The Phase III clinical trial of PROSTVAC (Bavarian Nordic, Inc., Mountain View CA, (NCT0322490) has completed targeted enrollment of 1200 patients and results may be reported as early as 2016. The 3-arm trial compares PROSTVAC alone or in combination with the immunostimulant granulocyte macrophage colony stimulation factor (GM-CSF) versus placebo controls in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Overall survival is the primary outcome measure.

Based on its encouraging performance in the Phase II trial and the expected success in Phase III, it is very likely to gain expedited FDA approval and become a significant addition to the expanding armamentarium to control this disease.

The Phase II trial (reported in 2010) compared PROSTVAC to a placebo in 125 patients with minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Results: 44% reduction of death and an 8.5 month improvement in median overall survival (mOS) — 25.1 v. 16.6 months for controls. PSA-specific T-cell recognition developed in 57% of patients.

A second single arm Phase II trial in a similar population involving 32 men showed a 9.2 month improvement in mOS compared to a median predicted survival in the Halabi model, a validated prediction tool. (Gulley et al. Cancer Immunol Immunother, 2010).

Although there has been no direct comparison of other agents treating chemotherapy-naive men with mCRPC, the improvement in median OS for Provenge in this setting was 4.1months ; Zytiga, 4.6, and Xtandi, 2.2 months.

What is PROSTVAC?

PROSTVAC is a subcutaneously administered immunotherapy candidate which targets prostate cancer cells exhibiting the prostate specific antigen (PSA). It induces the immune system to generate cytotoxic

T cells that recognize cells bearing the target antigen (PSA). Seven injections are administered: three in the first month, plus four additional monthly shots. The first is termed a “prime,” and is based on an attenuated vaccinia virus vector. The 6 subsequent administrations, the “boosts”, use an attenuated fowlpox virus as the vector.

How Does PROSTVAC work?

These two viral vectors have been genetically modified to incorporate the whole human PSA gene into their DNA, specifically modified to increase their immunogenicity. The viral vector enters subcutaneously located dendritic cells which then take up, express, and process the antigen, migrate to the nearby lymph nodes, and act as antigen-presenting cells. These dendritic cells program an army of circulating cytotoxic lymphocytes to seek out their target.

PROSTVAC, an “off-the-shelf” vaccine, can be administered subcutaneously in the office. This method offers significant advantage compared to Provenge, which requires three blood processing (aphereses) sessions followed by specimen transit to a manufacturing site and then back to the office for 3 intravenous administrations.

PROSTVAC continued:

PROSTVAC incorporates several additional mechanisms to enhance the strength of the immune response. PROSTVAC also engineers the viral vectors to expresses a triad of T-cell costimulatory molecules, termed “TRICOM.” The immune response consists of not only the activated CD4 and CD8 effector T-cells but also generates long-term memory cells alert to the same antigen, thus enabling sustained immunotherapy. Additionally, this immunotherapy candidate was associated with a reduction of T-regulatory cells, cells that diminish the intensity of an immune response.

“Antigen spreading” represents an additional feature of successful killing of cancer cells.  As the dead cells lyse, a variety of non-targeted patient-specific antigens are exposed which themselves promote immune recognition and generate a progressively expanding repertoire of new T-cell targets. In preclinical studies, 68% of patients treated with PROSTVAC exhibited this “antigen spreading”.

Although as clinicians we customarily associate PSA with the serum PSA (as in the “PSA” test), this antigen also is expressed (processed into small peptides) on the cell membranes of the tumor and are the target for recognition by activated T-cells. The activated T-cell’s recognition of these fragments of PSA also extends to within the body of the tumor cell.

Research is in progress to achieve synergy by combining PROSTVAC with other treatment modalities:

PROSTVAC and Ipilimumab (Yervoy):

Results of a Phase I trial combining PROSTVAC with ipilimumab were encouraging in treatment of men with mCRPC as reported in Madan et al. Lancet Oncol. May 2012.

Imilimumab is an immune checkpoint inhibitor that is approved for the treatment of metastatic melanoma. It is a monoclonal antibody that binds to and inhibits activated cytotoxic lymphocytes expressing CTLA-4, an immunomodulatory molecule that, when activated, blunts the immune response. The inhibition of CTLA-4 by ipilimumab intensifies the strength of the response.

The trial results were updated at the 2015 ASCO GU Cancers Symposium (J Clin Oncol 33, 2015, abstr 172): twenty-four of the 30 men were chemotherapy-naive; 58% of these showed a PSA decline, which in 6  was >50%. Follow-up was 80 months. The overall median OS for men at all doses was 31.6 months; 37.2 months for men at the highest ipilimumab doses with 20% of those men alive at 80 months.

PROSTVAC and Enzalutamide (Xtandi):

Preclinical and human studies have offered a biologic rationale for potential synergism between androgren-deprivation therapy (as effected by enzalutamide) and immunotherapy. “Androgen-deprivation therapy [ADT] has been shown to potentiate immune responses and mitigate immune tolerance to prostate-cancer antigens” (Gulley, Future Onco. 2009 Mar).

The thymus gland plays an important role in developing T-cells and the gland involutes with age. ADT has been shown to promote regeneration thymus function (ibid, Gully).

Two NCI protocols explore the potential of this synergism.

  1. “A randomized Phase II Trial Combining Vaccine Therapy with  PROSTVAC/TRICOM and Enzalutamide vs. Enzalutamide Alone in Men With Metastatic Castration Resistant Prostate Cancer” (NCT01867333) [without prior chemotherapy].
  2. “A Phase II Trial of Enzalutamide in Combination With PSA-TRICOM [PROSTVAC] in Patients with Non-Metastatic Castration Sensitive Prostate Cancer” (NCT01875250). This trial is recruiting men who exhibit a rising PSA following either radiation therapy or prostatectomy (prior to androgen deprivation).

Both trials are currently recruiting but are offered only at the NCI.

PROSTVAC Combined with Active Surveillance:

A “Phase II Randomized Placebo-Controlled Trial of PROSTVAC (PSA-TRICOM) In Patients With Clinically Localized Prostate Cancer Undergoing Active Surveillance” (NCT02326805). This trial has not opened for recruitment as yet.

BOTTOM LINE:

If the ongoing trials of PROSTVAC confirm its suggested potential it will become a significant addition to prostate cancer treatment options.

Dr. Neal Shore, Carolina Urologic Research Center, in his excellent review of past and future studies of PROSTVAC, “PROSTVAC targeted immunotherapy candidate for prostate cancer,” Immunotherapy (2014)6(3),  concludes, “Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response”.

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