Since their initial introduction as alternatives to docetaxel for mCRPC based on AFFIRM1/PREVAIL2 and COU-AA-3013 and 3024, docetaxel itself was promoted to first-line therapy for metastatic hsPCa, particularly in the setting of high-volume disease.5 Androgen axis inhibitors followed suit more recently, with the highly publicized results of LATITUDE6 and STAMPEDE7, which demonstrated significant survival benefit with the use of abiraterone in conjunction with ADT for metastatic hsPCa.
However, in all this development, an important disease state was effectively ignored. Patients with cM0 (no radiographic evidence of metastatic disease) castration-resistant prostate cancer (CRPC) had no approved therapies! As all the above studies had focused on safety and efficacy of androgen-axis inhibitors in the setting of metastatic disease, it was unclear if there was any survival benefit to initiating these medications prior to the development of radiographic or clinically evident metastases.
There is good clinical data by Smith et al7 that correlates higher baseline PSA and PSA doubling time (PSADT) in men with cM0 CRPC with development of metastatic disease. Hence, progression to metastatic disease is predictable. Unfortunately, metastatic CRPC is a uniformly fatal disease, and median survival is approximately 2.5 years from the time of metastases development.
As such, at this time, patients with cM0 CRPC are often managed expectantly. Most men eventually progress to metastatic disease, though at varying rates. A recent retrospective series identified that among nonmetastatic CRPC men, nearly 60% developed metastatic disease during the first 5-years, with most of the metastasis occurring within the first 3 years.9 Smith et al. also demonstrated that median bone-metastases free survival is 25-30 months in this patient population.7
At this year’s GU ASCO 2018 conference, two large prospective clinical trials are reporting specifically on nmCRPC disease state. The results have been eagerly awaited. The two studies are PROSPER and SPARTAN. PROSPER specifically assesses ENZA in the cM0 CRPC setting, while SPARTAN focused on apalutamide-ARN-509 (APA). Apalutamide is a next-generation competitive inhibitor of the androgen receptor under development for the treatment of patients with prostate cancer but perhaps with greater potency and reduced CNS effects. While the phase II results of APA in this setting were promising, demonstrating ≥50% PSA decline at 12 weeks in 89% of patients, median (time to PSA progression) TTPP of 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]) and median MFS was NR (95% CI, 33.4 mo-NR).
The safety profile is acceptable.10
Dr. Kantoff’s discussion: He provided a summary of the two studies and raised some important questions.
While these two studies are strongly positive, he highlights the fact that these are asymptomatic non-metastatic patients, and therefore the burden of treatment may be higher than in mCRPC patients. The burden of proof must therefore be much higher.
First, he correctly addresses the utility of MFS as an adequate surrogate for OS. While it has been established an accurate surrogate in localized disease,11 this is still not evident in advanced disease. Recent studies have started to hint at this association,12 but further research is needed to establish this surrogacy.
He also notes that SPARTAN and PROSPER provide the first long-term data on overall survival in the cM0 CRPC space. Looking at the OS curves from both studies, men treated in the placebo arms had anticipated median OS in excess of 5 years. Hence, untreated patients may survive 5 years. Thus, even high-risk cM0 CRPC patients live about 2 years longer than mCRPC patients. Treatment in this stage would mean an additional 2 years of treatment, with its associated exposures and adverse events. This should be considered before initiating treatment in all patients.
However, both studies have demonstrated delay of symptomatic progression. SPARTAN specifically demonstrated a 55% risk reduction of skeletal related events, pain progression/worsening symptoms, and clinically significant symptoms. This would ideally carry clinical implications as prior studies have established that skeletal related events in advanced prostate cancer are associated with worse overall survival outcomes.
Lastly, he points out, as noted above, there was a 15% mortality rate (death without documented progression) in the Enza arm, compared to only 2% in the placebo arm, which they could not adequately explain. In contrast, in the SPARTAN trial, there was a slightly higher absolute rate of grade 3-4 falls and fractures in the apalutamide arm than in the placebo arm (4.4% vs. 1.6% in the placebo arm).
Ultimately, he concludes by stating that the data, especially related to toxicity, needs to be scrutinized further, and it needs to be addressed in the setting of actual practice. However, the results are promising.
Presented by: Philip W. Kantoff, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto | @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
References:
1. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-1197.
2. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol 2017;71(2):151-154.
3. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13(10):983-992.
4. Rathkopf DE, Smith MR, de Bono JS, et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol. 2014;66(5):815-825.
5. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
6. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
7. Smith MR, Saad F, Oudard S, Shore N, Fizazi K, Sieber P, Tombal B, Damiao R, Marx G, Miller K, Van Veldhuizen P, Morote J, Ye Z, Dansey R, Goessl C. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013 Oct 20;31(30):3800-6. doi: 10.1200/JCO.2012.44.6716. Epub 2013 Sep 16.
8. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351.
9. Moreira DM, Freedland SJ, et al. Predictors of Time to Metastasis in Castration-resistant Prostate Cancer. Urology. 2016 Oct;96:171-176. doi: 10.1016/j.urology.2016.06.011. Epub 2016 Jun 16.
10. Smith MR, Antonarakis ES, Ryan CJ, Berry WR, Shore ND, Liu G, Alumkal JJ, Higano CS, Chow Maneval E, Bandekar R, de Boer CJ, Yu MK, Rathkopf DE. Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. Eur Urol. 2016 Dec;70(6):963-970. doi: 10.1016/j.eururo.2016.04.023. Epub 2016 May 6
11. Xie W, et al; ICECaP Working Group. Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer. J Clin Oncol. 2017 Sep 20;35(27):3097-3104. doi: 10.1200/JCO.2017.73.9987. Epub 2017 Aug 10.
12. Morris MJ et al. Radiographic Progression-Free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302. J Clin Oncol. 2017 Sep 20;35(27):3097-3104. doi: 10.1200/JCO.2017.73.9987. Epub 2017 Aug 10.
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