|Year : 2018 | Volume
| Issue : 4 | Page : 305-306
Apalutamide: A novel therapy for non metastatic castration-resistant carcinoma prostate
Department of Urology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||19-May-2018|
|Date of Acceptance||26-Jun-2018|
|Date of Web Publication||01-Oct-2018|
Department of Urology, Christian Medical College, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Jayasimha S. Apalutamide: A novel therapy for non metastatic castration-resistant carcinoma prostate. Indian J Urol 2018;34:305-6
| Summary|| |
The recently published trial from the SPARTAN group evaluated the role of adding Apalutamide, a pure androgen receptor antagonist to androgen deprivation therapy (ADT) in patients with high risk, non metastatic castration-resistant prostate cancer (nmCRPC). This was a multinational, multicenter, double-blinded, placebo controlled, randomized control trial published in the New England Journal of Medicine on February 8th, 2018.
The study recruited patients >18 years of age with histologically confirmed nmCRPC who were at increased risk for metastases (prostate-specific antigen [PSA] doubling time of <10 months on continuous ADT). The period of study was 38 months (October 14, 2013, to December 16, 2016). A total of 1207 men with a median age of 74 years were randomised in a 2:1 ratio to Apalutamide + ADT versus placebo + ADT at 332 centers in 26 countries. Apalutamide was prescribed at 240 mg once daily dose. The performance status required at inclusion was ECOG 0/1. At enrolment, the majority (71%) of patients had a PSA doubling time of <6 months and 16% had regional nodal disease (<2 cm nodes below the level of aortic bifurcation). All patients underwent PSA, technetium 99 bone scan and computed tomography of thorax, abdomen and pelvis pre-therapy and then every 16 weeks after the initiation of treatment. The response to therapy was evaluated using the RECIST criteria. At disease progression Abiraterone or other standard therapies were offered.
The primary endpoint was metastasis-free survival (MFS) (time from randomization to the first detection of metastases on imaging). Secondary endpoints included progression-free survival (PFS- time to detection of local/distant metastatic disease/death), time to symptomatic worsening/skeletal event, PSA progression, overall survival (OS), time to chemotherapy, and time to second progression (defined as clinical/PSA progression/detection of metastases/death after initiation of second-line therapy). The primary analysis was performed at a median follow-up of 20.3 months when 378 events (metastasis or death) had occurred.
Apalutamide improved MFS by 72% (40.5 vs. 16.2 months) (Hazard ratio [HR] 0.28, 95% confidence interval-0.23–0.35, P < 0.001) irrespective of age, PSA level, PSA doubling time, prior ADT, or status of regional nodes. PSA response was 89.7% in the study arm and 2.2% in the placebo arm. Apalutamide also improved PFS (40.5 vs. 14.7 months, HR 0.29, [0.24–0.36], P < 0.001), time to symptomatic progression (HR 0.45, [0.32–0.63], P < 0.001), and PSA progression (HR 0.06, [0.05–0.08]). The median OS was not reached. Apalutamide also delayed the time to second progression (HR 0.49, [0.36–0.66]). During the study, the disease progressed in 155 patients (19.2%) in the Apalutamide arm as compared to 210 patients (52.8%) in the control arm.
Three patients in each arm did not receive treatment after randomization. Seven percent of patients in apalutamide arm and 10.7% in control arm withdrew consent. Severe adverse events were comparable between the two arms (24.8% in apalutamide arm and 23.1% in placebo arm). Rash (23.8 vs. 5.5%), fatigue (30.4 vs. 21.1%), falls (15.6 vs. 9%), and fractures (11.7 vs. 2.7%) were more common in the apalutamide arm. Ten patients in the apalutamide arm died following adverse events as compared to 1 in the control arm.
| Comment|| |
Metastatic prostate cancer is associated with morbidity and mortality. All patients on ADT eventually progress to CRPC. Higher baseline PSA and shorter PSA doubling time (<10 months) predict shorter duration to distant metastases and death. Till the publication of this trial, there was no FDA approved therapy for high risk, nmCRPC. Apalutamide is a pure anti-androgen that directly binds to androgen-binding domain of the androgen receptor and prevents its nuclear translocation, DNA binding, and transcription. It does not have antagonist to agonist switch as seen with Bicalutamide. In pre-clinical studies Apalutamide showed greater anti-tumor activity at lower doses as compared to enzalutamide. In phase II trials, Apalutamide showed a PSA response in 89% of patients with nmCRPC and in 22% with metastatic CRPC who had progressed on Abiraterone.,
The SPARTAN trial shows Apalutamide as a viable option in high-risk nmCRPC, with improvements in MFS, PFS, symptomatic and PSA progression. It also delays progression after initiation of second-line therapy which suggests that the benefit derived from the initial anti-tumor activity of Apalutamide is sustained. However, there is a higher incidence of side effects which is relevant in nmCRPC patients with good performance status as their life expectancy is measured in years. Similar results were obtained in a yet to be published phase III trial of enzalutamide in patients with nmCRPC (PROSPER) where the MFS was 36.6 versus 14.7 months (HR 0.29, P < 0.0001). While these results are promising, the effect of these novel therapies on OS will better answer whether early initiation of therapy in nmCRPC is truly beneficial or not.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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