Recurrent Prostate Cancer
Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level include the following:[Level of evidence: 3iiiDiii];
One study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.
Sipuleucel-T, an active cellular immunotherapy has been shown to increase OS in patients with hormone-refractory metastatic prostate cancer. Sipuleucel-T consists of autologous peripheral blood mononuclear cells that have been exposed ex vivo to a recombinant fusion protein (PA2024) composed of prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor (gmCSF).
- In the largest trial (the Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACT [NCT00065442] trial), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (341 patients) versus placebo (171 patients) intravenously by 60-minute infusion every 2 weeks for a total of 3 times. Patients with visceral metastases, pathologic bone fractures, or Eastern Cooperative Oncology Group (ECOG) performance status worse than 0-1 were excluded from the study. At documented disease progression, patients in the placebo group could receive, at the physician's discretion, infusions manufactured with the same specifications as sipuleucel-T but using cells that had been cryopreserved at the time that the placebo was prepared (63.7% of the placebo patients received these transfusions). Time to disease progression and time to development of disease-related pain were the initial primary endpoints, but the primary endpoint was changed prior to study unblinding based upon survival differences in two prior trials of similar design (described below).
After a median follow-up of 34.1 months, the overall mortality was 61.6% in the sipuleucel-T group versus 70.8% in the placebo group (HRdeath = 0.78; 95% CI, 0.61-0.98; P = .03).[Level of evidence: 1iA] However, the improved survival was not accompanied by measurable antitumor effects. There was no difference between the study groups in rate of disease progression. In 2011, the estimated price of sipuleucel-T is $93,000 for a 1-month course of therapy. This translates into an estimated cost of about $276,000 per year of life saved.
- The same investigators performed two prior smaller trials (D9901 and D9902A [NCT00005947]) of nearly identical design to the IMPACT trial.[29,30] The combined results of the two smaller trials, conducted on a total of 225 patients randomized in a 2:1 ratio of sipuleucel-T to placebo were similar to those in the IMPACT trial. The HRdeath was 0.67 (95% CI, 0.49-0.91), but the time-to-progression rates were not statistically significantly different.
As noted above, studies have shown that chemotherapy with docetaxel or cabazitaxel and immunotherapy with sipuleucel-T can prolong OS in patients with hormone-resistant metastatic prostate cancer. Nevertheless, a hormonal therapy has also been shown to improve survival even in men who have progressed after other forms of hormonal therapy as well as chemotherapy. Abiraterone inhibits androgen biosynthesis by blocking cytochrome P450 c17 (CYP17). Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (n = 1195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1000 mg) (n = 797) or placebo (n = 398) orally once a day (COU-AA-301 [NCT00638690]). Both groups received prednisone (5 mg) orally twice a day. After a median follow-up of 12.8 months, the trial was stopped when an interim analysis showed an OS advantage in the abiraterone group. Median OS was 14.8 months in the abiraterone group versus 10.9 months in the placebo group (HRdeath = 0.65; 95% CI, 0.54-0.77; P < .001).[Level of evidence: 1iA] Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, and hypertension.