Androgen Deprivation plus Ipilimumab Immunotherapy in Hormone-Naïve Patients with Metastatic Prostate Cancer

Conference Correspondent - ESMO 2014 - Immuno-Oncology


Androgen-deprivation therapy (ADT) is an integral component of the management of patients with hormone-naïve metastatic prostate cancer (HN-mPCa). There is some evidence implicating ADT in immune regulation by increasing the thymic output of T-cells, antigen-specific T-cell responses, and infiltration of T-cells into the prostate, and antigen-specific T-cell responses. Ipilimumab is an approved immunotherapy that blocks the function of the immune checkpoint modulator cytotoxic T-lymphocyte antigen-4 (CTLA-4) to restore T-cell antitumor immune responses. It was, therefore, hypothesized that the combination of ipilimumab plus ADT might have synergistic interactions in men with HN-mPCa, and would thus achieve undetectable prostate-specific antigen (PSA) levels (?0.2 ng/mL); this PSA level is a strong predictor of survival. To test this hypothesis, Subhudu and colleagues conducted a single-arm observational study to evaluate the safety and antitumor efficacy of ADT, administered for 8 months, plus ipilimumab 10 mg/kg for up to 4 doses at 4-week intervals in 50 men with HN-mPCa (Subhudu et al. ESMO 2014: Abstract 1053PD). The primary end point was to estimate the rate of undetectable PSA at 7 months posttreatment initiation.

Subhudu and colleagues reported that 10 of the 25 (40%) evaluable patients achieved a PSA level of ?0.2 ng/mL 7 months after ADT initiation, and 1 patient had a sustained response 1 year after ADT completion. A total of 17 patients recovered their testosterone levels (?50 ng/dL). The median time to PSA progression was 330 days from the PSA nadir. Two of 25 (8%) patients achieved complete radiographic response, with PSA responses ongoing for 944 and 364 days, respectively. Immunologic changes, including increased rate of CD4+ T-cells, CD4+ central memory, and ICOS+CD+ T-cell changes, were also reported with this combination.

However, after a predetermined criterion based on the incidence of unacceptable toxicities, the trial was closed when 12 of the 27 (44%) evaluable patients developed grade 3 or 4 toxicity. These immune-related adverse events included hepatic (15%), gastrointestinal (11%), endocrine (11%), and dermatologic (4%) toxicities, which were reversible using standard ipilimumab management algorithms.

The results of this pilot study suggest that the combination of finite ADT plus ipilimumab has promising antitumor activity in patients with HN-mPCa. Subhudu and colleagues suggested that conducting future trials with a lower dose of ipilimumab would be considered, because of the concern of immune-related adverse events incidence in this trial.