Following the impressive results posted by the STAMPEDE and LATITUDE authors in 2017, 2 further trials have shown significantly improved survival for men with metastatic prostate cancer who are still responding to hormones.

TITAN study

This was a phase 3, double-bind trial of Apalutamide versus placebo. Apalutamide is Janssen’s successor compound to Abiraterone and has already shown benefit in the non-metastatic castrate-refractory population. There was stratification into prior docetaxel and high/low volume groups. Follow up is still quite short, but the hazard ration for overall survival is 0.67 and statistically significant. The other primary endpoint of radiographic progression free survival was also highly significant, albeit I’d question the clinical significance of this. From our experience with STAMPEDE, biochemical progression is much more likely to define entry to the castrate refractory phase.

ENZAMET (ANZUP 1304) study

This was a similarly sized phase 3 study to the above. The design was slightly different. The first group were given Enzalutamide and Standard of Care (with stratification between planned upfront docetaxel and no planned docetaxel). The second group were given a choice of non-steroidal antiandrogens plus SoC. Again, there was stratification into high and low volume groups, but it isn’t apparent from the abstract if this was controlled for the proposed docetaxel stratification.

Overall, the trial was positive for its primary endpoint of overall survival with a hazard ratio of 0.66. This is largely consistent with the results we have seen from STAMPEDE, LATITUDE and TITAN and would suggest that non-steroidal antiandrogens are not as useful as modern androgen-modifying agents. The results were consistent for the high and low volume disease groups. However, the most striking result was the lack of significant benefit in men who were planned for upfront docetaxel. This suggests the benefits of Enzalutamide are not additive to cytotoxic chemotherapy.

Does this change practice?

We now know that 4 agents (docetaxel, abiraterone, enzalutamide and apalutamide) can significantly improve overall survival if given early in the treatment of metastatic prostate cancer. In terms of cost, current estimates are that docetaxel is cost neutral (or it may even save money). The three other agents cost thousands of pounds each month and may be given for long periods of time. That is a real financial challenge, albeit abiraterone is beginning to shed patent protection in the US and in the next few years in Europe.

The toxicity profiles of the hormonal agents are superior to docetaxel, but is that sufficient to justify the cost or the duration of therapy? So far, we do not have any compelling evidence that the benefits of these drugs are additive to chemotherapy, so should the scheduling be for docetaxel in the hormone naive phase and abi/enza in the castrate refractory phase or vice versa? Is there enough evidence to differentiate on the basis of high versus low volume disease?