The treatment of castration-resistant prostate cancer (CRPC) has enjoyed a renaissance over the past decade, with a plethora of new treatments that have delayed the progression of disease; maintained or improved quality of life; and, most impressively, extended survival. Most of these efforts were derived from clinical trials that enrolled patients with metastatic CRPC, and almost exclusively those patients were eligible for treatment based on radiographic findings that resulted from conventional imaging. It was in that context that the enigma of nonmetastatic castration-resistant prostate cancer (M0 CRPC) was defined in that these patients had a rising PSA (2.0 or greater) despite a castrate level of testosterone on androgen deprivation therapy (ADT) and the absence of metastatic disease on conventional imaging.¹ Nuanced in this definition is the absence of metastatic disease based on conventional imaging: CT, MRI, or nuclear medicine bone scan. So, beginning in 2018 and continuing through 2020, 3 novel second-generation antiandrogens were trialed in phase 3 randomized placebo-controlled trials in patients with M0 CRPC, and this led to the Food and Drug Administration approval of enzalutamide, apalutamide, and darolutamide for the treatment of men in this disease state. Importantly, the approval of these agents was based on a new but meaningful intermediate end point: metastasis-free survival (MFS).² By allowing the trials to demonstrate an MFS primary outcome, the agents were able to be approved much faster than if an overall survival benefit had been mandated, and this undoubtedly extended the survival of thousands of men with M0 CRPC by allowing these medications with indications for M0 CRPC to get to market much more rapidly than would have otherwise happened.

Three randomized controlled trials were conducted using novel second-generation nonsteroidal antiandrogen agents. The PROSPER trial was an international, placebo-controlled randomized controlled trial that studied the impact of enzalutamide on MFS in patients with M0 CRPC.³ All patients in the study had a PSA doubling time (PSADT) of less than 10 months. Patients were then randomized in 2:1 fashion to receive either 160 mg per day of enzalutamide or placebo. In both arms, patients continued to receive ADT. The enzalutamide cohort experienced more than twice the duration of MFS vs placebo (36.6 vs 14.7 months), corresponding to a 71% improvement in the risk of metastasis or death. In absolute terms, at the time of the initial analysis, nearly half of the placebo group had died vs only 23% of the enzalutamide group. In 2020, mature overall survival results from the trial were reported. The enzalutamide group’s median overall survival was 67 vs 56.3 months in the placebo group, corresponding to a 27% reduction in the risk of death.⁴

In the phase 3 SPARTAN trial, investigators randomized 1207 participants with M0 CRPC in 2:1 fashion to receive ADT plus apalutamide (240 mg per day) vs ADT plus placebo.⁵ A total of 806 patients were assigned to receive apalutamide. In a similar design to PROSPER, all patients in SPARTAN exhibited PSADT of less than 10 months. Once again, MFS was the primary end point. ADT plus apalutamide demonstrated a 72% improvement in the risk of developing metastasis, with an MFS interval of 40.5 months for the apalutamide group vs 16.2 months for the ADT plus placebo group. An update to this trial with overall survival results demonstrated that ADT and the addition of apalutamide in M0 CRPC resulted in a 22% reduction in the risk of death over ADT and placebo, corresponding to 14 months of improved survival.⁶

Darolutamide was the third novel antiandrogen agent to be approved for use in M0 CRPC. Its mechanism of action is similar to that of apalutamide and enzalutamide in terms of its ability to inhibit androgen receptor binding, translocation, and androgen receptor–activated transcription.⁷ However, its unique chemical structure reduces the ability of darolutamide to cross the blood-brain barrier, an effect that may have implications on tolerability and adverse event rate.⁸ The phase 3 ARAMIS trial was similarly designed to PROSPER and SPARTAN and examined similar primary MFS end points.⁹ All patients met M0 CRPC criteria by conventional imaging standards, had a PSADT of less than 10 months, were randomized in 2:1 fashion vs placebo, and continued ADT. Patients in the darolutamide arm received 600 mg by mouth twice daily. The total number of patients in the study was 1509 (955 in the darolutamide arm vs 554 in the placebo arm). At the planned initial analysis, patients in the darolutamide group received a 22-month MFS advantage over placebo. When mature overall survival data were ultimately released, patients taking darolutamide experienced a 31% decrease in the risk of death, corresponding to 6% more patients being alive at 3 years with darolutamide.¹⁰

With the 3 agents currently approved for M0 CRPC having similar efficacy at prolonging time to metastasis, radiographic progression, and overall survival, the next question naturally raised has become how to select the most appropriate agent for patients.¹¹ Again, we lack randomized head-to-head comparative studies to guide us, and one approach has been to select the treatment based on the adverse effect profiles gleaned from each of the phase 3 trials. This, however, should be interpreted with caution as it lacks the rigor and standardization of a true comparative analysis. A surrogate for adverse event severity measured across PROSPER, SPARTAN, and ARAMIS was the treatment discontinuation rates due to adverse events. For enzalutamide, 17% (n = 158) of patients in the intervention arm discontinued therapy, citing an adverse event as the primary reason. A total of 51 patients (5% of the enzalutamide cohort) were determined to have died due to an adverse event.⁴ This compares with apalutamide, which saw 15% (n = 120) treatment discontinuation due to adverse events.⁶ Fewer patients in the SPARTAN trial died due to an adverse event on apalutamide (3.0%; n = 24). Darolutamide appears to carry the lowest rate of treatment discontinuation due to an adverse event, with an overall attrition rate of 8.9%.¹⁰

Treatment of patients with M0 CRPC continues to evolve. Recognizing that the disease state exists in part because of limitations with enhanced imaging that existed during the trials in this disease state, future recommendations will have to reconcile efficacy and outcomes in the setting of oligo-metastatic disease. The ability to detect and treat small-volume metastatic disease continues to improve with advances in prostate-specific membrane antigen positron emission tomography technology.¹² Currently, AUA/SUO guidelines advocate for the treatment of M0 CRPC patients with a PSADT of 10 months or less. Among those patients with slow PSA doubling times, observation and periodic restaging with positron emission tomography imaging and PSA monitoring may be appropriate. The decision to treat and choice of agent in the M0 CRPC space must also consider patient-specific factors, given the limitations of comparative data. In keeping with the AUA/SUO Advanced Prostate Cancer Guidelines, ADT is continued during treatment with enzalutamide, apalutamide, or darolutamide.¹ Finally, the frequent involvement of our multidisciplinary care team consisting of colleagues from medical and radiation oncology, as well as clinical research support staff, is paramount to ensuring these complex patients receive evidence-based and guideline-concordant care while having access to the latest clinical trials.