Prostate cancer is the second most common cancer in men, with approximately 1.1 million new cases and 307,000 deaths reported in 2012, making it the number one cause of cancer death in men. During a presentation at NAMCP 2020 Virtual Spring Managed Care Forum, Matthew R. Smith, MD, PhD, director of the genitourinary malignancies program at Massachusetts General Hospital Cancer Center and professor of medicine at Harvard Medical School, discussed treatment options for metastatic and non-metastatic castration-resistant prostate cancer (CRPC).
Six drugs are approved for metastatic CRPC based on improved overall survival (OS) outcomes: docetaxel, cabazitaxel, abiraterone acetate, enzalutamide, sipuleucel-T, and radium-223. Dr. Smith discussed various recent clinical trial data on some of these therapies, but noted that, overall, there is limited information about optimal treatment sequencing for this patient population.
Androgen deprivation therapy is the mainstay of treatment of metastatic disease, said Dr. Smith. However, nearly all men eventually progress to castration-resistant prostate cancer. A 2017 study published in the Journal of Clinical Oncology found that the combination of docetaxel 75 mg/m2 plus cabazitaxel 25 mg/m2 improved survival in patients with chemotherapy-naïve metastatic CRPC. A 2011 study published in The New England Journal of Medicine found that patients with metastatic CRPC previously treated with chemotherapy who received abiraterone acetate plus prednisone had longer overall survival (OS) compared with prednisone alone (14.8 months vs. 10.9 months; P<0.001).The 2014 PREVAIL study published inThe New England Journal of Medicine found that enzalutamide significantly reduced the risk of disease progression and death and delayed the initiation of chemotherapy in men with newly diagnosed metastatic prostate cancer.
A 2019 study published inThe New England Journal of Medicine found that cabazitaxel significantly improved OS and progression-free survival compared with the androgen-signaling targeted therapy with abiraterone or enzalutamide in previously treated patients with metastatic CRPC. Adverse events (AEs) were similar in the cabazitaxel (56.3%) and androgen-signaling targeted inhibitor (52.4%) cohorts.
For non-metastatic CRPC, various studies have shown strong support for U.S. Food and Drug Administration approvals for apalutamide, enzalutamide, and darolutamide. The risk-benefit ratio for these three drugs appears to be favorable, and the treatments were associated with maintenance of health-related quality of life, according to Dr. Smith.
The SPARTAN study, published in 2018 in The New England Journal of Medicine, found that metastasis-free survival (MFS) was 40.5 months in patients treated with apalutamide compared with 16.2 months in those treated with placebo (P<0.001) among patients with non-metastatic CRPC, representing a 72% reduction of distant progression or death and a 24-month MFS benefit with apalutamide. Time to symptomatic progression was significantly longer with apalutamide (P<0.001), and there was a 30% reduction in the risk of death with apalutamide (P=0.07).
The 2018 PROSPER trial, also published in The New England Journal of Medicine, found that median MFS for patients treated with enzalutamide was 36.6 months compared with 14.7 months among those treated with placebo (P<0.001), representing a 71% reduction of distant progression death with enzalutamide versus placebo and a 22-month MFS benefit. In addition, time to first use of a subsequent anti-neoplastic therapy was 39.6 months with enzalutamide and 17.7 months with placebo (P<0.001). There was a 20% reduction in the risk of death with enzalutamide (P=0.15).
The 2019 ARAMIS trial, published in The New England Journal of Medicine, observed a median MFS of 40.4 months with darolutamide and 18.4 months with placebo (P<0.001), representing a 59% reduction of distant progression or death and a 22-month MFS benefit. AE incidence was similar between treatments. There was a 29% reduction in risk of death with darolutamide (P=0.045).
In addition, Dr. Smith discussed results of a 2016 study published in The New England Journal of Medicine that found that among 692 men with metastatic prostate cancer, 84 germline DNA-repair gene mutations were presumed to be deleterious and were identified in 82 men (11.8%), which the researchers said is significantly higher than the incidence among men with localized prostate cancer (4.6%) and the general population without cancer (2.7%). Mutations were found in 16 genes, including BRCA2 (n=37 men; 5.3%), ATM (n=11; 1.6%), CHEK2 (n=10; 1.9%), BRCA1 (n=6; 0.9%), RAD51D (n=3; 0.4%), and PALB2 (n=3; 0.4%).
Finally, Dr. Smith discussed results of the PROfound study, which were presented at the European Society for Medical Oncology 2019 Annual Meeting. The study included previously treated patients with metastatic CRPC who had alterations in one or more of any qualifying genes. Cohort A included 245 men with BRCA1, BRCA2, or ATM genes, and cohort B included 142 men with other alterations. Each cohort was further split to receive the poly-ADP ribose polymerase (PARP) inhibitor olaparib 300 mg or physician’s choice of treatment. Among cohort A, median radiographic PFS (rPFS) was 7.39 months with olaparib and 3.55 months with physician’s choice (P<0.0001). Interim median OS in cohort A was 18.50 months with olaparib and 15.11 months with physician’s choice (P=0.017). Among patients in the physician’s choice arm, 80.6% in cohort A and 84.6% in cohort B crossed over to receive olaparib. The study concluded that there is evidence of clinical activity of olaparib in patients with BRCA1 and BRCA2 genes.
Since DNA repair defects occur in approximately 10% to 20% of patients with metastatic CRPC and BRCA2, BCRA1, and ATM appear to be the most commonly altered genes, PARP inhibitors may be active treatments for prostate cancer, and studies evaluating PARP inhibitor use in these patients are ongoing.
Presentation: Exploring New Treatment Paradigms in Prostate Cancer: Current and Emerging Treatment Strategies. NAMCP 2020 Virtual Spring Managed Care Forum, April 16-17.