SUMMARY: The FDA on February 14, 2018 approved ERLEADA® (Apalutamide) for patients with Non-Metastatic Castration Resistant Prostate Cancer (NM-CRPC). Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 164,690 new cases of Prostate cancer will be diagnosed in 2018 and 29,430 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for Castration Sensitive Prostate Cancer (CSPC). Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The median duration of response is approximately 1 year and majority of these patients progress to Castration Resistant Prostate Cancer (CRPC). The mechanism of resistance to Androgen Deprivation Therapy (ADT) include reactivation of Androgen Receptor signaling through persistent adrenal androgen production, modification of the biologic characteristics of Androgen Receptors, intratumoral testosterone production and parallel steroidogenic pathways. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen), and watchful waiting is recommended in men with non-metastatic CRPC. However, those with a rapidly rising PSA on ADT (doubling time of less than 8-10 months), are at significantly greater risk of developing metastases and death.
ERLEADA® is a next-generation, nonsteroidal, competitive inhibitor of the Androgen Receptor. ERLEADA® prevents binding of androgens to the Androgen Receptor by competitively binding directly to the ligand-binding domain of the Androgen Receptor, and prevents the translocation of the Androgen Receptor to the nucleus and thereby impedes Androgen Receptor mediated DNA transcription. ERLEADA® resulted in durable PSA responses in a phase II study, among men with non-metastatic CRPC, who were at high risk for disease progression (with a PSA level of 8 ng/ml or more or a PSA doubling time of 10 months or less). Based on this preliminary data, the authors evaluated the efficacy of ERLEADA® in men with non-metastatic CRPC, who were at a high risk for the development of metastasis.
SPARTAN (Selective Prostate Androgen Receptor Targeting with ARN-509) trial is an international, randomized, placebo-controlled, phase III study in which 1207 men were randomly assigned in a 2:1 ratio, to receive ERLEADA® 240 mg orally daily (N=806) or placebo (N=401). Eligible patients had non-metastatic CRPC and were at high risk for the development of metastasis, with a PSA doubling time of 10 months or less during continuous Androgen Deprivation Therapy (bilateral orchiectomy or treatment with Gonadotropin Releasing Hormone analogue agonists or antagonists).
All the patients at the time of screening for eligibility, underwent a technetium-99m bone scan and Computed Tomography (CT) of the head, chest, abdomen and pelvis, abdomen, and were excluded from the study if distant metastasis was detected. Androgen Deprivation Therapy was continued throughout the study period. Patients were eligible to receive treatment with sponsor-provided ZYTIGA® (Abiraterone acetate) plus Prednisone, after the first detection of distant metastasis. The Primary end point was Metastasis-Free Survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. Secondary end points included time to metastasis, Progression Free Survival, time to symptomatic progression, Overall Survival, and time to the initiation of cytotoxic chemotherapy. For those patients who developed metastases, the time between randomization to the first treatment for metastatic CRPC and subsequent progression (second Progression Free Survival-PFS2), was also evaluated.
At the time of the planned primary analysis, the median Metastasis-Free Survival was 40.5 months in the ERLEADA® group as compared with 16.2 months in the placebo group (HR for metastasis or death =0.28; P<0.001). This meant a 72% reduction in the risk of metastasis and death in the ERLEADA® group and significantly prolonged median Metastasis-Free Survival by 2 years, compared with placebo. Further, ERLEADA® significantly improved the time to metastasis, Progression Free Survival and symptom progression, compared with placebo. The time to symptomatic progression was significantly longer with ERLEADA® than with placebo (HR=0.45; P<0.001), which meant a 55% risk reduction in the time to symptomatic disease progression. All prespecified subgroups consistently benefited from ERLEADA®.
In spite of subsequent approved treatment for metastatic CRPC in 78% of placebo recipients (most common subsequent treatment being ZYTIGA® plus Prednisone), the second Progression Free Survival was significantly longer in the ERLEADA® group, compared to the placebo group (Hazard Ratio for progression or death=0.49). A trend toward improved survival was observed in the ERLEADA® group. At a median follow up of 20.3 months, 61% in the ERLEADA® group and 30% in the placebo group were still on therapy. Treatment discontinuation due to adverse events was 10.6% in the ERLEADA® group and 7.0% in the placebo group, and patients in the ERLEADA® group had a higher incidence of rash, hypothyroidism and fractures.
It was concluded that among patients with non-metastatic Castration Resistant Prostate Cancer, ERLEADA® significantly prolonged Metastasis-Free Survival and time to symptomatic progression, when compared to placebo. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. Smith MR, Saad F, Chowdhury S, et al. for the SPARTAN Investigators. N Engl J Med. February 8, 2018. DOI: 10.1056/NEJMoa1715546
