Few Unanswered Questions Remain for Nonmetastatic Prostate Cancer

Harsha Ranganath, MD, discusses the current and future treatment of patients with nonmetastatic castration-resistant prostate cancer.

Harsha Ranganath, MD

The FDA approvals of 2 antiandrogen agents in 2018 have shifted the needle forward in the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC), but a clear treatment sequence has yet to be established, said Harsha Ranganath, MD.

In February 2018, apalutamide (Erleada) became the first drug to be FDA approved for use in nonmetastatic CRPC, following the results of the phase III SPARTAN trial. Results of this study showed a 72% decrease in the risk of metastases or death with apalutamide versus placebo.2 The median MFS was 40.5 months versus 16.2 months in the apalutamide and placebo arms, respectively (HR, 0.28; 95% CI, 0.23-0.35; P <.0001). Treatment with apalutamide was also not associated with a significant impact on quality of life (QoL).

Time to symptomatic progression was significantly longer with apalutamide than with placebo (HR, 0.45; 95% CI, 0.32- 0.63; P <.001). The rate of AEs leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following AEs occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs 5.5%), hypothyroidism (8.1% vs 2.0%), and fracture (11.7% vs 6.5%).

Moreover, in July 2018, the FDA approved enzalutamide (Xtandi) as a therapy for this patient population. The decision was based on data from the double-blind, phase III PROSPER trial, in which the combination of enzalutamide and androgen deprivation therapy (ADT) reduced the risk of metastases or death by 71% compared with ADT alone.1 The median metastasis- free survival (MFS) was 36.6 months with enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P <.0001). The time to the first use of a subsequent therapy was longer with enzalutamide treatment than with placebo at 39.6 months versus 17.7 months, respectively (HR, 0.21; P <.001). The time to prostate-specific antigen progression also favored enzalutamide at 37.2 months versus 3.9 months (HR, 0.07; 95% CI, 0.05- 0.08; P <.001). Grade ≥3 treatment-related adverse events (AEs) occurred in 31% of patients who received enzalutamide compared with 23% of those who received placebo.

Ranganath, a fellow at the University of Tennessee West Cancer Center, added that enzalutamide has also shown potential in combination with radium-223 dichloride (Xofigo) for the management of bone metastases.

OncLive: What is important regarding treatment for patients with nonmetastatic CRPC?

What are the most notable drugs in this paradigm?

Do you want to use the most potent agent first?

What is the approach for those with bone metastases?

In an interview at the 2018 OncLive® State of the Science SummitTM on Genitourinary Cancers, Ranganath discussed the current and future treatment of patients with nonmetastatic CRPC.Ranganath: It is important to keep the patient’s QoL and overall life expectancy in mind, because this is an area where patients are living longer and longer. There is value in prolonging disease- free survival, but you are doing that at the risk of potentially toxic drugs; this includes financial toxicity. If you are starting therapy on someone who is asymptomatic and nonmetastatic, you may be burning a bridge by introducing a therapy you cannot use later in the treatment course. For patients who are eligible for just surveillance, it all depends on their comorbidities and their overall goals of care. I have run into cases, for example, where there are drug interactions that you want to avoid.The agents I spoke about today are enzalutamide and apalutamide. In practice, we are starting many patients on one of these agents. In many cases, these patients are going on androgen therapy in the first-line setting anyway. These are drugs we are very familiar with and they are well tolerated. There is not much difference between these drugs in terms of profile. The most common AE is fatigue.All the agents we use, for the time being, are active in later lines of therapy. Again, these are typically patients who are not going to have rapid progression. These patients will live for years and will have access to these drugs in a later disease course.We have good data showing the efficacy of radium-223 dichloride in this patient population. Recent data presented at the 2018 ESMO Congress discussed the use of combination therapy with radium-223 and antiandrogen agents.


  1. Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6S; abstr 3). doi: 10.1200/JCO.2018.36.6_suppl.3.
  2. Small EJ, Saad F, Chowdhury S et al. SPARTAN, a phase 3 double-blind, ran- domized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2018;3(suppl 6s; abstr 161). doi: 10.1200/JCO.2018.36.6_suppl.161.