Sipuleucel-T Helps ADT Boost Prostate Cancer Immunity

Emmanuel S. Antonarakis, MBBCh

Sipuleucel-T (Provenge) is effective when given either before or after androgen deprivation therapy (ADT) in men with biochemically recurrent prostate cancer (BRPC) who face a high risk of developing metastases, a study has found.

The study demonstrated that tumorspecific T-cell responses and broad‐based immune responses were augmented with both strategies, but investigators are still uncertain about which sequence is superior, said lead author Emmanuel S. Antonarakis, MBBCh, assistant professor of Oncology at Johns Hopkins Medicine. The preliminary clinical data, reported in the phase II STAND study, were presented this spring during the annual meeting of the American Society of Clinical Oncology (ASCO), in Chicago.

The results were in direct opposition to those presented at last year’s meeting, Antonarakis said. In 2013, after 2 to 4 weeks of follow-up, investigators concluded that sipuleucel-T was most helpful when administered after ADT. Now, after at least 6 months of follow-up, Antonarakis said, evidence seems to be pointing to sipuleucel-T before ADT as the strategy of choice, although he cautioned that one important test of immune response conflicts with that idea.

“Our conclusion is that the jury is out,” Antonarakis said. “We simply don’t know what all this means. We need to have information about metastasis-free survival before we can determine whether these immune responses that we think might mean something actually mean something. In the next 6 to 12 months, we’ll present mature data on PSA [prostate-specific antigen] progression and metastasis-free survival in these patients, none of whom had evidence of metastatic disease when they enrolled.”

He added that “We do studies to figure out and confirm or dispel our preconceived hypotheses, and this is an important lesson about having long-term follow-up and not making conclusions based on a short amount of follow-up.”

The STAND study was the first to look at the combination of sipuleucel-T and ADT in patients with no metastases; the patients all were hormone therapy-naive, Antonarakis said.

Sipuleucel-T is an autologous cellular immunotherapy targeting prostatic acid phosphatase (PAP), approved by the FDA for the treatment of patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. The investigators studied the drug in men with BRPC because these patients have a low disease burden and minimal immune tolerance. The authors noted that ADT has been shown to enhance anti-tumor immunity and augment the effects of cancer immunotherapies.

In the trial, 68 men with testosterone ≥200 ng/mL, a PSA doubling time of ≤12 months, and no metastases were randomized 1:1 to receive sipuleucel-T first, followed by ADT starting 2 weeks after the third dose of the immunotherapy (arm 1), or sipuleucel-T initiated after 3 months of ADT (arm 2). In all, the men received 3 doses of sipuleucel-T and 12 months of the ADT leuprolide (Lupron). The primary endpoint was cellular immune response to target antigen PA2024 measured via the ELISPOT test, the authors wrote. Secondary endpoints included humoral and cytokine responses, product parameters, clinical efficacy, and safety, they said.

The data they reported at ASCO comprised results for 65 men followed for 9 months or more after their final injection of ADT. In arm 1, which started treatment with sipuleucel-T, 10 of 32 men, or 31.3%, achieved undetectable prostate-specific antigen (PSA) (<0.02 ng/mL) and testosterone (<0.35 ng/mL) 9 months after their last ADT injection, the investigators reported in an abstract. In arm 2, the cohort that started treatment with ADT, 14 of 33 men, or 42.4%, achieved those goals in the same time period, the authors reported in the abstract, noting that 4 men in the 65-patient evaluable group developed PSA progression.

“We looked at T-cell responses using ELISPOT, which tells you how many activated CD8-specific T cells you have in response to a vaccinating antigen, in this case PA2024. It turned out that, with a follow-up of 6 months, T-cell responses as measured by ELISPOT in patients who got sipuleucel-T first and then ADT were better,” Antonarakis said. “The second thing we did was to look for antibodies against PA2024 using an ELISA test. At 15 months of follow-up, antibodies against PA2024 were higher in patients who received the sipuleucel-T first, which seems to suggest that sipuleucel-T before hormonal therapy was better, although that is the opposite of what we reported a year ago. The third thing we looked at was cytokines, proteins that immune cells make, and, surprisingly, they were higher in patients who received hormonal therapy first.”

Even without knowing which works best, Antonarakis emphasized that the study demonstrated that either sequence will work to increase the anti-tumor immune response in this population of patients.

“Overall,” he said, “anti-tumor immune response in all three of the tests are increased when you give hormonal therapy plus sipuleucel-T in patients that have biochemically recurrent prostate cancer without metastases.”

Adverse events occurred with similar frequency in each arm, with chills, headache, and fatigue the most frequent in both. Four and 7 patients, in arms 1 and 2 respectively, experienced grade 3 adverse events, and there were no grade 4 or 5 events, the authors reported in their poster.

Reference

Antonarakis ES, Kibel AS, Adams GW, et al. A randomized phase 2 study evaluating optimal sequencing of sipuleucel-T and androgen deprivation therapy in biochemically-recurrent prostate cancer: preliminary clinical data. Presented at: the Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2014; Chicago, Illinois. Abstract 5041.