Barcelona, Spain (UroToday.com) At the Friday session at the 2019 European Society for Medical Oncology annual meeting (ESMO) meeting on prostate cancer, Karim Fizazi, MD, Ph.D., provided a discussion of the updated docetaxel STAMPEDE trial and updated SPARTAN trial, which included overall survival (OS) data.
Dr. Fizazi highlighted that apalutamide was associated with a 25% reduction in risk of death compared to placebo among non-metastatic castration-resistant prostate cancer (nmCRPC) patients in SPARTAN.1 But, it is important to note that the p-value of 0.0197 was above the pre-specified p-value for significance of 0.0121, so these results are encouraging, but not statistically significant. He notes that it is also encouraging that apalutamide extended time to second radiographic progression (PFS2) when compared to placebo (55.6 months vs. 43.8 months, HR 0.55, 95% CI 0.45-0.68).
According to Dr. Fizazi, there are several unanswered questions from SPARTAN:
How many patients in the control arm subsequently received cross-over apalutamide/other AR axis targeted treatments? In his opinion, a strength of SPARTAN was that abiraterone was provided beyond the onset of metastases
How active (or not) was abiraterone post-apalutamide in the experimental arm? Dr. Fizazi notes that current data about the sequential use of next generation AR targeted agents suggest minimal efficacy, but to stay tuned for the CARD trial to be presented later at ESMO 2019.
Dr. Fizazi remarked that there are two main messages he takes from the updated STAMPEDE data for docetaxel: (i) updated OS data shows a <20% reduction in risk of death for patients treated with docetaxel, and (ii) the effect is similar by burden of disease. Dr. Fizazi then presented a table he made listing recent phase III trials in M1 castration sensitive prostate cancer in chronological order (red – HR for OS ~0.80; blue – HR for OS ~0.67):
He notes that when looking at this table, the “red” trials are docetaxel based, whereas the “blue” trials are AR targeted therapy based. When rearranging the trials, sorting from best to worst hazard ratio (HR) for OS, it is clear that the AR targeted trials outperform the docetaxel trials, with the exception of ARCHES (HR 0.81, 95% CI 0.53-1.25). Dr. Fizazi stated that this premonition for chemotherapy reminds him of metastatic HR+ breast cancer, where the guidelines recommended endocrine therapy as the preferred initial option, even in the presence of visceral metastases; it took nearly 20 years for clinicians to move away from chemotherapy in these breast cancer patients.
The debate about docetaxel for low vs. high metastatic burden has been ongoing: CHAARTED is suggesting that there is no benefit to low volume metastatic disease,2 and STAMPEDE today is suggesting there is no difference in benefit with regards to burden stratification. However, Dr. Fizazi notes that next generation AR targeting improves OS regardless of low or high metastatic burden (~35% reduction in mortality).Dr. Fizazi’s conclusions for M0 CRPC are that whether OS is improved by early intensification remains to be formally demonstrated, however he acknowledges that this SPARTAN analysis suggests that this may very well be the case. He concludes for M1 castration-sensitive prostate cancer that docetaxel reduces risk of death by <20% (based on this STAMPEDE analysis and other trials), but that AR axis-targeted drugs reduce risk of death by ~35%. Furthermore, access to treatments beyond progression does not seem to explain this difference in OS benefit. Additionally, for M1 de novo castration-sensitive prostate cancer, there is no real reason to believe that low and high burden of disease are biologically distinct: as Dr. James presented, docetaxel works (not that well) with HRs of 0.76 (low volume) and 0.81 (high volume). In his opinion, for M1 castration-sensitive disease, besides access to cost (and a few very specific situations, such as hard to treat hypertension), Dr. Fizazi does not see any good reason to choose docetaxel over androgen receptor targeting. But, to conclude, he notes that he would be happy to revise his opinion if ongoing trials eventually show that triplet therapy is better than doublet therapy.
Presented by: Karim Fizazi, MD, Ph.D, Medical Oncologist, Head of the Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France, Professor of Oncology, University of Paris, Paris, France
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378(15):1408-1418.
- Gravis G, Boher JM, Chen YH, et al. Burden of Metastatic Castrate Naïve Protate Cancer Patients, to Identify Men More Likely to Benefit from Early Docetaxel: Further Analyses of CHAARTED and GETUG-AFU15 Studies. Eur Urol 2018 Jun;73(6):847-855.