Prostate Tumors May Not Be Immunologic, Says Expert

Slovin, from Memorial Sloan Kettering Cancer Center, presented on immunotherapy agents for the treatment of genitourinary cancers, particularly prostate cancer, during a presentation at the Society for Immunotherapy of Cancer’s Cancer Immunotherapy 101 program held on August 18 in New York.

Over the past several years, immunotherapy treatments have been studied in prostate cancer. In fact, one of the first immunotherapy trials in solid tumors was of sipuleucel-T (Provenge), an autologous active cellular immunotherapy, in prostate cancer, which continued on to a phase III trial and ultimately FDA approval.¹

The double-blind, placebo-controlled multicenter trial studied the effects of the immunotherapy in men with metastatic castration-resistant prostate cancer. An improvement was seen in the median survival of the patients (n = 341) receiving sipuleucel-T infusions of 4.1 months over the control group (25.8 months versus 21.7 months). The sipuleucel-T group had a 31.7% probability of survival at 3 years compared with a 23% survival probability for the placebo group.

The most common adverse events (AEs) in patients receiving sipuleucel-T was chills, fever, fatigue, and nausea. Grade 3 AEs included chills, fatigue, back pain, hypertension, hypokalemia, muscular weakness, and 1 case of grade 4 intravenous catheter—associated bacteremia for a total incidence rate of 6.8% of patients.

Another vaccine studied in prostate cancer, PROSTVAC-VF, showed similar results. In a randomized, controlled, blinded phase II study of the prostate specific antigen (PSA)—targeted poxviral vaccine in patients with metastatic castration-resistant prostate cancer, a survival benefit was seen without an associated antitumor response.²

“What was rather paradoxical is that even though you lived longer, which could be a clinical benefit, it was really minimally associated with any antitumor response,” Slovin said.

Patients receiving PROSTVAC-VF had a longer median survival than the control group by 8.5 months (25.1 months versus 16.6 months). The overall survival (OS) rate at 3 years was 30% for the PROSTVAC-VF group versus 17% for the control. The phase III trial is ongoing.

OS, the primary endpoint used in both of these trials, may not be an appropriate endpoint for measuring responses to immunotherapy, especially in the case of immunotherapy for the treatment of prostate cancer, Slovin suggested.

The responses seen with both of these immunotherapies were not as robust as the responses seen to checkpoint inhibitors in melanoma and lung cancer, for example. Slovin pointed out that ipilimumab (Yervoy), the CTLA-4 inhibitor, did not perform as well in prostate cancer as it did in melanoma, for which it is approved.

In a multicenter, randomized, double-blind phase III study of ipilimumab in patients with metastatic castration-resistant prostate cancer who have progressed on docetaxel chemotherapy, patients on ipilimumab had a median OS of 11.2 months (95% CI, 9.5-12.7) compared with a 10-month (95% CI, 8.3- 11.0) OS for the placebo group.³

Limited efficacy was also seen with anti—PD-1 checkpoint inhibitors. Unlike with other tumor types, only 14% to 20% of patients with prostate cancer will have a tumor with some expression of PD-L1 so responses are not as notable, Slovin explained.

Another issue seen with immunotherapy treatments for patients with prostate cancer is that participants in the trials can often be scared away by pseudo-progression or PSA increases— which Slovin referred to as “promote stress and anxiety”— before the real antitumor response has had a chance to take effect. For example, 30% (118 of 387) of the patients in the ipilimumab trial discontinued treatment due to progression.

“The problem in prostate cancer is that it is a bone-trophic disease, we don’t have a lot of soft tissue involvement, so you really can’t tell how long it is going to take for an antitumor event to occur,” Slovin said.

Perhaps prostate cancer is not an immunologic solid tumor because it is not as hypermutated as other cancer types, Slovin said. A signifcantly higher proportion of somatic mutation frequencies are found in bladder cancer, both lung adenocarcinoma and lung squamous cell carcinoma, and melanoma—the most hypermutated of 27 different cancer types tested.⁴

Even after genomic profiling and various clinical trials, it is still unclear why the few patients with prostate cancer who do respond to immunotherapy treatments stand apart from the majority of patients who do not. However, Slovin noted that there are a few exceptional responders in this area who have durable responses lasting several years.

Slovin noted that prostate cancer immunotherapy trials have not shown any abscopal effects or T-cell response potentia- tion either, further adding to the expectations that the prostate may not be immunologic. The possibility remains, however, that with a boost to the immunologic signals of the organ with other immunotherapy strategies or combinations, the immune system could indeed respond in time.

References:

1. Kanto PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
2. Kanto PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II random- ized controlled trial of a Poxviral-based immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28(7):1099-1105.
3. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel che- motherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700-712.
4. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;44(7457):214-218.