Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe.

Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment. Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. Patients received enzalutamide 160mg/d orally. The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1-8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6-5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported. Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment. Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy, received enzalutamide. Although cross-resistance between the two agents was observed in a majority of patients, some still benefited from enzalutamide treatment.

de Bono JS ，Chowdhury S ，Feyerabend S ，Elliott T ，Grande E ，Melhem-Bertrandt A ，Baron B ，Hirmand M ，Werbrouck P ，Fizazi K ... -  《-》

Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6-not estimable) for subsequent abiraterone acetate plus prednisone and 2.8 mo (range 1.8-not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with abiraterone acetate plus prednisone or enzalutamide for patients who progressed on abiraterone acetate is associated with limited clinical benefit. This analysis showed limited clinical benefit for subsequent abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone.

Smith MR ，Saad F ，Rathkopf DE ，Mulders PFA ，de Bono JS ，Small EJ ，Shore ND ，Fizazi K ，Kheoh T ，Li J ，De Porre P ，Todd MB ，Yu MK ，Ryan CJ ... -  《-》

Impact of Abiraterone Acetate plus Prednisone or Enzalutamide on Patient-reported Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer: Final 12-mo Analysis from the Observational AQUARiUS Study.

Few studies have examined patient-reported outcomes (PROs) with abiraterone acetate plus prednisone (abiraterone) versus enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). To determine the impact of abiraterone and enzalutamide on PROs. AQUARiUS (NCT02813408) was a prospective, 12-mo, observational study in patients with mCRPC from Denmark, France, and the UK. Abiraterone or enzalutamide treatment according to routine practise. PROs were collected over 12 mo using Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Brief Fatigue Inventory-Short Form (BFI-SF), Brief Pain Inventory-Short Form, and European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (QLQ-C30) at baseline and routine visits. Outcomes included mean change in PROs, patients with clinically meaningful worsening (CMW) in PROs, and safety. Data were analysed using repeated measures linear and logistic models adjusted for baseline characteristics. Abiraterone-treated (N = 105) and enzalutamide-treated (N = 106) patients were included. Key PRO items (cognitive impairments and fatigue) were significantly (p < 0.05) in favour of abiraterone versus enzalutamide during the study. "Perceived cognitive impairment" and "comments from others" (FACT-Cog); "fatigue right now", "usual level of fatigue", and "worst level of fatigue" (BFI-SF); and "cognitive functioning" and "fatigue" (QLQ-C30) were significantly in favour of abiraterone over enzalutamide for three or more consecutive periods up to month 12. From study initiation, significantly fewer patients receiving abiraterone experienced one or more CMW episode in cognition and fatigue. Fatigue and asthenia (adverse events) were lower with abiraterone than with enzalutamide (5% vs 15% and 10% vs 11%, respectively). There were no treatment-related deaths. Limitations included lack of randomisation. In a real-world setting, this 12-mo analysis suggests an advantage of abiraterone acetate plus prednisone over enzalutamide on fatigue and cognitive function; this finding occurred early after treatment initiation. This difference should be considered when choosing treatment. This study looked at the effect of two treatments (abiraterone acetate plus prednisone and enzalutamide) for metastatic castration-resistant prostate cancer on patient quality of life over 12 mo. Using established questionnaires, patients reported that they experienced less fatigue and cognitive impairments (including memory loss and reduced thinking abilities) with abiraterone acetate plus prednisone than with enzalutamide.

Thiery-Vuillemin A ，Poulsen MH ，Lagneau E ，Ploussard G ，Birtle A ，Dourthe LM ，Beal-Ardisson D ，Pintus E ，Trepiakas R ，Lefresne F ，Lukac M ，Van Sanden S ，Pissart G ，Reid A ，AQUARiUS Investigators ... -  《-》

Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial.

Abiraterone acetate plus prednisone and enzalutamide are both used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the best sequence in which to use both drugs, as well as their second-line efficacy. In this multicentre, randomised, open-label, phase 2, crossover trial done in six cancer centres in British Columbia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group B). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from baseline) on second-line therapy, analysed by intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357. Between Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group B (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group B had crossed over. Time to second PSA progression was longer in group A than in group B (median 19·3 months [95% CI 16·0-30·5] vs 15·2 months [95% CI 11·9-19·8] months; hazard ratio 0·66, 95% CI 0·45-0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3-33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for abiraterone (χ2 p<0·0001). The most common grade 3-4 adverse events throughout the trial were hypertension (27 [27%] of 101 patients in group A vs 18 [18%] of 101 patients in group B) and fatigue (six [10%] vs four [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in group A and 20 (20%) of 101 patients in group B. There were no treatment-related deaths. Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit. Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Terry Fox New Frontiers Program, BC Cancer Foundation, Jane and Aatos Erkko Foundation, Janssen, and Astellas.

Khalaf DJ ，Annala M ，Taavitsainen S ，Finch DL ，Oja C ，Vergidis J ，Zulfiqar M ，Sunderland K ，Azad AA ，Kollmannsberger CK ，Eigl BJ ，Noonan K ，Wadhwa D ，Attwell A ，Keith B ，Ellard SL ，Le L ，Gleave ME ，Wyatt AW ，Chi KN ... -  《-》

Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone: A Multicentre Analysis.

The degree of antitumour activity of enzalutamide following disease progression on docetaxel and abiraterone remains controversial. To examine the effect of enzalutamide in patients progressing following taxane-based chemotherapy and abiraterone. Metastatic castration-resistant prostate cancer patients entering one of four European compassionate use programmes of enzalutamide. The primary end point was overall survival (OS). Secondary end points were association between OS and posttreatment prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. We identified 137 patients who prior to enzalutamide had progressed following a median of eight cycles of docetaxel and seven courses of abiraterone. The median time on enzalutamide was 3.2 mo; median OS from the time patients started enzalutamide was 8.3 mo (95% confidence interval, 6.8-9.8). Only 45 (38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively. Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p=0.001 and 12.6 vs 7.4 mo; p=0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. Median OS on enzalutamide following disease progression on taxane-based chemotherapy and abiraterone was modest, but patients who experience a PSA decline >30% or 50%, respectively, with enzalutamide in this setting had longer survival. Enzalutamide produces modest prostate-specific antigen (PSA) responses in patients progressing following chemotherapy and abiraterone. Despite a modest PSA response, survival may still be improved.

Brasso K ，Thomsen FB ，Schrader AJ ，Schmid SC ，Lorente D ，Retz M ，Merseburger AS ，von Klot CA ，Boegemann M ，de Bono J ... -  《-》