Custirsen–Cabazitaxel Fails To Boost mCRPC Survival

Adding the antisense oligonucleotide custirsen to second-line taxol chemotherapy does not improve metastatic castration-resistant prostate cancer survival

medwireNews: The AFFINITY trial has failed to show an overall survival (OS) advantage with the addition of the clusterin inhibitor custirsen to cabazitaxel plus prednisone for men with metastatic castration-resistant prostate cancer (mCRPC) that has been previously treated with docetaxel.

Tomasz Beer, from OHSU Knight Cancer Institute in Portland, Oregon, USA, and co-investigators therefore state in The Lancet Oncology: “Cabazitaxel and prednisone remains the standard of care in men with this cancer whose disease is progressing following docetaxel chemotherapy.”

Median OS was 14.1 months for the 317 men randomly assigned to receive cabazitaxel 25 mg/m2 every 21 days plus prednisone 10 mg/day alongside three loading doses of custirsen followed by 640 mg doses on days 1, 8 and 15.

This did not differ significantly from the median OS of 13.4 months for the 318 men given cabazitaxel plus prednisone only.

And although post-hoc analysis of the earlier SYNERGY trial suggested that patients with a poor risk prognosis may benefit from the addition of custirsen to docetaxel plus prednisone, the study authors found median overall survival for this subgroup in the AFFINITY trial was comparable with and without the agent, at 11.0 and 10.9 months, respectively.

Commentator Rahul Aggarwal, from the University of California, San Francisco in the USA, highlights, however, that “the risk criteria (based on concentrations of serum PSA, lactate dehydrogenase, and haemoglobin, and presence of liver metastases and performance status) are not linked to the mechanism of action of custirsen, and therefore the likelihood that they would be expected to provide predictive utility beyond their usual prognostic value was low.”

The study authors note that the treatment arms did not vary with regard to baseline levels of serum clusterin but custirsen-treated patients had a lower post-treatment clusterin nadir than those in the control group (34 vs 42 μg/mL) and a greater median change from baseline (–16.9 vs –9.1 μg/mL).

Exploratory landmark analysis suggested that custirsen-treated patients who achieved a clusterin decrease greater than the median of 26.14% had significantly longer survival than those who achieved a smaller decrease.

But the investigators caution that serum clusterin may not correlate with intratumoural levels and admit the difficulty in measuring concentrations in patients who are unlikely to have tumour tissue available for analysis.

“[A] further consideration is that in more heavily pretreated patients, prostate tumours might have activated several redundant resistance mechanisms, and inhibition of one such pathway might have proved insufficient to show an overall clinical benefit”, they add.

Nevertheless, the authors describe the combination of custirsen and cabazitaxel plus prednisone as “reasonably well tolerated” with a similar safety profile to the taxane regimen given alone. Neutropenia (22 vs 20%), anaemia (22 vs 16%) and fatigue (7 vs 6%) were the most common grade 3 or more severe adverse events.

Rahul Aggarwal praises the increasing use of molecular factors linking patient drug selection to drug mechanisms of actions in phase III trials of mCRPC, such as use of PARP inhibitors in a subgroup of patients with DNA repair genomic alterations.

“The burgeoning availability of molecular information from tissue-based, blood-based, and imaging-based assays in [mCRPC] provides the opportunity to further link investigational treatments with patient selection and stratification in prospective studies”, he writes.

“With more precisely defined patient cohorts, there is reason for optimism that the era of unselected phase 3 studies in metastatic castration-resistant prostate cancer is drawing to a close.”

References

Beer TM, Hotte SJ, Saad F, et al. 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. Lancet Oncol; Advance online publication 9 October 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30605-8

Aggarwal R. Moving toward a precision medicine approach in metastatic castration-resistant prostate cancer. Lancet Oncol; Advance online publication 9 October 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30718-0

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