In 2015, the ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) study was published by Dr. Sweeny in the New England Journal of Medicine.2 This was a prospective randomized controlled study randomizing patient with hormonal sensitive advanced prostate cancer disease into ADT alone or ADT with docetaxel. This study demonstrated an overall survival advantage to the docetaxel group, but when stratifying by disease volume, a survival benefit was seen only in patients with high volume disease.
Recently, data on the extended follow- of this trial was published, with a median follow-up of 53.7 months.3 In these updated analyses, it was demonstrated that the survival advantage was predominantly seen in high volume de novo disease, and not in low volume disease, or in high volume disease occurring after local treatment had been already given.
The Systemic Therapy in Advancing or Metastatic Prostate Cancer Evaluation for Drug Efficacy (STAMPEDE) trial is a multi-arm British study comparing different therapies to the standard of care (ADT alone). One of these arms included standard of care (ADT) + docetaxel. In this specific comparison4, a similar survival advantage was seen in the docetaxel arm (as was seen in CHAARTED), with a hazard ratio of 0.76, p=0.003. This study also demonstrated that the greatest advantage for docetaxel was seen in metastatic patients, and especially in those with denovo metastatic disease.
The definition of MHSPC high-volume disease varies significantly across the literature demonstrating the various definitions for high volume disease in different studies.
In a meta-analysis that included 2993 patients from CHAARTED, GETUG-15, and STAMPEDE and comparing ADT alone to ADT + docetaxel, the overall survival hazard ratio was 0.77 (0.68-0.87), favoring the docetaxel + ADT group.5
The next trial discussed was the LATITUDE trial, which included newly diagnosed MHSPC patients with 2 or more of the following: Gleason 8-10, >=3 bone metastases, and measurable visceral disease.6 Patients who had neuroendocrine differentiation or small-cell histologic features were excluded from the trial. Patients were randomized to either ADT + placebo, or ADT + abiraterone and prednisone. The results demonstrated a clear advantage to the abiraterone arm in progression free survival and overall survival.
One of the studies in STAMPEDE is a direct comparison between abiraterone and docetaxel. In this comparison a difference favoring abiraterone was seen in failure free survival and progression free survival.7 In contrast, no significant differences were seen in metastatic free survival, symptomatic skeletal events, cancer specific survival, or overall survival. However, in a meta-analysis incorporating all trials comparing docetaxel +ADT to abiraterone + ADT, a clear advantage was seen favoring abiraterone.8
Other relevant drugs have also been assessed, although in much smaller scale studies. There is a phase-two open-label, single arm study examining enzalutamide monotherapy in HSPC patients. 9 However, only 39% of the patients were metastatic at study entry, so the analyzed population of this study is mostly non-metastatic HSPC. Another study examining the response rate of daily enzalutamide160 mg in 26 MHSPC patients, who received this therapy for 3 years. The results showed a complete response rate of 53.8% in the enzalutamide treated patients.10
Radium 223 for primary bone metastasis in MHSPC patients was examined as well, but this was a very small study including only 10 patients, therefore making any conclusions from it is quite difficult. 11
Dr. Moorselaar ended his interesting update by mentioning some of the ongoing relevant studies. These include the currently recruiting PEACE-1 trial (NCT01957436), which is a multi-arm trial comparing ADT + docetaxel, ADT + docetaxel + abiraterone + prednisone, ADT + docetaxel + radiotherapy, and ADT + docetaxel + abiraterone + prednisone + radiotherapy.
Another trial that is active but not recruiting is the ARASENS trial (NCT02799602) comparing ADT + docetaxel + darolutamide to ADT + placebo + docetaxel. Two additional active but currently non-recruiting trials are ENZAMET (NCT02446405) comparing ADT + enzalutamide to ADT + placebo, and lastly, the TITAN trial (NCT02489318) comparing apalutamide + ADT to placebo + ADT.
The current European Association of Urology (EAU) guidelines recommend offering ADT combined with either chemotherapy or abiraterone to patients fit enough for these treatments. When deciding whether to administer docetaxel or abiraterone, one should consider the volume of disease, and be inclined to give docetaxel for high volume disease. In general Dr. Moorselaar believes that it is better to give docetaxel as soon as possible, as later on, the patient might not be fit enough to receive this treatment. Other factors that need to be considered when deciding which treatment to administer include the fact that docetaxel is given intravenously in six cycles, vs. long term oral abiraterone and prednisone. Whether the disease is de novo metastases or the patient has received prior local treatment should also be considered. The differences in side effects should be taken into account and the much higher cost of abiraterone compared to docetaxel is undoubtedly an important factor.
Speaker: J. van Moorselaar, Amsterdam (NL)
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2nd EAU Update on Prostate Cancer (PCa18)– September 14-15, 2018 – Milan, Italy
1. Gravis et al. Lancet Oncol 14:149, 2013
2. Sweeney et al. NEJM 373: 737, 2015
3. Kyriakopoulos et al. J Clin Oncol 36: 1080, 2018
4. James et al. Lancet 387: 1163, 2016
5. Vale et al. Lancet Oncol 17:243, 2016
6. Fizazi et al. NEJM 377:351, 2017
7. Sydes et al. Ann Oncol 29: 1235, 2018
8. Wallis et al. Eur Urol 73: 834, 2018
9. Tombal B et al. Lancet Oncol 2014; 15: 592-600
10. Tombal B et al. J URol 199: 45, 2018
11. Wenter V et al. Oncotarget 8 (27):44131, 2017