Immunotherapies Promising But Still Challenging in CRPC

Robert Dreicer, MD, MS

Increasing efficacy with immunotherapies in some cancers led to the strategy being deemed Breakthrough of the Year by Science magazine in 2013.¹ However, for Robert Dreicer, MD, and colleagues at the Interdisciplinary Prostate Cancer Congress (IPCC) held March 15, 2014, enthusiasm regarding these therapies for patients with castration-resistant prostate cancer (CRPC) comes with some reservations.

While approved immunotherapy sipuleucel-T (Provenge) improved overall survival (OS) for patients with prostate cancer in a phase III trial,² it is still finding its place in the arsenal of drugs used to treat the disease, and other immunotherapies tested in prostate cancer have been associated with some drawbacks, according to Dreicer.

“It gets to be a challenge to use a therapy that, from a mechanistic perspective, leaves you with less insight, and that has limited some of what we have done,” said Dreicer regarding combining sipuleucel-T with various targeted therapies.

Dreicer, chair of the Department of Solid Tumor Oncology at the Cleveland Clinic’s Taussig Cancer Institute and professor at the Lerner College of Medicine, presented an evolution of evidence for immunotherapies in prostate cancer, beginning with granuloctye macrophage colony-stimulating factor (GM-CSF), which is used in the development of sipuleucel-T and has been extensively studied in the disease.³

In 2010, he said, the groundbreaking IMPACT trial² showed an increase in the probability of survival with sipuleucel-T, compared with placebo, in patients with metastatic CRPC who were asymptomatic or minimally symptomatic.

Dreicer reviewed data from a retrospective analysis of subsets within the IMPACT trial,⁴ which showed that patients with PSA levels ≤22.1 ng/mL had a median OS of 41.3 months compared with 28.3 months for placebo. In patients whose PSA was >22.1 to 50.1 ng/mL, OS was 27.1 and 20.1 months, respectively; in men with PSA levels >50.1 to 134.1, OS was 20.4 and 15 months, respectively; and in the subset of patients with PSAs >134 ng/mL, OS was 18.4 and 15.6 months, respectively.

“What this basically tells us is that if you are going to use an immune-based therapy, using it very early in the clinical course—early meaning castrate, metastatic, asymptomatic, without a crescendo of disease that is about to explode—is the ultimate [setting for] a therapy like this,” he said.

While results from the IMPACT trial brought forth hope for these patients with what Dreicer deemed the “unprecedented development and integration of a novel therapy,” the findings did not come without challenges. Despite its demonstrated impact on OS, sipuleucel-T is not a replacement for treatments designed to induce an objective anti-tumor response in real time, and it has not been shown to improve progression-free survival (PFS), according to Dreicer. He added that access and cost continue to pose problems.

Dreicer mentioned that many of his patients with prostate cancer are also reluctant to put forth the time and effort for this treatment, which is infused in three doses at intervals of 2 weeks, each administered after cell collection (leukapheresis or apheresis). “Men make treatment decisions much differently than women,” he said, mentioning that women are more likely to invest additional time in their own healthcare.

Due to all those factors, “It is not surprising that its uptake has been a little bit challenging,” Dreicer said of sipuleucel-T. But he stressed that the drug is part of a therapeutic paradigm in which multiple agents are used. “You layer this therapy on; it’s not an end all and be all,” he said. “Understanding that this therapy, when falling in the right place, may increase utility, is important.”

Fellow IPCC faculty member Daniel P. Petrylak, MD, agreed that sipuleucel-T is an active agent for prostate cancer, especially when used early on. He acknowledged that cost remains a challenge, but sees a future where this might change.

“I think that cost is certainly an issue, but also innovation helps to drop cost over time. When you are looking at the overall costs, you have to think about what’s being returned: People are able to spend more time with their families; people are able to do other things, just surviving, that are hard to put a price tag on,” said Petrylak, professor of Medicine and Medical Oncology and director of Prostate and Genitourinary Medical Oncology at Yale Cancer Center in New Haven, Connecticut. “So I think that, over time, some of these treatments, with competition, with further innovation, may find that production drops in price. But I think one thing that we have to be careful of is not to throw the baby out with the bathwater, and make sure that we continue to innovate.”

Dreicer also discussed PROSTVAC, an immunotherapeutic vaccine in phase III trials.³ “The NCI has been trying for a long time to figure out the optimal combination of stimulatory molecules and co-stimulatory molecules,” Dreicer said. The phase III, three-arm PROSPECT trial is comparing PROSTVAC-VF combined with GM-CSF (n = 400) against PROSTVAC-VF (n = 400), and also against placebo (n = 400) in patients with asymptomatic or minimally symptomatic CRPC. The trial includes a 5-month treatment phase, after which other therapies are left to the discretion of individual investigators. This is an open and active ongoing multinational randomized trial with long-term follow-up every 6 months for 5 years.

Dreicer expressed concern, however, about whether or not there ultimately will be a place for this therapy in practice.

“I am not sure the therapeutic paradigm 5 years from now would need another agent that might have similar activity to sipuleucel-T,” he said, mentioning that this is often a challenge for drugs that are in clinical trials for long periods of time.

Next-generation immunotherapeutics, such as checkpoint inhibitors that seem to be showing promise in other types of cancer, have faced problems with low efficacy and high toxicity when studied in patients with prostate cancer, according to Dreicer. There is currently limited data for PD-1 and PD-L1 in prostate cancer, and these inhibitors have shown limited activity in patients with prostate cancer to date.

Ipilimumab, approved for the treatment of melanoma, was studied in a randomized, double-blind, phase III trial⁵ that compared the drug with placebo following radiotherapy in patients with CRPC who had received prior treatment with docetaxel. In the intent-to-treat analysis (N = 799), the hazard ratio (HR) for OS, although not statistically significant, favored ipilimumab (HR = 0.85; 95% CI = 0.72-1.00; P = .053) and median OS for ipilimumab was 11.2 months (95% CI = 9.5-12.7) compared with 10.0 months (95% CI = 8.3-11.0) for placebo. Median PFS also favored ipilimumab over placebo (HR = 0.70; 95% CI = 0.61-0.82), as did PSA declines of ≥50% in evaluable patients (13.1% vs 5.3%, respectively).

Dreicer noted that ipilimumab has overt anti-tumor activity. “You will see biochemical soft-tissue responses in some patients,” he said. However, he cautioned that “Ipilimumab is a different type of immunomodulatory therapy than sipuleucel-T. Ipilimumab has toxicity. In many instances, it can actually be surprisingly toxic in some patients.”

Dreicer concluded by stating that low toxicity is important with immunotherapy because, in order for the treatment of CRPC to move forward, multiple targets will need to be hit at the same time with different agents, including immunotherapies. Community oncologists already have several therapies on hand that can achieve that effect, he added.

“When you talk about this complex disease stratum that we have, one of the things that I would make people believe is that, in order to make progress in a disease in which resistance develops with many of its therapies, [we need] to hit multiple targets,” he said.

References

1. Couzin-Frankel J. Cancer Immunotherapy. Science. 2013; 342(6165):1432-1433.
2. Kantoff PW, Higano CS, Shore, ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
3. Drake C. Prostate cancer as a model for tumour immunotherapy. Nature Rev Immun. 2010.10(8):580-593.
4. Schellhammer PF, Chodak G, Whitmore JB, et al. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013. 81(6):1297-1302.
5. Gerritsen WR, Kwon ED, Fizazi K, et al. CA184-043: A randomized, multicenter, double-blind phase 3 trial comparing overall survival in patients with post-docetaxel castration-resistant prostate cancer and bone metastases treated with ipilimumab vs placebo, each following single-dose radiotherapy. Presented at: the European Cancer Congress; September 27-October 1, 2013; Amsterdam, Netherlands. Abstract 2850.

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