Basel, Switzerland ( At the Advanced Prostate Cancer Consensus Conference (APCCC) 2019 Drs. Maha Hussain and Celestia Higano presented during the management of castration-resistant prostate cancer (CRPC) debate. Each clinician presented on one side of comparison regarding the treatment of non-metastatic (nmCRPC). Dr. Maha Hussain presented the “pros” of treating men with nmCRPC. Until early 2018, nmCRPC was an area of unmet need with no approved therapies. Looking back to 2011, the FDA convened an Oncologic Drugs Advisory Committee (ODAC) meeting with a focus on clinical trial endpoints and trial designs to support drug approval. What was proposed was that a transition from nmCRPC to M1 disease is a clinically relevant event and metastasis-free survival (MFS) is a reasonable endpoint. Certainly, the clinical benefit of a drug would require a substantial magnitude of improvement and a favorable benefit-risk evaluation in this context. In 2012, another ODAC meeting examined the results of denosumab in nmCRPC trial, noting that an estimated median improvement of only 4 months in bone-only MFS was not favorable enough for approval. For patients with nmCRPC, the development of metastases is predictable and is associated with increasing baseline PSA and PSA doubling time < 10 months with median bone MFS of 25-30 months. 

According to Dr. Hussain, there are several reasons to focus on the treatment of nmCRPC, what she calls the“window of opportunity”:

  1. The lower tumor burden may portend for a better and more durable response
  2. Advancing effective and systemic therapy earlier has a greater “return on investment”, for example, enzalutamide in mCRPC post docetaxel vs pre-docetaxel vs metastatic hormone-sensitive prostate cancer
  3. M1 CRPC is a deadly disease–delaying time to all metastases is clinically relevant, with potential to delay cancer-related mortality and prolong overall survival

The past 18 months have seen the reporting and FDA approval of three new agents in the nmCRPC disease space: apalutamide (SPARTAN1), enzalutamide (PROSPER2), and darolutamide (ARAMIS3).

The SPARTAN trial was a multi-institutional, double-blind, randomized, placebo-controlled, phase III trial at 332 sites in 26 countries in North America, Europe, and Asia-Pacific region [1]. This trial randomized 1,207 men 2:1 to receive apalutamide vs placebo. In the planned primary analysis at 378 events, median MFS was 40.5 months in the apalutamide group compared with 16.2 months in the placebo group (HR for metastasis or death 0.28, 95%CI 0.23-0.35). Time to symptomatic progression was significantly longer with apalutamide than with placebo (HR 0.45, 95%CI 0.32-0.63). The conclusions from SPARTAN were that apalutamide decreased the risk of metastasis or death by 72% and prolonged the median MFS by more than two years in men with high-risk M0 CRPC. Furthermore, the MFS benefit was consistent across all subgroups, and the results were supported by consistent improvement across all evaluable endpoints: time to metastasis, PFS, time to symptomatic progression, time to PSA progression, and PSA decline.

The PROSPER trial was an international, double-blind, randomized, placebo-controlled, phase III trial approved at more than 300 sites in 32 countries [2]. In this trial, 1,401 patients with M0 CRPC were randomized 2:1 to enzalutamide vs placebo, with a primary outcome of MFS. Secondary endpoints were time to PSA progression, time to first use of new therapy, and OS. The median MFS was 36.6 months in the enzalutamide arm versus 14.7 months in the placebo group: a 71% improvement for men receiving enzalutamide (HR 0.29, 95%CI 0.24-0.35). Time to PSA progression was 37.2 months for the enzalutamide group vs 3.9 months for the placebo arm (HR 0.07, 95% CI 0.05-0.08), and time to subsequent therapy was 39.6 months for enzalutamide patients compared to 17.7 for the placebo group (HR 0.21, 95%CI 0.17-0.26). At the interim analysis for OS, the HR was 0.80 (favoring enzalutamide), but was not statistically significant (p=0.15).

ARAMIS was a double-blind, placebo-controlled phase III randomized controlled trial in which nmCRPC patients were randomized 2:1 to receive either darolutamide 600 mg (two 300mg tablets) twice-daily or placebo while continuing androgen deprivation therapy[3]. Patients were stratified by PSA doubling time (≤6 months or >6 months) and use of osteoclast-targeted therapy; key inclusion criteria were men with PSA ≥ 2 ng/mL, ECOG 0-1, and PSADT ≤ 10 months. Median MFS was 40.4 months with darolutamide vs 18.4 months with placebo (HR0.41, 95%CI 0.34–0.50), representing a 59% reduction in metastases or death among patients receiving darolutamide. OS favored darolutamide (median not reached for either arm, HR 0.71,95% CI 0.50–0.99, 2-sided p=0.045), as did time to pain progression (HR 0.65, 95%CI 0.53–0.79; 2-sided p< 0.0001), however the OS data is still immature. Other secondary and exploratory efficacy endpoints also favored darolutamide over placebo. PFS: 62% reduced risk of local progression, distant metastases or death (36.8 months vs. 14.8 months, HR 0.38, p < 0.0001); time to first cytotoxic chemotherapy: HR 0.43, p < 0.001; time to SSRE: HR 0.43, p = 0.011. Total Grade 3-5 AE’s were similar between the two groups: 24.7% in the darolutamide arm vs.19.5% in the placebo arm.

Dr. Hussain concluded with several important thoughts from her presentation, specific to men with nmCRPC and a rapid PSA doubling time:

  • Enzalutamide, apalutamide, and darolutamide resulted in a clinically meaningful and statistically significant reduction in the relative risk of developing M1 CRPC
  • Therapy for all three medications was overall well-tolerated
  • The FDA approval of all three agents is not restricted to PSA doubling time
  • Therapy decisions should take into account disease risks, comorbidities, life expectancy, and potential toxicities in a shared decision-making fashion
  • Future directions include the role of better imaging and novel multi-targeted combination therapy

Presented by: Maha Hussain, MD, FACP, FASCO, is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, and the Deputy Director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.

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  Advanced Prostate Cancer Consensus Conference (APCCC) #APCCC19, Aug 29 – 31, 2019 in Basel, Switzerland


  1. 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.
  2. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun 28; 378(26):2465-2474.
  3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2019; 380(13):1235-1246.

Read the Opposing Debate:
Con: – Celestia S. Higano, MD, FACP