In June 2009 we reported on data suggesting that the monocolonal antibody ipilimumab appeared to be capable of “downstaging” more advanced forms of prostate cancer such that the patients became re-eligible for localized therapy with curative intent. It’s time for an update based on data presented at the Genitourinary Cancers Symposium last Friday and Saturday.
There were two posters presented on ipilimumab in prostate cancer at this meeting.
In the first of these posters, Tollefson et al. reported data from the randomized Phase II clinical trial of ipilimumab + androgen deprivation therapy (ADT) vs. ADT alone. ADT was given as leuprolide acetate + bicalutimide. “Advanced disease” encompassed patienst who had a rising PSA after first line treatment right through to patients with metastatic disease (but exclusing metastases to the central nervous system). Patients who received ADT only were eligible to “cross-over” and receive ipilimumab + ADT after any appropriately documented initial progression.
A total of 108 patients with non-localized prostate cancer were enrolled in this trial between June 2005 and April 2009:
- 54 patients were treated with ipilimumab 3 mg/kg + ADT.
- 54 patients were treated with ADT alone.
The results of this study showed the following:
- Median age at study entry was 65 years.
- 35/108 patients (32 percent) had a PSA > 50 ng/ml at study entry.
- 72/108 patients had a Gleason score of 8 to 10.
- No significant baseline differences were apparent between the two patient groups
- The decline in testosterone level was 97 percent or higher in both groups after treatment.
- 55 percent of patients treated with ipilimumab + ADT had an undetectable PSA at 3 months.
- 38 percent of patients treated with ADT only had an undetectable PSA at 3 months.
- Common and severe (Grade 3/4) adverse effects in patients receiving ipilimumab + ADT included colitis (4.5 percent) and diarrhea (4.5 percent).
- 15 patients treated with ipilimumab + ADT experienced cutaneous (skin-related) side effects.
The authors of this poster concluded that ipilimumab acts synergistically with ADT to produce a series of clinical effects and that further study is warranted. In fact, one Phase III clinical trial of ipilimumab in castration-resistant prostate cancer has already started, and a second is in development.
In the second poster, Granberg et al. addressed specifically the occurrence of downstaging of patients to apparent, organ-confined, minimal residual disease.
At the time that the abstract of this poster was written, 73 patients with intact prostates had been enrolled in the Phase II trial described above.
- After treatment,12 patients opted for an off-study radical prostatectomy.
- All 12 patients had received ipilimumab 3 mg/kg + ADT.
- All 12 patients had originally presented with advanced, unresectable disease (clinical stage T2c-T4 and/or N+).
- 6/12 patients were downstaged to pathologic stage T2 after their radical prostatectomy.
It has previously been demonstrated that neoadjuvant hormone therapy is not particularly useful in the attempt to downstage patients with locally or regionally advanced prostate cancer. However, it appears that, in contrast, the combination of neoadjuvant ipilimumab + ADT can induce such a response in a subset of patients. We are therefore faced with two new questions that need to be addressed:
- How durable are the responses to curative surgery in men who can be downstaged with ipilimumab + ADT?
- Can we identify these patients with a significant degree of accuracy prior to initiation of treatment for locally advanced disease?
If such reponses are indeed durable, even in a small group of patients, there are significant ramifications for the management of locally advanced and perhaps even high-risk, localized forms of prostate cancer.