Provenge (Dendreon, Inc, ‘Sipuleucel-T’) is an autologous (i.e., based on a patient’s own cells) vaccine targeted to the highly expressed prostatic acid phosphatase (PAP) antigen on malignant prostate cells. It was FDA approved based on the IMPACT trial reporting a median 4.1 month improvement in overall survival compared to a placebo in a study of 455 men who had asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). The men in this study had advanced metastatic disease: 42% had both bone and soft tissue cancer with 48% having more than 10 bone lesions; 20% had had chemotherapy; 74% had Gleason Score 7 (3+4 or 4+3) or greater. Based on the trial results the National Comprehensive Cancer Network lists Provenge as a category 1 treatment recommendation as first-line therapy for men with mCRPC with asymptomatic or minimally symptomatic disease.
Despite this 4.1 month median survival benefit, Provenge has been utilized in relatively few men with mCRPC, perhaps due to the delay in PSA and objective response, as compared to, say, chemotherapy. (Wei et al., Prostate Cancer and Prostatic Disease, 2020). Wei explains that these features were to be expected due to the time requirement needed to develop an immune-mediated anti-tumor response.
Provenge is prepared by first collecting a patient’s blood, separating his immune cells (via ‘leukopheresis’) thereby collecting the antigen presenting cells (APC), the cells that train the T-cells, B-cells and natural killer cells what to target. This population of mononuclear cells are then cultured in the lab with the target antigen, PAP linked to granulocyte-macrophage colony stimulating factor resulting in APC activation. PAP is extensively expressed on prostate cancer cells (similar to PSMA) The culturing promotes the activation of antigen presenting cells. These cells stimulate expansion and activation of the T cells, B cells and natural killer cell population — to a minimum of 40 million cells. The preparation is then infused into the patient. This procedure is repeated three times at two-week intervals.
What has been learned since FDA approval?
- The response to Provenge is PSA dependent. The median PSA in the men in the IMPACT trial was 51.7 ng/mL and medium overall survival (mOS) was 25.8 months compared to 21.7 months for the placebo arm. However, men with PSA values <22 ng/mL demonstrated a 13.1 months improvement in overall survival compared to men with PSA values >22 ng/mL.
This PSA dependence was again reported in the PROCEED Registry of 1900 men with mCRPC. The mOS in men with PSAs of < 5.27 was 48 months; for men with values between 5.27 – 15.8 the mOS was 33 months.
The importance of initiating Provenge at low PSA values was additionally apparent in that the mOS for PSA ranges15-46 and >46 ng/mL were 27 and 18 months, respectively. The overall survival at 3 years for men with a pre-treatment PSA of <22ng/mL was 65%. [mOS rates include the effect of further treatment after Provenge.]
Early detection of metastatic disease, facilitated by the Pylarify or Axumin PET/CT scans can detect low-burden metastatic disease and support Provenge intervention at an optimal opportunity.
2) Provenge directs activated T cells to tumor tissue. In a study in which Provenge was administered prior to prostatectomy, the surgical specimen showed a greater influx of tumor infiltrating activated T cells compared to control.
3) Provenge effects ‘antigen spread.’ Mandan et al. JNCI, June 2020 (an excellent review) found that in addition to sensitizing T cells to PAP, the activated T cell targeted other malignant antigens (‘neoantigens’) that had been exposed when the PAP targeted cells were destroyed. Provenge elicits long-term immune memory in the T cells such that a second course of treatment effects a recall response.
4) African American men have a stronger response to Provenge compared to Caucasians. Sartor et al., (Prostate Cancer and Prostatic Diseases, Feb. 2020) evaluated the outcome of Provenge treatment in a matched cohort comparison based on the large PROCEED Registry in which 12% of the men were African American. They reported a mOS of 35.3 months for African American men versus 25.8 for Caucasians at a median follow-up of 46.6 months. The explanation for the difference in survival is unknown, but Sartor raises the “hypothesis of racial differences in the immune system and immune response.”
5) The Mandan article concluded by conjecturing that in the future Provenge may be used in combination therapy. The article cites protocols investigating combinations: with active surveillance, Rad-223 (Xofigo), Stereotactic Body Radiotherapy, checkpoint inhibitors and enzalutamide.
6) Provenge, when used alone early in the course of mCRPC delays the initiation of subsequent therapy. This was reported by Wie et al., ”Outcome in men with metastatic castration-resistant prostate cancer who received sipuleucel-T and no immediate subsequent therapy at Dana Farber and in the PROCEED Registry. (Prostate Cancer and Prostatic Diseases. 2002). Provenge was used as first-line treatment for mCRPC in over 90% of the men in the study. Bone metastases were present in 74% and lymph node disease in 35% of men. A 50% decline in PSA was recorded at 5.5 months in 20% The median time to initiation of subsequent treatment was 9 months; a median of 20% had no additional treatment for 15 months.
Provenge, when administered early in the course of metastatic castration-resistant prostate cancer at a time when the PSA and tumor burden are low, delays subsequent treatment and significantly improves overall survival.