New paper below [1].
"Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial.
"Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial.
"Median follow-up was 96 months ... in the abiraterone trial and 72 months ... in the abiraterone and enzalutamide trial.
"In the abiraterone trial, median overall survival was 76·6 months ... in the abiraterone group versus 45·7 months ... in the standard of care group ...
"In the abiraterone and enzalutamide trial, median overall survival was 73·1 months ... in the abiraterone and enzalutamide group versus 51·8 months ... in the standard of care group".
Charles Huggins first targeted the androgen receptor [AR] before most of us were born, when he discovered that castration could temporarily delay PCa progression.
When I was diagnosed, castrate-resistance was thought to be due to androgen-independence. When it was eventually realized that the AR remained in play, the hunt was on for better AR-axis mousetraps. In terms of androgen deprivation, Abiraterone [Abi] improved on Lupron [1985], etc, by inhibiting adrenal sources and even PCa cell production, in addition to gonad production. In terms of AR inhibition, Enzalutamide [Enza] was more effective than any of the "lutamides" that began with Flutamide [1989]. One could hardly therefore expect much incremental benefit in combining Abi & Enza.
In fact, "Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy."
As with castration, Abi & Enza are not cures. It's certainly good to know that Abi + classic ADT might add a couple of years of life to ADT monotherapy, but at age 56 I would not have been impressed.
"Discussion
Combining abiraterone and enzalutamide with androgen deprivation therapy is more effective than androgen deprivation therapy alone, but from an indirect comparison we showed no improvement over abiraterone and androgen deprivation therapy. We have not formally compared the abiraterone and enzalutamide trial with trials testing enzalutamide. But, given the similar efficacy reported when combining enzalutamide with androgen deprivation therapy, we also conclude that combining abiraterone with enzalutamide would not be more effective. Overall, increased toxicity with the combination of abiraterone and enzalutamide does not justify further exploration in unselected patients.
"Combining apalutamide or enzalutamide with abiraterone for patients with metastatic castration-resistant prostate cancer might improve progression-free survival but consistent with our findings, these trials showed no improvement in overall survival. Similarly, there was no improvement in overall survival of patients with high-risk localised prostate cancer when abiraterone was indirectly compared with abiraterone and enzalutamide (administered as adjuvant therapy for 2 years). Therefore, treatment efficacy with abiraterone is unlikely to be reduced by an increase in androgens or reactivation of ligand-binding domain-dependent reactivation of androgen receptor signalling (given that combining abiraterone with an effective androgen receptor antagonist, enzalutamide, has no discernible long-term benefit). This finding is consistent with the low response rate observed from sequential use of either treatment.
"The periods of accrual to both trials overlapped with another separate trial that randomly assigned patients with metastatic cancer to radiotherapy to the primary tumour and reported improved overall survival for those with low-volume metastatic disease. Although abiraterone-containing trials shared patients who received standard of care (control) with the radiotherapy trial, none were randomly assigned to the study drug groups so we are unable to comment on the interaction between radiotherapy and hormone intensification.
"By leveraging resources across several trials, our follow-up of patients allocated to abiraterone was longer than feasible in other trials, which allowed us to make additional observations. Notably, the survival benefit of starting abiraterone with androgen deprivation therapy is maintained with longer follow-up and 23% of patients in the abiraterone trial and 22% in the abiraterone and enzalutamide trial continued abiraterone with no indication for a treatment change after more than 82 months of follow-up.
"We also report fewer deaths attributed to prostate cancer in patients who received abiraterone with or without enzalutamide than in those who received standard of care (413 [79%] of 521 in treatment groups vs 581 [88%] of 663 in standard of care groups), suggesting that for some patients with metastatic disease hormone intensification at the start of androgen deprivation therapy controls the prostate cancer for long enough for death from other causes to occur.
"Since 2022, the benefit of triplet therapy with androgen deprivation therapy supplemented by docetaxel and either abiraterone or enzalutamide, or darolutamide has been debated. As with previous trials, none of the patients who received androgen deprivation therapy and abiraterone or enzalutamide were randomly assigned to docetaxel but a small subgroup in the abiraterone and enzalutamide trial received docetaxel as standard of care. The point estimates for risk of death in patients with planned use of docetaxel versus those with no planned use of docetaxel were numerically different but we found no statistically significant interaction. Conclusions on the efficacy of docetaxel given before abiraterone and enzalutamide are confounded by physicians electing to use docetaxel for younger patients and putatively more aggressive cancers on clinical and pathological criteria and are limited by the small number of patients.
"The interaction with NSAID or aspirin is statistically significant but not clinically significant. Moreover, the interaction is in the opposite direction to that observed in patients with non-metastatic disease recruited to STAMPEDE trials.
"Our trial design was limited to only detect large benefits from combining enzalutamide and abiraterone with androgen deprivation therapy. However, given the toxicity and cost of abiraterone and enzalutamide, missing small differences in treatment effect is an acceptable limitation. There was a 2-year difference in accrual periods that, given the changes in clinical practice in the past 10 years, resulted in patients allocated to the abiraterone and enzalutamide trial receiving different treatment sequences after progression than those in the abiraterone trial. We provided updated information on first therapy instituted at trial-defined progression in the abiraterone trial and new data from the abiraterone and enzalutamide trial. Given that funding for these agents before chemotherapy became more widely available in the UK National Health Service after 2015, more patients had this option at progression in the abiraterone and enzalutamide trial than in the abiraterone trial. Collection and reporting of treatment after progression can be difficult, particularly for later lines and when patients move hospitals or join subsequent trials. Although we anticipate the use of subsequent treatments might be under-reported, we have no reason to think there is bias according to the allocated treatment in these trials. We do not have a detailed assessment of the long-term metabolic toxic effects of intensified hormone treatment plus androgen deprivation therapy and abiraterone with or without enzalutamide. Any increase in mortality from treatment toxicity is offset by the improvement in prostate cancer control, but given the increased life expectancy, management of long-term treatment effects should be prioritised in clinical practice and future trials.
"The excellent outcomes for 23% of patients who continued abiraterone or abiraterone and enzalutamide at trial closure introduces concerns regarding the risks of harm from continuous treatment to progression, especially for unselected patients with low-volume disease for whom treatment deintensification clinical trial protocols should be considered. Conversely, these and previous trials have reported that despite hormone intensification, a substantial proportion of patients with metastatic prostate cancer relapse and die within 36 months and identification of these patients to offer additional treatment options is a high priority for future trials. Both our trials have closed to further data collection, although we might explore long-term patient outcome monitoring using linkage with health-care systems data. In conclusion, enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy; but clinically important improvements in overall survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years.
-Patrick
