Ask the Experts – Andrew J. Armstrong, MD

Question 1. What was the objective in the PROCEED registry study?

Answer
The intent was to describe the safety and efficacy in a broader population of men, especially African-American men, with metastatic castration-resistant prostate cancer (mCRPC) than was included in the pivotal phase 3 IMPACT trial.³ African-American men were not well represented in the IMPACT trial nor in the majority of phase 3 trials of new agents for men with mCRPC. The registry includes more than 1900 patients treated on-label with sipuleucel-T, a population much larger than enrolled in the IMPACT trial. The registry also includes a higher proportion of African-American men (12%) than the three phase 3 trials (5.5%), and was open in states and cities such as Durham, New Orleans, and Detroit that had a large number of African-American patients. Despite the small numbers of African American men in IMPACT, analyses of pooled data from this trial suggested differences in overall survival between African-American men and Caucasian men favoring African-American men. This provided the basis for our analysis of the PROCEED registry based on self-reported race.

Question 2. What do you see as the main findings?

Answer
This is the first study to show that an immunotherapy may have greater efficacy in African-American patients. Overall, patients in PROCEED were treated earlier than patients in the IMPACT trial. The median PSA at initiation of sipuleucel-T was a lot lower in PROCEED than in the IMPACT study, 14 to 33 ng/mL depending on race compared with 54 ng/mL in the IMPACT study). The median overall survival was, in general, much longer compared with the IMPACT study: around 3 years compared with 2 years. In the PROCEED analysis, the median overall survival time was 35.3 months among African-American men compared with 25.8 months for Caucasians. Survival is clearly longer for African-American men than anticipated and as compared to Caucasian-American men, all with mCRPC treated with sipeuleucel-T on label. We did not see any differences in side effects by race, suggesting that the overall benefits to risk ratio may be greater for African American men treated with sipuleucel-T.

Question 3. Your study looked at overall survival in a subset of PSA-matched African American and Caucasian men. What did that analysis show?

Answer
In general, the United States is moving toward the earlier use of sipuleucel-T in the natural history of the disease. That tends to be associated with better survival, with the longest survival in both races observed among men in the lowest PSA quartiles, validating prior work from IMPACT suggesting that lower PSA values at the time of sipuleucel-T therapy were associated with a greater relative and absolute survival benefit.⁴ The median survival in PROCEED was 54 months among African Americans and 37 months among Caucasians in this lowest PSA quartile defined as a PSA less than 8 ng/mL. When we looked at patients in the PROCEED registry by race, the greatest benefit for African Americans seemed to be at lowest PSA levels. If sipuleucel-T is given before the PSA is 30, there’s actually quite a large difference in overall survival, about a year and a half between the 2 groups, suggesting that African-American men may have a real significant benefit when treated with this agent early. There are still differences by race at higher PSA quartiles, but the magnitude of difference is lower (differences of 3-5 months vs 17-18 months).

Question 4. What would explain physicians’ earlier use of sipuleucel-T in PROCEED vs IMPACT?

Answer
They’ve adapted their practice patterns to reflect data suggesting that sipuleucel-T should not be used as a last line of therapy. It really should be one of the first lines of therapy, perhaps even before using one of the newer androgen receptor (AR) inhibitors. I regard sipuleucel-T almost as an adjuvant therapy in this asymptomatic to minimally symptomatic mCRPC setting, given that it only takes 4 weeks and does not have any short term impact on PSA, imaging, or progression, and further therapies are typically needed subsequent to sipuleucel-T. Its use is not to the exclusion of these AR inhibitors, it’s complementary of those therapies as we do not see any significant negative drug or immune interactions with concurrent or sequential use of these agents.

In the PROCEED registry, men were treated with subsequent therapies like abiraterone and enzalutamide and cabazitaxel and docetaxel and radium-223. Sipuleucel-T does not prevent patients from progressing over time and thus needing those therapies. Sipuleucel-T is given over a 4-week period to improve long-term outcomes. The main efficacy of sipuleucel-T is measured in improved overall survival rather than PSA declines or radiographic responses.

Question 5. In your opinion, where does sipuleucel-T belong in therapeutic sequencing?

Answer
The typical patient should be asymptomatic or minimally symptomatic, have a relatively slow disease progression, and not urgently need AR inhibitor or chemotherapy. It is safe to give sipuleucel-T concurrently with AR inhibitor therapies. In PROCEED, most patients were treated sequentially. After a patient has completed sipuleucel-T treatment, their disease will progress and clinicians have to be prepared to use these other agents. To get the greatest magnitude of benefit, this would be when the PSA level is relatively low, and patients are minimally symptomatic. We recently presented interesting data suggesting that the combination of radium-223 with sipuleucel-T may provide greater disease control than sipuleucel-T in these men, and further validation studies of this combination are ongoing. But this data suggests that sipuleucel-T may have some synergy with radiation therapy to bone metastases.

Question 6. What would explain the better overall survival in black men?

Answer
Immune responses may differ between the races. Some evidence suggests that African-American men have different immune responses to infectious diseases and that leukocyte counts differ between Caucasians and African Americans. There are also differences in the genomics of prostate cancer between the races, including differences in specific tumor suppressors, tumor mutation burden, RNA splicing variants, and different prevalence of cancer-related genes. We were not able to distinguish differences in responses by race in CD54 upregulation by sipuleucel-T, but there are a host of other important cellular and humoral immunonologic responses that are worthy of future investigation.