As time has gone on, we’ve learned much more about optimizing patient outcomes with sipuleucel-T. For instance, a post-hoc, retrospective analysis of baseline PSA levels, demonstrated the best outcomes and the greatest benefit between the therapeutic and control arms in those in the lowest baseline PSA quartile (PSA <22 ng/ml).2 This makes reasonable intuitive sense, given the fact that lower PSA at baseline probably corresponds with lower volume disease that might provide more time for an active cellular immunotherapy to educate the patient immune system and provide long term patient benefit. Additionally, although none of these immune markers are approved for standard use in the clinic, correlative science studies have shown markers like CD54 antigen presenting cell upregulation,3 antigen spread,4 antigen-specific CD8 lysis5 and antibodies to prostatic acid phosphatase (PAP)1 and the fusion protein used to make sipuleucel-T, PA2024,1 have correlation with overall survival.
Since the IMPACT trial, we’ve also had multiple prospective clinical trials in different clinical settings with sipuleucel-T. The PROTECT trial treated biochemically-recurrent prostate cancer patients with 3-4 months of androgen deprivation then randomized the patients in a 2:1 fashion to sipuleucel-T vs. control.6 The trial showed that sipuleucel-T prolonged PSA doubling time 48% after testosterone recovery compared to control. The STAND trial randomized biochemically-recurrent patients between sequencing sipuleucel-T first then androgen deprivation vs. the opposite order.7 No definitive conclusions could be drawn, but it appeared that the sequence with sipuleucel-T first followed by androgen deprivation led to superior antitumor immune responses. A neoadjuvant trial with sipuleucel-T demonstrated increase in T cell recruitment to the tumor-benign interface.8 The STAMP trial, saw no decrement in antigen presenting cell activation when sipuleucel-T was combined up front with abiraterone acetate and prednisone compared with sipuleucel-T first followed by abiraterone 10 weeks later.9 Similarly, in the STRIDE trial, enzalutamide 2 weeks prior to sipuleucel-T revealed similar immune biomarker response and clinical outcomes compared to sipuleucel-T followed by enzalutamide 10 weeks later.10
There are multiple ongoing clinical trials evaluating additional biomarkers with sipuleucel-T. For instance, at Duke University, sipuleucel T is being evaluated as a single agent and with either abiraterone acetate or enzalutamide to determine change in circulating tumor cell immune checkpoint composition of PD-L1, PD-L2, B7-H3 and CTLA-4 (NCT02456571). At our center, at the University of Washington, we are performing metastatic biopsies to quantify increase in T cell infiltration into tumor metastases after sipuleucel-T therapy to begin to form correlation with outcomes. Washington University in St. Louis will also soon be joining in our trial.
In regards to combination therapies, sipuleucel-T is being evaluated with multiple regulatory approved and experimental agents in metastatic castration-resistant prostate cancer. A small pilot trial (n=9) of low dose ipilumumab (1 mg/kg X 1-3 dose q3wks) was administered after sipuleucel-T with enhanced antibody responses and rather long survival.11 A trial with ongoing accrual at MD Anderson Cancer Center and University of California San Francisco, randomizes the combination of sipuleucel-T with immediate vs. delayed CTLA-4 blockade with ipilumumab (NCT01804465). The primary endpoint is the evaluation of antibody responses to PAP and PA2024. Another actively accruing trial looks to take advantage of the priming effect of sipuleucel-T with PD-L1 blockade with atezolizumab (NCT03024216). As this is a phase 1 trial administered at the University of Hawaii, tolerability is the primary endpoint. Other trials with sipuleucel-T look to augment the immune response with a potential abscopal effect, using stereotactic ablative body radiation (SABR) (NCT01818986) or radium-223 (NCT02463799). Interestingly, the primary endpoint of the SABR trial is to evaluate time to progression compared to historical controls. Time to progression is an endpoint worth evaluating with sipuleucel-T, given the previous history demonstrating lack of effect on this endpoint.
The upcoming randomized, phase 3 PROVENT trial with sipuleucel-T, will evaluate the ability of sipuleucel-T to decrease the upgrading of low-grade prostate cancer in men who would normally undergo active surveillance (NCT03686683). This trial will randomize 450 men in a 2:1 fashion of sipuleucel-T vs. active surveillance. Patients with Grade Group 1 or 2 cancer will be enrolled, and the primary endpoint will be the reduction of histopathologic reclassification to a higher Grade Group than baseline over a 3 year period.
Although sipuleucel-T has been regulatory approved now for 8 years for the overall survival benefit it provides men with asymptomatic or minimally-symptomatic metastatic castration-resistant prostate cancer, there is still much to learn. With the above described trials, we hope to learn not only who is apt to have an optimal response to sipuleucel-T, but we hope to further augment response to the agent with rationally-designed combination regimens. Additionally, the goal of expanding the therapeutic window for sipuleucel-T will be tested by moving the agent very early in the treatment paradigm.
Sipuleucel-T trials actively accruing:
- Defining the Relevant Immune Checkpoints Expressed on Metastatic Prostate Cancer Circulating Tumor Cells
- A Randomized Phase 2 Trial of Immediate vs. Delayed Anti-CTLA4 Blockade Following Sipuleucel-T Treatment for Prostate Cancer Immunotherapy
- Phase Ib Study Assessing Different Sequencing Regimens of Atezolizumab (Anti-PD-L1) and Sipuleucel-T in Patients Who Have Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer
- Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation (SABR) for Patients With Metastatic Castrate-resistant Prostate Cancer (mCRPC)
- A Phase 2 Study of Sipuleucel-T With or Without Radium-223 in Men With Asymptomatic or Minimally Symptomatic Bone-Metastatic Castrate-Resistant Prostate Cancer
- A Randomized Phase 3, Open-Label Trial of Sipuleucel-T Administered To Patients On Active Surveillance For Newly Diagnosed Prostate Cancer
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- Schellhammer PF et al. Urology 2013; 81:1297-302.
- Sheikh NA et al. Cancer Immunol Immunother 2013; 62:137-47.
- GuhaThakurta D et al. Clin Cancer Res 2015; 21:3619-30.
- Antonarakis ES et al. Clin Cancer Res 2018; 24:4662-71.
- Beer TM et al. Clin Cancer Res 2011; 17:4558-67.
- Antonarakis ES et al. Clin Cancer Res 2017; 23:2451-9.
- Fong L et al. J Natl Cancer Inst 2014; 106(11):dju372 doi:10.1093/jnci/dju372
- Small EJ et al. Clin Cancer Res 2015; 21:3862-9.
- Petrylak DP et al. J Clin Oncol 36, no. 6_suppl (February 20, 2018) 246-246.
- Scholz M et al. Immunotargets Ther 2017; 6:11-6.