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Sipuleucel-T received an FDA approval in 2010 and a subsequent CMS coverage decision in 2011. At Lancaster Urology in Pennsylvania, we began infusing sipuleucel-T in 2011, and at the 7-year mark, we conducted a review to evaluate these first years of therapy.
Paul R. Sieber, MD, FACS
Sipuleucel-T (Provenge) received an FDA approval in 2010 and a subsequent CMS coverage decision in 2011. At Lancaster Urology in Pennsylvania, we began infusing sipuleucel-T in 2011, and at the 7-year mark, we conducted a review to evaluate these first years of therapy. We had complete information on 94 patients.
Sipuleucel-T is for first-line therapy for men with metastatic castration-resistant prostate cancer (mCRPC) who are asymptomatic or have minimal symptoms, and it is now incorporated into treatment guidelines issued by the American Urological Association, European Association of Urology, and National Comprehensive Cancer Network.1-3 The original trials4 excluded men with visceral metastasis, although the guidelines now recommend sipuleucel-T for this population. Many papers have been written since the agent’s 2010 approval, but the patient cohorts have tended to be small. In addition, papers have tried to address the plethora of new treatments and how they might be best sequenced, layered, and used cost-effectively.5-8 This review was undertaken to see how our practice has addressed all this information in the management of men with mCRPC. In addition, we hoped to gain insights into our survival outcomes.
We reviewed all patients treated with sipuleucel-T over a 7-year period at a busy community urology practice. The patients were categorized by year of sipuleucel-T treatment, prostate-specific antigen (PSA) at time of therapy, subsequent therapies, and overall survival. As Table 1 illustrates, most of these men were alive at the time of this review. The median age was 74. Roughly 70% of men with a PSA <22.1 were alive at the time of this review.
The majority received sipuleucel-T in the past 4 years, partly because of an improved understanding of the optimal patient for this therapy (Table 2). Although survival appears shorter in recent years, the majority of men treated since 2016 were alive at the time of this review (Table 2).
PSA at treatment was also reviewed (Table 3). The patients were placed into PSA quartiles, as previously described from the original trials.9 Again, the majority of men in the favorable lowest quartile remained alive at the time of this review.
Finally, we addressed the addition of other therapies and their impact on overall survival. Most men went on to receive additional therapies. At the time of this review, several patients were still on their first or second therapy following sipuleucel-T.
The incorporation of sipuleucel-T in the management of mCRCP has gradually changed in our practice since the agent received FDA approval, and its use continues to rise. Because we are seeing stage migration in prostate cancer, as are others,10,11 we feel the incidence of metastatic prostate cancer will continue to increase. The first article to better address the timing of sipuleucel- T came from Schellhammer et al.10 The authors looked at the original pivotal trials with sipuleucel-T and found that the PSA level at treatment was exceedingly important. They sorted patients into quartiles based on PSA at the time of sipuleucel-T administration. The hazard ratio for those patients with a PSA <22.1 (the lowest quartile) was a striking 0.51 compared with a PSA >134 (highest quartile) hazard ratio of 0.84. This translated into a median survival improvement of 13 months for the lowest quartile. In addition, performance status, increased tumor burden, and PSA doubling time appear to predict for more rapid deterioration after sipluleucel-T.12,13 Thus, we have moved to earlier administration of sipuleucel-T in regard to PSA at time of administration, more prolonged PSA doubling times, and better performance status. These 3 factors are helpful in identifying the ideal patient for immunotherapy with sipuleucel-T. It is encouraging that we are seeing longer survivals post administration of sipuleucel- T, as this lends credence to these measures for patient selection.
The majority of patients receiving sipuleucel-T have also gone on to 1 or more therapies. Both timing and layering have continued to evolve,5,8 but this has not been without setbacks. The first trials combining radium-223 (Xofigo) and abiraterone (Zytiga) versus radium-223 alone were halted and led to a warning from the manufacturer against combination therapy after an increase in bone fractures and deaths was noted in the combination arm of the study.14 Multiple studies have been completed and are ongoing looking at combination therapy with sipuleucel-T. Small et al looked at the combination with abiraterone and found no evidence of vaccine production interference as measured by cumulative antigen presenting cells number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) suggested no interference from concurrent use of abiraterone acetate plus prednisone.15 Scholz et al have looked at adding additional immunotherapy with ipilimumab with some success.16 Finally, Antonarakis et al have looked at administration of sipuleucel-T prior to androgen deprivation therapy in men. with biochemically recurrent prostate cancer who are at high risk for metastasis.17
Present guidelines suggest the sequential use of agents post sipuleucel-T. Our experience with sequential therapy has been very positive, with most patients having received multiple therapies. Many of our patients have received sipuleucel-T in the past 3 years and are only on their first or second subsequent therapies, and we assume most will receive second and third, even fourth, lines of therapy. We have already noted that patients who receive multiple lines of therapy seem to have the longest survival. We hope to see ongoing extensions in survival as we move to the ideal patient for sipuleucel-T and better understand how to sequence the multiple options now available. Most likely, this will continue to rapidly evolve with the multitude of new agents being tested in castration-resistant cancer.8
The management of mCRPC continues to evolve. As we continue to add new agents, new ideas about the sequencing and of layering of therapies will undoubtedly develop. We have seen our early findings with sipuleucel-T appear consistent with what other authors have reported. We are seeing median survivals for patients with mCRPC extending well beyond the results of multiple single-agent clinical trials
We continue to follow the current guidelines, placing sipuleucel-T first in the treatment algorithm in asymptomatic patients with mCRPC. We believe we have been successful in identifying the optimal patient for immunotherapy. The use of additional layers of therapy is now routine and most likely will continue to evolve, hopefully, with the addition of new novel agents.