Novel Biologics for Castration-Resistant Prostate Cancer
Until recently, patients with metastatic prostate cancer progressing on androgen blockade had few therapeutic options.1,2 Anti-androgen withdrawal (AAWD) yields responses in 15%-30% of cases. These responses are associated with a longer duration of prior anti-androgen treatment.3
Retrospective studies have demonstrated the activity of ketoconazole in chemonaïve patients and also following chemotherapy.4-6 Disappointingly, ketoconazole is associated with many toxicities and potentially life-threatening drug interactions due to CYP3A4 inhibition.7
Docetaxel-based chemotherapy has been established as standard first-line chemotherapy for the management of metastatic castration-resistant prostate cancer (CRPC) based on two landmark trials: the TAX327 and SWOG-9916.8-10
On long-term follow-up, docetaxel every three weeks plus prednisone (DP) extended median overall survival (OS) modestly to about 19 months, and 18.6% had three-year survival, representing a 21% improvement in survival compared with mitoxantrone and prednisone (MP).9 This article briefly discusses recent data that have led to the addition of novel therapeutic and supportive modalities to the armamentarium.
Sipuleucel-T for minimally symptomatic or asymptomatic patients
Sipuleucel-T is a cellular product consisting of autologous peripheral blood mononuclear cells obtained by leukapheresis and enriched for a CD54+ dendritic cell fraction pulsed with PA2024, a Prostatic Acid Phosphatase (PAP)-GM-CSF construct. Promising results in early trials prompted the landmark IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial.11,12
The IMPACT trial randomized 512 men with relatively asymptomatic (not on narcotic analgesics) metastatic CRPC and no visceral metastases to sipuleucel-T or placebo intravenous infusions over one hour every two weeks × 3 in a 2:1 ratio. It is noteworthy that the vast majority of patients (80%-85%) were chemonaïve and were required to be off steroids for four weeks, and the patients who were pretreated with chemotherapy were required to be more than three months beyond chemotherapy.
After premedication with acetaminophen and an antihistamine, patients received sipuleucel-T or placebo intravenously over approximately 60 minutes. The median survival was 25.8 months with sipuleucel-T compared with 21.7 months with placebo, and the three-year survival improved significantly (31.7% vs. 23.0%). The treatment effect remained after adjusting for docetaxel use following trial therapy.
However, there was no delay in the time to disease progression. Confirmed PSA declines of 50% or greater were observed in eight of 311 patients (2.6%) in the sipuleucel-T group and two of 153 patients (1.3%) receiving placebo. Toxicities were mostly low grade, with chills reported in 54.1% of sipuleucel-T patients (vs. 12.5% with placebo), fever in 29.3% (vs. 13.7%), headache in 16.1% (vs. 5%) and flu-like symptoms in 9.8% (vs. 4.3%). These data led to the approval of sipuleucel-T by the FDA in the 2010, making it the first “vaccine” to be approved for patients with any malignancy.
Second-line cabazitaxel chemotherapy following docetaxel
Cabazitaxel, a novel semi-synthetic taxane, stabilizes microtubules as potently as docetaxel and is active in both docetaxel sensitive and resistant cell lines and appears resistant to the P-gp efflux pump. In addition, it can penetrate the blood-brain barrier.13,14 Following preliminary evidence of activity in a phase 1 trial, cabazitaxel plus prednisone was compared to MP in patients with progressive metastatic CRPC following prior docetaxel in the TROPIC trial.15
This trial included 755 patients with metastatic CRPC with clinical or PSA progression following docetaxel.16 Patients were randomized 1:1 to a maximum of 10 cycles of cabazitaxel 25 mg/m2 every three weeks (378 patients) or mitoxantrone 12 mg/m2 every three weeks (377 patients); both groups received prednisone 10 mg daily. Premedications in the cabazitaxel group were an antihistamine, corticosteroid, and H2 antagonist (owing to the polysorbate-80 solvent) administered intravenously 30 minutes before cabazitaxel, which was given as a one-hour IV infusion.
The majority of patients were heavily pretreated with docetaxel, having received a median of seven cycles. Importantly, the median time from prior docetaxel treatment and progression was 0.7 to 0.8 months, perhaps indicating a generally docetaxel-resistant population. Median survival was significantly higher in the cabazitaxel group than in the mitoxantrone group (15.1 vs. 12.7 months), which translated into a 30% improvement in survival. Notably, the extension of survival was observed regardless of performance status (PS), number of prior chemotherapy regimens, time to progression from prior docetaxel treatment, and age.
Researchers also noted a benefit in the third of patients who were docetaxel-refractory and had progressed during docetaxel therapy. Secondary endpoints also demonstrated significant improvements with cabazitaxel compared with mitoxantrone with respect to progression-free survival (2.8 vs. 1.4 months), measurable tumor response rate (14.4% vs. 4.4%), PSA response rates (39.2% vs. 17.8%). Pain response, however, was similar (9.2% vs. 7.7%).
Grade 3 or higher toxicities were greater in the cabazitaxel group than in the mitoxantrone group and were as follows: febrile neutropenia (8% vs. 1%), diarrhea (6% vs. <1%), fatigue (5% vs. 3%), asthenia (5% vs. 2%), back pain (4% vs. 3%), nausea (2% vs. less than 1%), vomiting (2% vs. 0%), hematuria (2% vs. 1%), and abdominal pain (2% vs. 0%).
Deaths due to adverse events occurred in 5% in the cabazitaxel arm compared with 2% in the mitoxantrone arm. Given the substantial myelosuppression, frequent blood counts and prophylactic granulocyte growth factor support are advocated in accordance with American Society of Clinical Oncology guidelines. A randomized trial is planned to compare frontline docetaxel chemotherapy with cabazitaxel 25 mg/m2 or 20 mg/m2.