Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17a-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M 0 ).Experimental Design: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA 0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints.Results: Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9-9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan-Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade !3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2.Conclusions: Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible.
on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival analyzed on an intention-totreat basis. Adverse events were assessed according to treatment received. Results: Between 22 May 2015 and 12 March 2018, 503 patients were randomly allocated to treatment. Median overall survival was 13.6 months (95% CI, 10.9e16.5) for the 251 patients allocated to docetaxel and 16.2 months (95% CI, 14.4e19.0) for the 252 patients allocated to nab-paclitaxel (hazard ratio, 0.85; 95.2% CI, 0.68e1.07). Median progression-free survival was 4.2 months (95% CI, 3.9e5.0) for the nab-paclitaxel group versus 3.4 months (95% CI, 2.9e4.1) for the docetaxel group (hazard ratio, 0.76; 95% CI, 0.63e0.92; p¼0.0042). The objective response rate was 29.9% (95% CI, 24.0e36.2) for the nab-paclitaxel group and 15.4% (95% CI, 10.9e20.7) for the docetaxel group (p¼0.0002), and it showed a significant improvement for nabpaclitaxel versus docetaxel regardless of tumor histology. Adverse events of grade 3 included febrile neutropenia (55 [22%] of 249 patients in the docetaxel group versus 5 [2%] of 245 patients in the nab-paclitaxel group) and peripheral sensory neuropathy (2 [1%] versus 24 [10%], respectively). Conclusion: The trial showed that nabpaclitaxel was noninferior to docetaxel in terms of overall survival. Nab-paclitaxel should thus be considered a standard treatment option for previously treated patients with advanced NSCLC.
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