The PCWG3 consensus for PSA progression on ADT is the most accepted definition of nmCRPC: a 25% PSA increase from nadir (starting PSA ≥1.0 ng/mL), with a minimum rise of 2 ng/mL in the setting of castrate testosterone (< 50 ng/dL).2 The most common clinical scenario of nmCRPC is no detectable disease in the primary site, no detected lymph nodes by CT or MRI, and no disease in the bone or visceral organs.3 The most commonly used imaging for conventional detection of metastasis is a technetium-99 bone scintigraphy scan to detect bone metastases, and a CT (or MRI if CT contraindicated) of the chest, abdomen and pelvis for evaluating soft tissue metastases. Prior to the trials and data presented in this article, one in three men with nmCRPC would develop metastatic disease within 2 years.4 The objective of this article is to review the practice changing data presented in 2018 for patients with nmCRPC and discuss studies and opinions that have emerged since phase III randomized controlled trial (RCT) data was published.
Enzalutamide is a novel androgen receptor (AR) signaling competitive inhibitor of androgen binding. It inhibits nuclear translocation of the AR, DNA binding, and coactivator recruitment. Two large phase III trials confirmed enzalutamide efficacy and ability to improve overall survival (OS) versus placebo in men with mCRPC both in the pre-chemotherapy (PREVAIL study5,6) and post-chemotherapy (AFFIRM study7) disease state. These results set the stage for assessing efficacy of enzalutamide in early disease states. Given that enzalutamide binds the AR with a 5-8-fold greater affinity than bicalutamide, the STRIVE trial (published in 2016) was a mixed population of men diagnosed with non-metastatic (n=139) or metastatic (n=257) CRPC randomized 1:1 to receive enzalutamide (160 mg/day) or bicalutamide (50 mg/day), with both arms remaining on ADT.8 Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (HR 0.24, 95%CI 0.18-0.32), as well as demonstrated significant improvements in all key secondary end points: time to PSA progression (HR 0.19, 95%CI 0.14-0.26), proportion of patients with a ≥ 50% PSA response (81% v 31%; P < .001), and radiographic progression free survival (PFS) in metastatic patients (HR 0.32, 95%CI 0.21-0.50). Importantly, these beneficial effects with enzalutamide were observed in both the nonmetastatic and metastatic subgroups. Even before results of the STRIVE trial were published, recruitment was already underway for two large phase III trials that would report in 2018 and change clinical practice for men with nmCRPC: the PROSPER and SPARTAN trials.
Non Metastatic CRPC: Recent Clinical Trials
The PROSPER trial was an international, double-blind, randomized, placebo-controlled, phase 3 trial approved at more than 300 sites in 32 countries.9 In this trial, 1,401 patients with nmCRPC were randomized 2:1 to enzalutamide vs placebo, with a primary outcome of metastasis-free survival (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).
Apalutamide is a nonsteroidal anti-androgen AR inhibitor, which binds to the ligand-binding domain of the AR after nuclear translocation; apalutamide has a 7-10-fold higher affinity for the AR than bicalutamide. The SPARTAN trial was a multi-institutional, double-blind, randomized, placebo-controlled, phase 3 trial at 332 sites in 26 countries in North America, Europe, and Asia-Pacific region.10 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 nmCRPC. 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.
Following presentation of the SPARTAN trial at the GU ASCO annual meeting in February 2018 and concomitant publication in The New England Journal of Medicine (NEJM)10, the FDA moved quickly on February 14, 2018 to approve apalutamide (240 mg daily) for men with nmCRPC. The PROSPER trail was also published in NEJM in June 20189, and enzalutamide (160 mg daily) also gained FDA approval on July 13, 2018.
Non Metastatic CRPC Since PROSPER and SPARTAN
Prior to FDA approval of enzalutamide, the American Urological Association (AUA) provided an amendment to their AUA CRPC Guideline11, first presented at the AUA 2018 annual meeting. This amendment focused solely on Index Patient 1—patients with non-metastatic CRPC, providing four updated Guideline Statements11:
- Guideline Statement 1: Clinicians should offer apalutamide or enzalutamide with continued androgen deprivation to patients with non-metastatic CRPC at high risk for developing metastatic disease (Standard; Evidence Level Grade A [apalutamide]/Grade B [enzalutamide])
- Guideline Statement 2: Clinicians may recommend observation with continued androgen deprivation to patients with non-metastatic CRPC at high risk for developing metastatic disease who do not want or cannot have one of the standard therapies (Recommendation; Evidence Level Grade C)
- Guideline Statement 3: Clinicians may offer treatment with a second-generation androgen synthesis inhibitor (i.e. abiraterone + prednisone) to select patients with non-metastatic CRPC at high risk for developing metastatic disease who do not want or cannot have one of the standard therapies and are willing to accept observation (Option; Evidence Level Grade C)
- Guideline Statement 4: Clinicians should not offer systemic chemotherapy or immunotherapy to patients with non-metastatic CRPC outside the context of a clinical trial (Recommendation; Evidence Level Grade C)
As noted above, both apalutamide (HR 0.28, 95% CI 0.23-0.35) and enzalutamide (HR 0.29, 95% CI 0.24-0.35) demonstrated statistically significant improvements in MFS compared with placebo. On indirect comparison of apalutamide and enzalutamide, there was no significant difference in MFS between the two agents (HR 1.04, 95% CI 0.78-1.37). Similarly, there were no significant differences in time to PSA progression, OS, any AEs, serious AEs, or AEs leading to treatment discontinuation. The authors concluded that while indirect comparisons cannot supplant direct comparative data, the analysis suggests that apalutamide and enzalutamide are similarly effective in delaying metastases for patients with nmCRPC.
Since indirect comparison between enzalutamide and apalutamide demonstrated no appreciable difference in efficacy or toxicity, subsequent studies and editorials have focused on several initiatives, including quality of life. In a letter to the NEJM editor, Rachner and colleagues noted that patients receiving apalutamide had a higher rate of bone fracture (11.7%) compared to placebo (6.5%)13, noting that only 10% of patients in SPARTAN received bone-protective therapy at the beginning of the trial. In the author’s response to this editorial, Smith et al. noted that patients treated with enzalutamide in the PROSPER trial had a higher rate of falls and fractures than the placebo patients, attributing these findings to a medication case effect. 14 This dialogue highlights the NCCN guideline recommendations to assess for fracture risk and treat with a bisphosphonate or denosumab when the absolute fracture risk warrants drug therapy.
Specific health-related quality of life (HRQOL) data from both trials has also been presented since original publication of the phase III trials. The SPARTAN trial collected Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaire data at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter.15 Notably, FACT-P and EQ-5D-3L scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for American adult men. Furthermore, group mean patient-reported outcome scores over time showed that HRQOL was maintained from baseline after initiation of apalutamide and similar over time. Mean change from baseline analysis showed that HRQOL deterioration was more apparent in the placebo group than those receiving apalutamide. The SPARTAN investigators noted that in addition to improved MFS and time to symptomatic progression compared to men receiving placebo, they achieved these improved outcomes while preserving quality of life.
Similarly, PROSPER has reported results of HRQOL and pain evaluations.16 FACT-P and Brief Pain Inventory, Short Form, were used to assess HRQOL and pain at baseline and every 16 weeks during treatment. The authors defined pain progression as ≥2 points in pain severity items and mean scores increase from baseline. Baseline characteristics and scores were similar between the enzalutamide and placebo arms with low pain (median 0) and high HRQoL (median FACT-P total score: 121). Decrease in attrition rate was greater in the placebo arm (53%) compared to the enzalutamide arm (68%), mainly due to disease progression at week 49. Most patients reported no change or improvement in HRQoL. The proportion of patients with pain progression at week 49 was similar between those receiving enzalutamide (11–20%) and placebo (14–21%). There was a non-statistically significant lower risk of pain progression observed with enzalutamide vs. placebo in the confirmed analysis (HR 0.78–0.93, p > 0.05). Furthermore, there was a statistically significant lower risk of deterioration observed for patients receiving enzalutamide for FACT-P total (HR 0.83, 95%CI 0.69-0.99), FACT Advanced Prostate Symptom Index (HR 0.79, 95%CI 0.65-0.94), prostate cancer subscale (HR 0.79, 95%CI 0.67-0.93), and emotional well-being (HR 0.69, 95%CI 0.55-0.86). Taking HRQOL data together from both PROSPER and SPARTAN, enzalutamide and apalutamide are both associated with maintaining quality of life throughout the trial follow-up.