Recent Advances Revolutionize Treatment of Metastatic Prostate Cancer

Ravi A Madan; Philip M Arlen

Disclosures

Future Oncol. 2013;9(8):1133-1144. 

In This Article

Immunotherapy

Immunotherapy represents an alternative approach to treating prostate cancer (Table 2). Unlike targeted hormonal therapy and cytotoxic chemotherapy that directly kill cancer cells, immunotherapy targets the immune system. The goal of all immunotherapies is to activate immune cells to target and kill cancer cells. Strategies for achieving this goal are as disparate as the characteristics of various immunotherapeutic agents. Since the tumor is not directly targeted by the treatment and immune activation is required, the potential impact of immunotherapy is likely to be delayed relative to cytoreductive therapies.[30] For this reason, prudence dictates that immunotherapy be investigated or employed early in the disease process so that patients have time to benefit from its potential, albeit delayed, benefits. The attendant side effects of immunotherapy are also quite different from those of cytotoxic agents. Immune checkpoint inhibitors have been associated with autoimmune adverse events, while therapeutic cancer vaccines have a negligible toxicity profile that primarily consists of local injection-site reactions or transient fevers.

There are several reasons for immunotherapy's potential efficacy in prostate cancer. First and foremost, prostate cancer's indolent disease course allows patients with metastatic disease to survive many years beyond the detection of radiographic metastasis.[31] This markedly prolonged disease course relative to more aggressive tumors, such as lung or pancreatic cancer, potentially allows for immunotherapy to generate an immune response that could ultimately yield clinical benefit. In addition, multiple tumor-associated antigens (TAAs) rarely expressed elsewhere in the body are overexpressed on prostate cancer cells.[32–34] Studies have shown that the TAAs PSA, PAP and prostate-specific membrane antigen are targeted in a minority of patients with prostate cancer prior to immunotherapy.[35] The fact that these TAAs are focally expressed on malignant cells may enable the potential anti-tumor effects of immunotherapy. Another distinctive characteristic of prostate cancer is that myelosuppressive chemotherapy regimens are not indicated for prostate cancer unless a patient has aggressive disease that is either symptomatic and/or rapidly progressing. Although the true impact of chemotherapy can be immunostimulatory, as has been demonstrated with docetaxel, it is possible that multiple myelosuppressive regimens can impair the immune system's ability to respond to immunotherapy.[36] The absence of such treatment in early-stage prostate cancer may preserve the immune system's potential to be effectively activated by immunotherapy.

Sipuleucel-T

Sipuleucel-T is a therapeutic cancer vaccine approved by the FDA for the treatment of asymptomatic mCRPC. The vaccine is generated from an individual patient's own peripheral immune cells, collected via apheresis.[37,38] Once collected, these immune cells are shipped to a central processing center where they are exposed to a fusion peptide consisting of PAP and granulocyte macrophage-colony stimulating factor (GM-CSF). PAP is the target antigen that immune cells will use to identify cancer cells, beginning a process that will potentially end in immune-mediated cell lysis. GM-CSF serves as an immune adjuvant to enhance immune activation. The patient's immune cells are exposed to this PAP/GM-CSF construct for approximately 48 h during ex vivo processing. The immune cells are then shipped back to an infusion facility where they are administered intravenously to the patient. A full course of sipuleucel-T vaccine consists of three separate apheresis collection/ex vivo processing/reinfusion cycles, performed every 2 weeks.

Early clinical trials of sipuleucel-T demonstrated the safety of this form of therapy, with no increased risk of autoimmunity.[39] The most common adverse reactions were transient fever and flu-like symptoms. Two small Phase III trials then evaluated the ability of sipuleucel-T to treat minimally symptomatic mCRPC.[40,41] The first of these trials failed to meet the primary end point, conventionally established as TTP, resulting in the premature discontinuation of the second small Phase III trial. Ultimately, the initial Phase III trial demonstrated a survival advantage for patients treated with sipuleucel-T relative to the placebo, but since this was a secondary end point, it was not sufficient to lead to FDA approval.[40]

Subsequently, a second, larger Phase III trial with OS as the end point definitively addressed the clinical benefit of sipuleucel-T in mCRPC.[42] The IMPACT trial enrolled 512 patients with minimally symptomatic mCRPC, randomizing them 2:1 in favor of sipuleucel-T relative to the placebo. As with previous studies, there was no significant difference in TTP based on objective parameters (3.7 months in the sipuleucel-T arm vs 3.6 months in the placebo arm; HR: 0.95; p = 0.63). The findings for OS, however, did show a significant advantage for patients treated with sipuleucel-T. Median OS was 25.8 versus 21.7 months in favor of patients treated with sipuleucel-T, with a 3-year survival probability of 31.7 versus 23.0% (HR: 0.77; p = 0.02). Based on these findings, the FDA approved sipuleucel-T for the treatment of minimally symptomatic mCRPC, ushering in a modern age of immunotherapy for the treatment of cancer.[107]

Prostvac

Two other forms of immunotherapy are currently being evaluated in Phase III trials. PSA-TRICOM (Prostvac®; Bavarian Nordic Inc., Kvistgaard, Denmark), an alternative vaccine strategy to sipuleucel-T, is composed of modified poxviruses that activate immune cells in vivo and, therefore, does not require apheresis or off-site cellular processing.[43] This off-the-shelf vaccine is injected subcutaneously, with the goal of delivering targeting information to immune cells, activating them to target and lyze prostate cancer cells. Early clinical trials with Prostvac have demonstrated that it is well tolerated, with fever, flu-like symptoms and injection-site reactions the most common toxicities. Phase II trials have also demonstrated that the vaccine can enhance the ability of T cells to target PSA on prostate cancer cells and improve survival.[44,45] A Phase III study is being conducted internationally in minimally symptomatic, chemotherapy-naive mCRPC patients, and results are anticipated in 2016.[108]

Ipilimumab

Another form of immunotherapy augments immune response by interfering with T-cell regulation. Within 24–48 h after activation, T cells express CTLA-4. This molecule's interaction with antigen-presenting cells has a moderating effect on T cells.[46] The importance of this molecule is demonstrated in CTLA-4-knockout mice, who rapidly succumb to T-cell hyperactivity, which leads to T-cell infiltration and destruction of vital organs.[47] Ipilimumab is a monoclonal antibody that blocks the interaction between antigen-presenting cells and the CTLA-4 molecule on T cells, preventing T-cell regulation, with the goal of having the constitutively activated T cells attack cancer cells.[48] Ipilimumab has demonstrated improved survival in metastatic melanoma.[49] However, unlike vaccines, it is associated with autoimmune side effects, such as rash, colitis and autoimmune endocrinopathies.

Two Phase III trials are evaluating ipilimumab in mCRPC. The first, in chemotherapy-naive patients, will compare ipilimumab versus placebo.[109] The second, in patients with mCRPC who have been treated with chemotherapy, will use isolated external-beam radiation on a minority of bone lesions to potentially enhance the immune response.[110] This strategy is based on preclinical data and the clinical phenomenon of the abscopal effect, all of which suggest that radiation can potentiate and enhance an immune response.[50,51] To fully explore this hypothesis, patients will receive either ipilimumab or placebo postradiation. The primary end point of each of these trials is OS.[109,110]

The Sipuleucel-T Dilemma

Any new form of therapy raises a host of new issues for clinicians and patients. While the limited toxicity profile of sipuleucel-T makes it very attractive to patients and their oncologists, the clinical dilemma created by sipuleucel-T is unique to this class of emerging immunotherapies.[52] How can physicians determine if sipuleucel-T is working in a given patient if it does not lead to short-term improvement in disease progression, as demonstrated in multiple Phase III trials? Furthermore, patients may become concerned since their PSA level is likely to continue to rise after therapy. Although some associations between immunologic response and clinical outcome have been presented, they fall short of the criteria required for use as surrogate biomarkers.[53] Indeed, the complexity of the immune response, which is perhaps its greatest strength, may prevent a simple assay from identifying responders from nonresponders. Variations in patients' immune responses to therapy may further limit the development of a universal biomarker as an indicator of future clinical benefit. These complex questions are new to medical oncologists accustomed to dealing with standard therapies, where long-term benefits can be expected only when short-term benefits are measurable. Furthermore, this dilemma has quelled some of the enthusiasm for sipuleucel-T in common clinical practice and has even given rise to specious suggestions that sipuleucel-T trials were somehow significantly flawed in their design and data analysis, although more practical scientific considerations do not support these allegations.[54–57] It is more probable that a new form of therapy that differs mechanistically, such as sipuleucel-T, needs to be perceived and evaluated differently to conventional cytotoxic agents. Emerging data from multiple clinical trials suggest that modern immunotherapies may affect tumor growth differently to cytotoxic therapies, as evidenced by results of the previously described trials of ipilimumab and PSA-TRICOM where these agents also improved OS without changing short-term progression.[44,49]

One hypothesis that could explain the phenomenon of improved OS without a change in TTP (which may be characteristic of cancer vaccine therapy and not unique to sipuleucel-T) is that, over time, the effects of immunotherapy slow tumor growth without causing a short-term decrease in tumor volume.[58,59] This hypothesis is supported by retrospective analyses of multiple vaccine trials in prostate cancer by which PSA level seems to be rising at a significantly slower rate after treatment with vaccine.[60,61] Although PSA should not be used as the sole indicator for discontinuing therapy, it may signal the manner in which immunotherapy is affecting the tumor. Ultimately, prospective trials will be required to evaluate this hypothesis and clinical outcomes will need to be associated with changes in PSA/tumor growth rates. In the meantime, clinicians should consider sipuleucel-T for patients with minimal symptoms, but should not wait for evidence of clinical response to sipuleucel-T to initiate subsequent therapies.[52]

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