Second-Generation Antiandrogens for the Treatment of Prostate Cancer: A Look at Efficacy and Safety

Seon Jo Park, PharmD, BCOP; Tammy Li, PharmD

Second-generation antiandrogens have been studied in 6 large, randomized, double-blind, placebo-controlled, phase 3 clinical trials, PROSPER (enzalutamide), SPARTAN (apalutamide), and ARAMIS (darolutamide) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and TITAN (apalutamide), ARCHES (enzalutamide), and ARASENS (darolutamide) in patients with metastatic castration-sensitive prostate cancer (mCSPC) populations. This article will review the primary and secondary end points and adverse events (AEs) in these trials.

The clinical trials PROSPER, SPARTAN, and ARAMIS evaluated the primary end point of metastasis-free survival in men with nmCRPC with a prostate-specific antigen (PSA) doubling time of ≤10 months.^1-3 The PROSPER trial compared enzalutamide plus androgen deprivation therapy (ADT) with placebo plus ADT, the SPARTAN trial compared apalutamide plus ADT with placebo plus ADT, and the ARAMIS trial compared darolutamide plus ADT with placebo plus ADT. Median metastasis-free survival rates were significantly improved when compared with placebo at 36.6 versus 14.7 months for enzalutamide (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.24-0.35; P<.001) in the PROSPER trial, 40.5 versus 16.2 months for apalutamide (HR, 0.28; 95% CI, 0.23-0.35; P<.001) in the SPARTAN trial, and 40.4 versus 18.4 months for darolutamide (HR, 0.41; 95% CI, 0.34-0.5; P<.001) in the ARAMIS trial.^1-3

Secondary end points for overall survival (OS) were evaluated in all 3 trials in patients with nmCRPC, which showed significant improvements with second-generation antiandrogen use.

Secondary end points for overall survival (OS) were evaluated in all 3 trials in patients with nmCRPC, which showed significant improvements with second-generation antiandrogen use. In the PROSPER trial, median OS was 67 months with enzalutamide and 56.3 months with placebo (HR, 0.73; 95% CI, 0.61-0.89; P=.001).⁴ In the SPARTAN trial, median OS was 73.9 months with apalutamide and 59.9 months with placebo (HR, 0.78; 95% CI, 0.64-0.96; P=.016).⁵ In the final analysis of the ARAMIS trial, median OS with darolutamide was not reached in either arm, but 83% were alive in the darolutamide group compared with 77% in the placebo group at 3 years, which was statistically significant (HR, 0.69; 95% CI, 0.53-0.88; P=.003).⁶ The secondary end points of time to PSA progression were significantly longer with all 3 agents as well. Time to PSA progression was 37.2 versus 3.9 months with enzalutamide (HR, 0.07; P<.001), 40.5 versus 3.7 months with apalutamide (HR, 0.07; P<.0001), and 33.2 versus 7.3 months with darolutamide (HR, 0.13; P<.001) when compared with placebo in their respective trials.^1,3,5 Patient-reported quality of life was also similar in the antiandrogen and placebo arms in their respective trials.^1-3

AEs leading to trial regimen discontinuation were similar among all 3 trials 9%, 10.6%, and 8.9% with enzalutamide, apalutamide, and darolutamide, respectively. Most common any-grade AEs reported in the PROSPER trial with enzalutamide included fatigue (33%), hot flush (13%), hypertension (12%), and falls (11%).¹ Similarly, the SPARTAN trial reported fatigue (30.4%), hypertension (24.8%), rash (23.8%), diarrhea (20.3%), and falls (15.6%).² The ARAMIS trial reported fatigue (12.1%), back pain (8.8%), arthralgia (8.1%), diarrhea (6.9%), hypertension (6.6%), and falls (4.2%).³ Three patients reported seizures on enzalutamide and 2 patients each with apalutamide and darolutamide.^1-3 It is important to note that the PROSPER and SPARTAN trials excluded patients with a preexisting history of seizures, in contrast to the ARAMIS trial, which allowed enrollment of these patients. Preclinical trials have shown that darolutamide has lower blood–brain barrier penetrations compared with enzalutamide (46 times lower) and apalutamide (26 times lower), which explains the lower risk of central nervous system AEs.⁷

Second-generation antiandrogens were also studied in mCSPC populations. These clinical trials included TITAN, ARCHES, and ARASENS. The TITAN trial compared apalutamide plus ADT with placebo plus ADT, the ARCHES trial compared enzalutamide plus ADT with placebo plus ADT, and the ARASENS trial compared darolutamide combined with docetaxel and ADT with placebo combined with docetaxel and ADT.

The TITAN trial enrolled 66.9% of patients with a Gleason score >7 and 61.9% with high-volume disease, the ARCHES trial enrolled 67.2% of patients with a Gleason score >8 and 61.7% high-volume disease, and the ARASENS trial enrolled 77.6% of patients with a Gleason score >8 and 79.4% of M1b disease (indicating that the cancer has spread the bones) and 17.1% of M1c disease (the cancer has spread to organs such as the liver, brain, or lungs).^8-10

The primary end points for the TITAN trial were radiographic progression-free survival (rPFS) and OS. rPFS improved significantly at 24 months with 68.2% in the apalutamide group compared with 47.5% in the placebo group (HR, 0.48; 95% CI, 0.39-0.6; P<.001). OS was also significantly improved at 24 months with 82.5% in the apalutamide group and 73.5% in the placebo group (HR, 0.67; 95% CI, 0.51-0.89; P=.005). In the ARCHES trial, enzalutamide improved rPFS by 61% compared with the placebo group. Median rPFS was not reached with enzalutamide versus 19 months with placebo (HR, 0.39; 95% CI, 0.30-0.5; P<.001). The median OS was not reached in either group; however, enzalutamide showed a 34% reduction in the risk of death compared with placebo (HR, 0.66; 95% CI, 0.53-0.81; P<.001). In the ARASENS trial, darolutamide showed a 32.5% reduction in the risk of death compared with placebo (HR, 0.68; 95% CI, 0.57-0.8; P<.001).^8-11

A notable secondary end point in the TITAN trial was time to PSA progression. In the apalutamide group, it was not reached versus in the placebo group at 12.91 months (HR, 0.26; 95% CI, 0.21-0.32). In the ARCHES trial, time to PSA progression was not reached in the enzalutamide group versus 16.6 months in the placebo group (HR, 0.19; 95% CI, 0.14- 0.24). In the ARASENS trial, the time to development of castration-resistant disease was significantly longer in the darolutamide group compared with the placebo group (HR, 0.36; 95% CI, 0.30-0.42; P<.001).^8-10

AEs leading to trial regimen discontinuation were similar among all 3 trials: 8%, 7.2%, and 13.5% with apalutamide, enzalutamide, and darolutamide, respectively. Most common any-grade AEs reported in the TITAN trial included hot flush (22.7%), fatigue (19.7%), hypertension (17.7%), and back pain/arthralgia (17.4%). Similarly, the ARCHES trial reported hot flash (27.1%), fatigue (19.6%), arthralgia (12.2%), back pain (7.5%), and hypertension (8%). The ARASENS trial reported alopecia (40.5%), neutropenia (39.3%), fatigue (33.1%), anemia (27.8%), arthralgia (27.3%), and peripheral edema (26.5%). Three patients reported seizures on apalutamide, 2 patients with enzalutamide, and 4 patients with darolutamide.^8-10

All agents studied in patients with mCSPS improved rPFS and OS significantly in low-volume and high-volume disease.

All agents studied in patients with mCSPS improved rPFS and OS significantly in low-volume and high-volume disease. They also showed significant differences in secondary end points such as PSA progression and time to castration-resistant disease. AEs were not substantially different between second-generation antiandrogens and placebo.

For nmCRPC, apalutamide, enzalutamide, and darolutamide improved the median metastasis-free survival rate to 40.5 months, 36.6 months, and 40.4 months respectively. For mCSPC, apalutamide showed improved rPFS at 24 months with 68.2%, enzalutamide improved rPFS by 61%, and darolutamide showed 32.5% reduction in the risk of death, all compared with placebo. AEs were all similar with 3 agents with the most common side effects being fatigue, hot flush, hypertension, and arthralgia. Overall, these second-generation antiandrogens remain a backbone of treatment for patients with prostate cancer. They have shown statistically significant improvements in survival outcomes in patients with nmCRPC and mCSPC with manageable safety profiles.^1-10

References

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