ArticlesCustirsen (OGX-011) combined with cabazitaxel and prednisone versus cabazitaxel and prednisone alone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel (AFFINITY): a randomised, open-label, international, phase 3 trial
Introduction
Prostate cancer is the second most frequently diagnosed cancer and the fifth leading cause of death from cancer in men worldwide.1 In the European Union, the number of new cases of prostate cancer was estimated to be about 416 732 in 2012, and the number of deaths from prostate cancer was 75 800 in 2016.2, 3 In the USA, it is estimated that in 2016 there will be 180 890 new cases of prostate cancer and 26 120 deaths from this disease.4 Although most patients with metastatic disease initially respond to medical or surgical castration, many subsequently develop metastatic castration-resistant prostate cancer.
Treatment for metastatic castration-resistant prostate cancer has improved substantially in recent years, with several agents extending life.5, 6, 7 Docetaxel plus prednisone has become a standard of care as first-line chemotherapy for patients since the 2004 US Food and Drug Administration approval. This drug combination can even be used in fit elderly patients,8 and evidence was recently provided9 that an earlier use in patients with metastatic hormone-sensitive disease increases survival benefit.10, 11 Abiraterone acetate12, 13 and enzalutamide14, 15 have also shown a survival benefit both before and after docetaxel, while radium-22316 has shown improved survival after docetaxel. Until 2010, options for second-line chemotherapy included docetaxel retreatment,17 mitoxantrone, or other chemotherapies without proven clinical benefit.18 Cabazitaxel is a semi-synthetic taxane that showed in-vitro efficacy in docetaxel-resistant cell lines.19 In 2010, cabazitaxel was reported to have a survival advantage when compared with mitoxantrone in a phase 3 randomised controlled trial (TROPIC) in men with docetaxel-treated metastatic castration-resistant prostate cancer.20 The median overall survival for patients given cabazitaxel was 15·1 months (95% CI 14·1–16·3) compared with 12·7 months (11·6–13·7) in those who received mitoxantrone, highlighting a need to develop new treatments that build on the TROPIC results. Of note, cabazitaxel was recently suggested to remain active in patients progressing after abiraterone.21, 22
Clusterin is an antiapoptotic protein that is upregulated in response to cell death triggers such as chemotherapy and that confers treatment resistance.23 Clusterin protects cells from programmed cell death and has been associated with treatment resistance through several mechanisms, including prevention of protein aggregation,24, 25 inhibition of the pro-apoptotic Bcl-2 family member Bax,26 and increased nuclear factor-κB.27 Inhibition of clusterin is therefore an attractive target for drug development.
Custirsen (OGX011) is a second generation highly specific antisense oligonucleotide that binds to a portion of clusterin mRNA to block clusterin production. Inhibition of clusterin expression using custirsen enhances tumour cell death following treatment with chemotherapy. Findings of in-vitro and in-vivo studies have shown that the antitumour activity of taxanes was enhanced when combined with custirsen-induced clusterin suppression.28, 29 A phase 1 pre-surgery study assessed custirsen given before prostatectomy and established that clusterin inhibition in prostate cancer tissues was custirsen dose dependent, with a biologically effective dose confirmed at 640 mg.30 In a randomised phase 2 study,31 patients with metastatic castration-resistant prostate cancer who received first-line docetaxel and prednisone in combination with custirsen had a longer overall and progression-free survival than did patients who received first-line docetaxel and prednisone alone (median overall survival 23·8 months [95% CI 16·2 months to not reached] vs 16·9 months [12·8–25·8], hazard ratio [HR] 0·50 [95% CI 0·29–0·87]). A further phase 2 trial32 was done in patients previously treated with docetaxel, in which 42 patients were randomly assigned to receive retreatment with docetexel and prednisone plus custirsen or mitoxantrone and prednisone with custirsen. Overall survival and time to pain progression in the patients who received retreatment with docetaxel and custirsen was encouraging at 15·8 and 10·0 months, respectively, and was also superior to the results recorded with mitoxantrone and custirsen (11·5 and 5·2 months, respectively). Findings of exploratory analyses showed that achieving a minimum threshold serum clusterin concentration of 45 μg/L or lower during custirsen treatment was associated with improved overall survival.32
Despite these encouraging initial results, the recently completed phase 3 SYNERGY trial33 reported that the addition of custirsen to standard first-line docetaxel and prednisone treatment did not improve overall survival in molecularly unstratified men with metastatic castration-resistant prostate cancer. However, an exploratory analysis noted an improvement in survival in the poor prognosis group,33 suggesting the clusterin suppression might be most important in this patient subset. The feasibility of combining custirsen with cabazitaxel was shown in the SATURN trial,34 a pain-focused trial that was stopped after only 14 patients were enrolled as a consequence of its overly complex design and poor accrual. These results, as well as those from previous studies that combined custirsen with docetaxel, served as the basis for our expectation that the combination of another taxane with cutirsens would not result in significant unanticipated toxicities.
In the phase 3 AFFINITY trial, we therefore aimed to assess whether custirsen plus second-line cabazitaxel and prednisone treatment could improve survival compared with cabazitaxel and prednisone treatment alone in metastatic castration-resistant prostate cancer, either in the overall study population or in poor-prognosis patients.
Section snippets
Study design and participants
In this randomised, open-label, international phase 3 trial, patients were recruited from 95 cancer treatment centres in eight countries (Australia, Canada, Czech Republic, France, Hungary, Russia, the UK, and the USA; appendix pp 15, 16).
Eligible patients had metastatic castration-resistant prostate cancer (histologically or cytologically diagnosed) with evidence of metastatic disease on CT imaging or bone scan; current progressive disease as defined by measurable disease (according to RECIST
Results
Between Sept 9, 2012, and Sept 29, 2014, 795 patients were screened for enrolment. 635 patients were eligible and were enrolled and randomly assigned to receive either cabazitaxel and prednisone plus custirsen (custirsen group; n=317) or cabazitaxel and prednisone (control group; n=318; figure 1). The final primary analysis was done on July 29, 2016, based on 530 deaths. Table 1 summarises patient baseline characteristics; demographic and clinical characteristics were similar between the two
Discussion
The findings of the AFFINITY trial show that the addition of custirsen to cabazitaxel in second-line metastatic castration-resistant prostate cancer chemotherapy treatment does not improve survival, either in unselected patients or in men with poor prognosis. Notably, the trial failed to confirm prospectively a positive outcome in a poor prognosis group of patients suggested by a post-hoc analysis of the SYNERGY trial.33
Both the baseline serum concentration of clusterin and the recorded
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2022, Bioactive MaterialsCitation Excerpt :ASOs are interesting in cancer therapy because their possibilities of decreasing the expression of oncogenic genes and targeting non-coding RNAs [36]. There are several ASOs based drugs currently in phase I clinical trials, such as STAT3 transcriptional inhibitor Danvatirsen (AZD9150) [37], TGF-β signal pathway inhibitor Trabedersen (OT-101) [38], the clusterin mRNA targeting second-generation ASO Custirsen (OGX-011) [39] and etc. Small interference RNA (siRNA) and microRNA (miRNA) can be regarded as two types of RNA interference (RNAi) that follow different pathways, which are forms of double stranded RNA (dsRNA)-mediated gene silencing at the transcriptional, posttranscriptional, and/or translational levels [40,41].
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2021, Clinical Genitourinary CancerCitation Excerpt :Of interest, the relative dose intensity was 100%, another favorable result compared with that of the TROPIC trial (96.1%). More recently, the AFFINITY study evaluated the efficacy of custirsen combined with cabazitaxel in mCRPC post-docetaxel.16 The use of growth factor was recommended for patients at high risk of febrile neutropenia (primary prophylaxis) and as secondary prophylaxis for the remaining patients.
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2021, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :In another randomized phase II trial, using OGX-011 and combined treatment of docetaxel and prednisone showed higher patient survival in metastatic CRPC [158]. Even though these phase I/II clinical trials show promising outcomes with the patient's survival, the phase III synergy trial was not that positive as no improvement was seen in patient's overall survival with metastatic CRPC [159,160]. An alternative approach of developing inhibitors against different upstream or downstream CLU regulators could further accelerate CLU-based treatment regimens.
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