 3 years, the authors noted. However, a subset of patients with adverse clinical features had worse outcomes, they explained. The adverse features included visceral metastases, rapid progression on androgen deprivation therapy, performance status, and elevated lactate dehydrogenase and alkaline phosphatase.

Optimal first-line treatment for poor-prognosis mCRPC remains undetermined, the authors continued. Some evidence suggests that aggressive cancers might be less dependent on AR signaling. For example, somatic defects in RB1, TP53, and AR enrich for poor prognosis and poor outcomes with ARPI, which does not preclude response to taxane-based therapy.

In general, ARPIs are the preferred first-line therapy for mCRPC because of proven survival benefits and tolerability, they stated. Consensus guidelines for poor-prognosis mCRPC have suggested upfront chemotherapy, but the recommendation has limited clinical evidence support.

To investigate a potential preferred treatment sequence (first-line ARPI or taxane), the authors conducted a multicenter randomized trial limited to patients with poor-prognosis mCRPC and no prior exposure to an ARPI. Patients received either cabazitaxel plus prednisone or investigator's choice of abiraterone or enzalutamide plus prednisone. Granulocyte colony stimulating-factor was allowed but not mandated.

Treatment continued until disease progression, unacceptable toxicity, or withdrawal of patient consent. Progression was defined as a two-level or greater increase in performance status or change in cancer therapy for worsening cancer-related symptoms, PSA progression, or radiologic progression. Crossover to the alternate therapy was allowed at progression, provided that the patient continued to meet eligibility criteria.

The primary endpoint was composite investigator-assessed CBR, defined as PSA decline ≥50%, measurable radiographic response of any duration, or stable disease for ≥12 weeks in the absence of other indicators of disease progression. At investigator's discretion, patients with PSA progression only could continue treatment.

Data analysis comprised 95 randomized patients with a median follow-up of 21.9 months. The primary-endpoint analysis showed that patients treated with cabazitaxel had superior CBR (P=0.039). Patients randomized to cabazitaxel had a median OS of 37.0 months as compared with 15.5 months with an ARPI. The difference represented a 42% reduction in the survival hazard for the cabazitaxel arm, but the difference did not achieve statistical significance (P=0.073). Median PFS was 5.3 months with cabazitaxel and 2.8 months with an ARPI (HR 0.87, P=0.52).

First-line grade ≥3 treatment-related adverse events that occurred more often with cabazitaxel were neutropenia (32% vs 0%), diarrhea (9% vs 0%), and infection (9% vs 0%).

Biomarker analysis showed that a baseline ctDNA above the median and on-treatment ctDNA increase predicted a shorter time to disease progression (HR 2.38, P<0.001 and HR 4.03, P<0.001). Baseline ctDNA fraction >30% ctDNA was associated with markedly worse OS as compared with patients who had undetectable baseline ctDNA (HR 38.22, P<0.001).

The study provided evidence to support clinicians' intuition favoring chemotherapy as initial treatment for patients with aggressive mCRPC and no prior exposure to an ARPI, said Moshe Ornstein, MD, of the Cleveland Clinic.

"Many of us in the field intuitively think of using chemotherapy for patients who we consider as having more aggressive disease, but having randomized data to support it is important," Ornstein told 番茄社区app via email. "Patients who might otherwise be given ARPI should at least be considered for a taxane-based chemotherapy especially if they have a more aggressive phenotype...The initial clinical benefit is important for patients."

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