Esmo 2017 – Academic boffins Stampede over the pharma industry

The latest results from the Stampede trial in prostate cancer look to confirm a seismic shift in the treatment landscape in favour of Johnson & Johnson’s ageing Zytiga, but the impact for the whole industry – following a study run by academics – could be even more significant.

Already, evidence of companies reacting can be found in Pfizer/Astellas’s recent decision to alter the Prosper trial of Xtandi in non-metastatic castration-resistant prostate cancer (CRPC) to give an earlier read-out. Unless Zytiga generics next year can be held off J&J itself will not benefit, and its lifecycle strategy with apalutamide could now be scuppered by Stampede.

Apalutamide is among a slew of competing agents with phase III trials under way, particularly those targeting the disease’s later stages, that could now be rendered moot by Stampede. Xtandi looks likely to be among the most affected by Zytiga’s advance up the treatment cascade, and Pfizer/Astellas’s change looks designed to optimise chances of retaining some of its current market share.

At Esmo yesterday Stampede investigators reported the first head-to-head comparison of docetaxel and Zytiga, given on top of androgen deprivation therapy, in hormone-sensitive prostate cancer (HSPC). Both agents have independently been shown to confer large survival benefits in HSPC in earlier Stampede read-outs, but the two had not been compared directly until now.

Docetaxel plus androgen deprivation has rapidly become the standard of care for HSPC in Europe, with Zytiga’s use in newly diagnosed patients growing since the stunning data reported at Asco earlier this year (Zytiga moves back to centre stage in prostate cancer, June 03, 2017). 

Stampede: Zytiga vs docetaxel in HSPC Hazard ratio* (95% CI)
Failure-free survival 0.51 (0.39-0.67), p<0.001
Progression-free survival 0.65 (0.48-0.88), p=0.005
Metastasis-free survival 0.77 (0.57-1.03), p=0.08
Skeletal-related events 0.83 (0.55-1.25), p=0.38
Overall survival 1.16 (0.82-1.65), p=0.40**
Note: *hazard ratio of <1 favours Zytiga, while >1 favours docetaxel. **not powered to show a difference.

The latest Stampede data show significant differences in favour of Zytiga in early outcome such as failure-free and progression-free survival, with positive numerical changes in other outcome measures. However, there was no statistical difference on overall survival, an analysis – undertaken opportunistically – not powered to show such a difference.

Other factors that might have affected the OS comparison include docetaxel patients being likely to receive Zytiga on progression, with those initially randomised to Zytiga possibly getting docetaxel, but not all patients would have chosen to do so. At the same time, docetaxel was given for six cycles, potentially only a portion of the hormone-sensitive stage, whereas Zytiga might be used for a much longer period.

Triple combination

The study authors concluded that, based on the new data, either drug would be an acceptable choice, but in reality oncologists are likely to be keen to use both in patients who could tolerate a triple combination with androgen deprivation. This puts the Unicancer collaborative group-sponsored Peace 1 trial – giving androgen deprivation plus docetaxel with or without Zytiga – centre stage. Results from the trial are due imminently. 

J&J is of course the commercial beneficiary of Zytiga’s move up the treatment cascade, but the longer-term value will be determined by its ability to maintain commercial exclusivity in the face of forthcoming patent expiries.

Zytiga is expected to face generics next year, so any commercial benefit J&J sees might be short-lived (As Zytiga’s importance grows, so does that of generics, August 15, 2017). Prescription data suggest that Zytiga has already seen an inflection since Asco.

Stampede-linked landscape changes are having a major impact on competing studies, with those directed at CRPC now having much less value. Other trials will find their results rendered moot by virtue of the fact control arms have been superseded.

It is ironic that J&J’s own succession strategy, which seeks to replace Zytiga with apalutamide, has to some extent been frustrated by Stampede. The group’s Spartan study of apalutamide in non-metastatic CRPC is due to report later this year, but the now more important Titan study of the same drug in HSPC does not report until 2020.

This will be followed by Bayer’s Arasens study of darolutamide, which is testing a triple combination with docetaxel and androgen deprivation, but its results are not expected before 2022. Cynics would say it is little wonder that the industry itself is not running trials like Stampede and Peace 1.

Key phase III studies in newly diagnosed HSPC
Product Study Enrolment Design Trial ID Data
Zytiga Peace I* 916 ADT (+/-RT) +/- docetaxel +/- NCT01957436 May 2017
Zytiga - 1,200 ADT +/- NCT01715285 Jul 2018
Jevtana Peace II* 1,048 ADT +/- NCT01952223 Sep 2019 
Apalutamide Titan 1,000 ADT +/- NCT02489318 Nov 2020 
Xtandi Embark 1,860 ADT +/- NCT02319837 Sep 2021
Darolutamide  Arasens 1,300 ADT + docetaxel +/- NCT02799602 Jan 2022 
Xtandi Arches 1,100 ADT+/- NCT02677896 Apr 2020 

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