Age-standardized incidence rates for prostate cancer in the European Union (EU) are 106.2 per 100 000, with an age-standardized mortality rate in the EU of 23.2 per 100 000, making it the highest incidence and third highest cancer mortality rate for males, behind lung and colorectal cancer . Surgery and radiation therapy are effective for localized prostate cancer, but 20–30% of patients will have a recurrence. While androgen-deprivation therapy (ADT) achieves stabilization of disease in most patients, over time, most patients will develop hormone-refractory cancer, also known as castration-resistant prostate cancer (CRPC). Until the development of the therapeutic immunotherapy, sipuleucel-T (PROVENGE®; Dendreon Corp. Seattle, WA, USA), only chemotherapeutic agents docetaxel and recently, cabazitaxel, have been shown to prolong survival for patients with metastatic CRPC (mCRPC), conferring a 2–3 month median survival benefit [2,3].
There are two broad categories of active cancer immunotherapies: preventative and therapeutic. Preventive immunotherapies are similar to the traditional vaccines against infectious agents, and serve to protect against an antigen in healthy populations. Gardasil, a vaccine against human papillomavirus, is one example of a preventative cancer vaccine. In contrast, a therapeutic cancer vaccine or therapeutic active cancer immunotherapy is intended to treat cancers that already exist by increasing the anticancer immune response of the patient through immunization. Targeting an immune response against cancer requires identification of an antigen on tumour cells that can be eliminated with few harmful host side-effects, as well as an effective means of priming the host immune system to respond to that antigen. In many types of cancer, immune suppression is part of the disease state involved in cancer, so priming the immune system requires overcoming the suppression induced by the cancer.
In the case of sipuleucel-T, a therapeutic vaccine, autologous peripheral mononuclear blood cells (PMBCs), including antigen-presenting cells, are activated by exposure to a recombinant antigen called PA2024. PA2024 has parts of prostatic acid phosphatase, an antigen highly expressed in prostate tissue but minimally in other tissues, and granulocyte-macrophage colony-stimulating factor, a component that activates the immune cells. Therapy with sipuleucel-T is individualized, involving three separate leukapheresis procedures at baseline, and 2 and 4 weeks later. PMBCs containing antigen-presenting cells are cultured for 36–44 h with the PA2024 antigen ex vivo (outside the body). After this incubation period, the cell product is washed and packaged for delivery to the treatment site, and infusion of the primed cells into the same patient. This procedure is repeated three times, over the course of ≈1 month, as shown in Fig. 1.
Two randomized, double-blind trials comparing sipuleucel-T with control in men with mCRPC showed evidence of survival prolongation [4,5]. These early trials were unable to show a significant effect on time to disease progression. To examine the survival benefit in a larger population, a phase III trial in 512 men with mCRPC prostate cancer was carried out . Patients in the sipuleucel-T-treatment arm had a 22.5% reduction in risk of death (hazard ratio 0.775; 95% CI 0.614, 0.979; P= 0.032) and a 4.1-month improvement in median survival (25.8 months for sipuleucel-T compared with 21.7 months for control). The 36-month survival probability was 32.1% for sipuleucel-T vs 23% for control.
Integrated safety results from the four randomized, double-blind sipuleucel-T studies, including three studies in CRPC and one in androgen-dependent prostate cancer showed that the most common side-effects associated with sipuleucel-T were chills, pyrexia, headache and myalgia. These side-effects were slightly more common after the second and third infusions than the first infusion. Most of the infusion reactions occurred in £1 day after infusion, were mild or moderate in severity, and resolved in £2 days. These reactions can generally be managed in the outpatient setting . In contrast to the side-effects seen with sipuleucel-T, chemotherapeutic agents such as docetaxel or cabazitaxel can frequently cause neutropenia, fatigue, and diarrhoea, while less commonly resulting in anaemia, thrombocytopenia, infections, hypersensitivity and fluid retention, as well as being administered over much longer periods that increase the cumulative risks of adverse events. In addition, these agents are indicated combined with prednisone that can result in additional immunosuppression, glucose intolerance, and adrenal suppression.
The implications of availability of sipuleucel-T for current practice are significant. First and foremost, it will require more aggressive screening of men for the development of metastatic disease. The patients studied in Phase 3 trials of sipuleucel-T had asymptomatic or minimally symptomatic mCRPC, with most being chemotherapy naive. In our current disease-state models, we do not differentiate between asymptomatic and symptomatic CRPC; however, this will become increasingly important as we determine the optimal sequence of therapies for patients. In the past many patients in the asymptomatic disease state may have been managed conservatively with only continued ADT and watchful waiting, or more modestly active secondary hormonal manipulations. Active screening of men with asymptomatic non-mCRPC for the development of metastases will be increasingly important to identify patients early for treatment with sipuleucel-T as well as for prevention of skeletal-related events. Furthermore, it appears from the Kaplan–Meier curves that the absolute benefit associated with sipuleucel-T therapy increases with longer survival, so administering such a strategy early in CRPC makes sense to maximize the cost effectiveness of this treatment. If therapeutic vaccines such as sipuleucel-T function in concert with subsequent treatments to improve overall survival, then it would follow that identifying these patients early would allow for more sequential therapies and thus more opportunity for synergy.
In summary, sipuleucel-T is an active immunotherapy associated with a low incidence of transient adverse events but with a significant impact on overall survival in this patient population. Early and aggressive re-staging of CRPC will allow us to identify patients in a new disease state, minimal burden, asymptomatic mCRPC, and offer them the greatest absolute benefit to this, well tolerated, treatment approach that is administered over ≈1 month.