Activity and Safety of Enzalutamide in Patients with mCRPC Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks.

[pjoshea13]

New European study below. The author is Johann de Bono of the Royal Marsden.

We know that cross-resistance has been reported for Abiraterone Acetate [Zytiga ... Abi] & Enzalutamide [Xtandi ... Enz]. In this study, men were on Abi for at least 24 weeks before starting Enz.

"The data herein indicate that approximately one-third of patients who had progressed after abiraterone treatment for ≥24 wk remained on the study after 9 mo of enzalutamide treatment"

The link is to the full text. I have pasted in the Discussion section.

-Patrick

[1] europeanurology.com/article...

This study was conducted to evaluate the efficacy and safety of enzalutamide treatment in patients with mCRPC following disease progression after at least 24 wk of abiraterone treatment in order to fulfil a regulatory commitment. In the overall population, the median duration of rPFS {radiographic prolonged progression-free survival} was 8.1 mo, median survival time was not reached, and the unconfirmed PSA response rate was 27%. The antitumour activity with enzalutamide in some patients appeared independent of the use of chemotherapy before abiraterone treatment. Reported AEs {adverse events} were consistent with the established safety profile of enzalutamide and were as expected for the study population. No further deterioration of quality of life, as assessed by the European Quality of Life 5-Domain scale, was reported during enzalutamide treatment.

Currently, there is no expert consensus on the use of second-line treatment with enzalutamide or abiraterone in symptomatic men who develop resistance after first-line abiraterone or enzalutamide, respectively, due in part to the absence of prospective clinical data in these settings [13]. The prospective data herein show the antitumour activity of enzalutamide in patients who progressed following ≥24 wk of abiraterone and support the use of enzalutamide in some patients in the postabiraterone setting.

This large study evaluating the antitumour activity of enzalutamide in patients with prostate cancer after progression with abiraterone provides additional prospective data to previously published retrospective studies. In retrospective analyses, patients treated with enzalutamide following progression with abiraterone treatment of any duration reported lower proportions of patients with ≥50% decline in PSA from baseline ranging from 5.0–45.7%, shorter PFS (range, 2.8–18.4 mo), and shorter OS (range, 7.1 mo–not yet reached) compared with the analysis herein [[14], [15], [16], [17], [18], [19], [20], [21]]. In another small, prospective study of 24 patients with mCRPC who were treated with enzalutamide after progression with docetaxel and abiraterone postchemotherapy, PSA response of ≥50% was 17% and median OS was 4.8 mo [22]. Additionally, two retrospective analyses of chemotherapy-naïve patients with mCRPC treated with enzalutamide after progressing with abiraterone reported PSA responses ≥50% of 11.0% and 34.0% and PFS durations of 3.6 mo and 4.7 mo [[21], [23], [24], [25]]. A systematic analysis that pooled data from 10 available clinical studies reported a ≥50% PSA response of 22.9% (range, 19.3–27.1%), median PFS of 3.1 mo (range, 1.4–4.9 mo), and median OS of 8.3 mo (range, 2.9–10.6) [26].

The data herein indicate that approximately one-third of patients who had progressed after abiraterone treatment for ≥24 wk remained on the study after 9 mo of enzalutamide treatment, with a median rPFS of 8.1 mo and median time-to-PSA progression of 5.7 mo. The rPFS may have been impacted by the censoring rate due to patients not having radiological progression at time of trial discontinuation. Moreover, per the study design, treatment discontinuation was independent from PSA assessments and enzalutamide treatment was often continued despite the absence of a PSA response. It is also important to note that rate of PSA decline, median rPFS, and median time-to-PSA progression observed in the present study are inferior to those observed in abiraterone-naïve men with mCRPC treated with enzalutamide [[3], [4], [7]], suggesting a degree of cross-resistance between these two agents.

Evidence of more modest antitumour activity of abiraterone with the reverse sequence (ie, after progression on enzalutamide) has also been previously reported by small, retrospective analyses of patients with mCRPC who had been enrolled in the AFFIRM study. In these analyses, patients with mCRPC treated with abiraterone after progressing with docetaxel and enzalutamide reported PSA responses ≥50% of 3% and 8%, median PFS of 2.7 mo and 3.6 mo, and OS of 7.2 mo and 11.6 mo [[11], [12]]. A similarly modest clinical response was recently reported in a small retrospective analysis of chemotherapy-naïve patients with mCRPC who were treated with abiraterone after progression with enzalutamide, in which PSA response ≥50% was 7%, median PFS was 3.4 mo, and median OS was 9.1 mo [27].

Overall, a better understanding of the biology of abiraterone and enzalutamide resistance is key to optimise the use of these agents. A recent study reported the conversion of abiraterone to the more active Δ4-abiraterone metabolite in mice and patients with prostate cancer [28]. However, conversion of abiraterone to Δ4-abiraterone is unlikely to have any impact on most enzalutamide-resistant prostate cancer cells expressing constitutively active androgen receptor splice variants (AR-SVs) that lack the ligand-binding carboxy-terminal domain. AR-SVs are believed to drive treatment resistance and may be generated through increased AR splicing under selective therapeutic pressure [29]. A recent study reported that AR-SV expression results in resistance to both abiraterone and enzalutamide [30].

This study's limitations include the single-arm, open-label design, due to the absence of treatment options available at the time of enrolment, and the censoring rate. Furthermore, the study was not designed to provide definitive answers regarding the most appropriate treatment sequence, and additional studies are needed to address this question. A phase 2, randomised study (n = 202) evaluating sequencing for abiraterone and enzalutamide is currently ongoing (ClinicalTrials.gov, NCT02125357). Symptomatic improvement and symptomatic deterioration, measured using patient-related outcomes, were not comprehensively assessed in this trial.