Elsevier

The Lancet Oncology

Volume 18, Issue 11, November 2017, Pages 1532-1542
The Lancet Oncology

Articles
Custirsen (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

https://doi.org/10.1016/S1470-2045(17)30605-8Get rights and content

Summary

Background

Docetaxel and cabazitaxel improve overall survival compared with mitoxantrone in patients with metastatic castration-resistant prostate cancer. Custirsen (OGX011) is a second generation highly specific antisense oligonucleotide that inhibits the production of clusterin, an antiapoptotic protein that is upregulated in response to chemotherapy and that confers treatment resistance. We aimed to assess whether custirsen in combination with cabazitaxel and prednisone increases overall survival in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel.

Methods

In this randomised, open-label, international, phase 3 trial, men with radiographically documented metastatic castration-resistant prostate cancer that had progressed after docetaxel treatment with a Karnofsky performance status of more than 70% and who were fit for chemotherapy, were recruited from 95 cancer treatment centres in eight countries. Patients were randomly assigned (1:1) centrally using permuted blocks (block size 8) to receive cabazitaxel plus prednisone (cabazitaxel 25 mg/m2 intravenously every 21 days plus oral prednisone 10 mg daily) with or without custirsen (640 mg intravenously on days 1, 8, and 15, plus three previous loading doses) until disease progression, unacceptable toxicity, or the completion of ten treatment cycles. Randomisation was stratified by use of opioids for prostate cancer-related pain at screening, disease progression following first-line docetaxel treatment established by radiographic evidence, and previous treatment with abiraterone or enzalutamide. The co-primary endpoints were overall survival in all randomly assigned patients and in a poor-prognosis subgroup. All analyses were intention to treat with the exception of safety, which was reported for patients who received any assigned treatment. The trial has been completed and the results presented here are the final analysis. This trial is registered with Clinicaltrials.gov, number NCT01578655.

Findings

Between Sept 9, 2012, and Sept 29, 2014, 795 patients were screened for enrolment. 635 men were eligible for inclusion and were randomly assigned (n=317 in the cabazitaxel and prednisone plus custirsen group and n=318 in the cabazitaxel and prednisone group). Median follow up was 28·3 months (IQR 24·4–34·5) for the custirsen group and 29·8 months (IQR 25·3–35·2) for the control group. Median overall survival in all randomly assigned patients did not differ between the two groups (14·1 months [95% CI 12·7–15·9] in the curtisen group vs 13·4 months [12·1–14·9] in the control group; hazard ratio [HR] 0·95 [95% CI 0·80–1·12]; log-rank p=0·53). In the poor prognosis subgroup, median overall survival also did not differ between the two treatment groups (11·0 months [95% CI 9·3–13·3] in the custursin group vs 10·9 months [8·2–12·4] in the control group; HR 0·97 [95% CI 0·80–1·21]; two-sided p=0·80). The most frequently reported grade 3 or worse adverse events in the custirsen versus control groups were neutropenia (70 [22%] of 315 vs 61 [20%] of 312), anaemia (68 [22%] vs 49 [16%]), fatigue (23 [7%] vs 18 [6%]), asthenia (16 [5%] vs 8 [3%]), bone pain (16 [5%] vs 5 [2%]), and febrile neutropenia (16 [5%] vs 9 [3%]). Serious adverse events were reported in 155 (49%) versus 132 (42%). 27 patients died within 30 days of treatment in the cabazitaxel and prednisone plus custirsen group, seven of which were deemed to be treatment related, versus 17 in the cabazitaxel and prednisone group, eight of which were deemed to be treatment related. Of the 21 deaths reported, 15 were reported as complications related to study treatment, either chemotherapy (eight and three, respectively) or study drug (none and four, respectively).

Interpretation

We noted no survival benefit in men with metastatic castration-resistant prostate cancer with the addition of custirsen to cabazitaxel and prednisone treatment. Cabazitaxel and prednisone remains the standard of care for patients with metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy.

Funding

OncoGenex Pharmaceuticals.

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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