Prostate cancer is the most common malignancy and the second leading cause of cancer death cancer in males in the United States.1 Prostate cancer is an androgen-dependent disease and many early-stage prostate cancers need normal levels of testosterone to grow. Treatment therefore involves lowering androgen levels. However, the tumour may progress to the lethal phenotype of castration-resistant prostate cancer (CRPC), which is still driven by androgens and requires the androgen receptor for progression. Androgen deprivation therapy (ADT) is the mainstay of treatment in men with CRPC.2
Enzalutamide (Xtandi®, Astellas, Tokyo, Japan), an androgen receptor inhibitor, is indicated for the treatment of asymptomatic or mildly symptomatic metastatic CRPC, after failure of androgen deprivation. Approval was based on two studies: AFFIRM, involving chemotherapy-treated patients,3 and PREVAIL, which recruited chemotherapy-naïve patients with a relatively low symptom burden.4
The next rational step in the development of enzalutamide in CRPC was to turn to earlier stages of the disease. Until recently there were no approved therapies for nonmetastatic CRPC, an important unmet need. In February 2018, the US Food and Drug Administration (FDA) approved apalutamide (Erleada®, Janssen, Beerse, Belgium), another inhibitor of the androgen receptor, for the treatment of nonmetastatic CRPC. This approval was the first to use the endpoint of metastasis-free survival, and was based on results of the SPARTAN study, in which men with nonmetastatic CRPC and a prostate-specific antigen (PSA) doubling time of 10 months or less (the doubling time for PSA is the best marker of the pace of disease progression)5 were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All patients received ADT. Treatment with apalutamide resulted in a 72% reduced risk of metastasis or death.6
The PROSPER trial (NCT02003924) compared the efficacy and safety of enzalutamide (160 mg/day) plus ADT versus placebo plus ADT in asymptomatic men with nonmetastatic CRPC and PSA doubling time of 10 months or less. Participants were randomly assigned to receive enzalutamide (n=933) or placebo (n=468), respectively. Data from this study was first presented in February 2018 at the at American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, CA, US. Patients treated with enzalutamide had a significantly longer time to metastasis (36.6 months) compared with placebo (14.7 months, HR: 0.29).7 The median treatment duration was 18.4 months among those assigned enzalutamide plus ADT and 11.1 months for those assigned placebo plus ADT. Patients in the enzalutamide group also had a longer time to first use of new antineoplastic therapy (39.6 months versus 17.7 months; hazard ratio [HR] 0.21) and a 93% reduction in the risk of PSA progression in the enzalutamide arm (37.2 months versus 3.9 months; HR: 0.07) compared with ADT alone. The initial results from the PROSPER trial were available 2 years earlier than estimates, which predicted data maturation in 2020. Median overall survival was not reached in either group. Adverse events were consistent with those reported in the AFFIRM and PREVAIL studies, with grade ≥3 adverse events being experienced by 31% of men in the enzalutamide arm compared with 23% of those in the placebo arm. The grade ≥3 adverse events that were more common in the enzalutamide group versus placebo, respectively, were hypertension (5% versus 2%) and fatigue (3% versus 1%). As a result of these data, the FDA has granted a priority review to a supplemental new drug application for enzalutamide for the treatment of men with nonmetastatic CRPC, with a decision expected in July 2018.
Since patients with nonmetastatic CRPC are usually asymptomatic, and are likely to be receiving treatment over prolonged periods, the effect of therapy on health-related quality of life (HRQoL) has been increasingly recognised. A number of tools are available to assess HRQoL in CRPC, including disease-specific questionnaires such as Functional Assessment of Cancer Therapy–Prostate (FACT-P), a 12-item questionnaire designed to measure symptoms and problems specific to prostate cancer.8 A recent analysis of SPARTAN found that the addition of apalutamide to ADT had no detrimental effect on HRQoL.9
Investigators assessed HRQoL and pain at baseline and every 16 weeks during treatment using FACT-P and the Brief Pain Inventory, Short Form. They defined pain progression as ≥2 points in pain severity items and mean scores increase from baseline. HRQoL improvement or deterioration was defined as an increase or decrease from baseline using previously established thresholds for clinically meaningful difference. Kaplan-Meier estimates and Cox proportional hazards models were used to assess time to first confirmed (at two consecutive visits) and unconfirmed HRQoL deterioration and/or pain progression.
Baseline characteristics and scores were similar between both study arms with low pain (median 0) and high HRQoL (median FACT-P total score, 121).
A presentation on June 2, 2018 at the 54th Annual Meeting of the ASCO, in Chicago, IL, US, reported the final results of the HRQoL and pain evaluations. Most patients reported no change or improvement in HRQoL. The proportion of patients with pain progression at week 49 was similar in the enzalutamide (11–20%) and placebo (14–21%) groups. Patients receiving enzalutamide were found to have a lower risk of pain progression compared with those receiving placebo (HR: 0.78–0.93; p>0.05). The enzalutamide group also reported lower deterioration risks for FACT-P total, FACT Advanced Prostate Symptom Index, prostate cancer subscale, and emotional well-being (HR 0.75, 0.77, 0.77, 0.69, respectively; p<0.05).10
In summary, compared with placebo, enzalutamide significantly delayed the time to metastasis without worsening HRQoL in patients with nonmetastatic CRPC and significantly reduced the risk of clinically meaningful HRQoL deterioration in several FACT-P domains. Enzalutamide, therefore, represents a potentially important treatment option in this patient population. Physicians may soon have a choice of two therapies in a condition for which, f5 months ago, no treatments were approved.
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9. Saad F, Small E, Hadaschik B, et al. Patient (pt) reported outcomes (PROs) in SPARTAN, a phase 3, double-blind, randomized study of apalutamide (APA) plus androgen deprivation therapy (ADT) vs placebo (PBO) plus ADT in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). European Urology Supplements. 2018;17:e1070-1, abstr 743.
10. Attard G, Saad F, Tombal BF, et al. Health-related quality of life (HRQoL) deterioration and pain progression in men with non-metastatic castration-resistant prostate cancer (M0 CRPC): Results from the PROSPER study. J Clin Oncol. 2018;36:suppl; abstr 5010.