Researchers Hope to Breathe New Life Into Immunotherapy for Prostate Cancer

Neeraj Agarwal, MD

Since the auspicious 2010 FDA approval of sipuleucel-T (Provenge) as the first immunotherapy vaccine for cancer, advancement with immunotherapy has been slow in the field of prostate cancer.

Researchers are hoping to change that with ongoing clinical trials, including 2 that are exploring the the pox viral vaccine rilimogene galvacirepvec/rilimogene glafolivec (PROSTVAC). The BNIT-PRV-301 study is an international, placebo-controlled, randomized phase III study evaluating the efficacy of PROSTVAC with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (NCT01322490). The primary endpoint of the trial is overall survival (OS).

Additionally, PROSTVAC is being investigated in combination with ipilimumab (Yervoy) as a neoadjuvant treatment for patients with localized prostate cancer who are undergoing radical prostatectomy (NCT02506114). The open-label phase II trial will randomize patients to PROSTVAC monotherapy, ipilimumab monotherapy, or the 2 agents combined.

During a lecture at the 2016 OncLive State of the Science Summit on GU Cancer, Neeraj Agarwal, MD, discussed these 2 PROSTVAC studies, as well as patient selection for immunotherapy and personalized medicine in prostate cancer.

“Prostate cancer is not a highly mutationally rich tumor such as lung cancer, melanoma, or bladder cancer,” said Agarwal. “Hence, immunotherapy has not achieved the kinds of successes seen in those cancers compared with prostate cancer. Having said that, we should not forget that the first immunotherapy for cancers overall was approved for prostate cancer. There are many drugs that are coming up and look promising.”

OncLive: Can you please provide an overview of your lecture from this State of the Science Summit?

How does sipuleucel-T work and what have we seen with it so far?

Why is sipuleucel-T not yet a preferred treatment by oncologists?

In an interview with OncLive, Agarwal, associate professor in the Division of Oncology, Department of Medicine, director of the Genitourinary Medical Oncology Program, Huntsman Cancer Institute at the University of Utah, provided his perspective on immunotherapy in prostate cancer.Agarwal: I spoke on patient selection for sipuleucel-T (Provenge), the only immunotherapy approved for prostate cancer as of now, and what is ahead for us as far as immunotherapy in prostate cancer is concerned. There are recent advancements in immunotherapy, and [I discussed] what can we look forward to.The currently approved immunotherapy for metastatic castration-resistant prostate cancer is sipuleucel-T, more commonly known as Provenge. This has been approved for almost 6 years now. In my view, the patients who benefit most with this therapy are those who have low-volume disease and who are expected to live for at least 2 years based on the Halabi nomogram, which we usually use for prognostication of these patients.There are various reasons, I believe. If you look at the original survival outcome data from the registration trial, which led to approval of sipuleucel-T, the median OS benefit was quite modest at 4 months. There was no progression-free survival (PFS) benefit. There were no objective response benefits, and that has tempered the enthusiasm among doctors and patients.

Let’s discuss the future. Where do you see immunotherapy going in this field over the next several years?

Having said that, immunotherapy has come to the forefront of cancer medicine now. I see increasing recognition about the roles and mechanism of action of immunotherapy in prostate cancer, in general. We are going to see many more immunotherapies coming up.In the immediate future, the most promising immunotherapy in prostate cancer is PROSTVAC. This is an immunotherapy that uses 2 kinds of pox viruses—vaccinia virus and fowl pox virus—which are genetically engineered to express PSA transgene and trickles to molecules of T cells.

The phase II trial that was conducted many years ago yielded very encouraging data in terms of improvement in OS by approximately 8 months. In fact, those data were just updated last week, and the median OS benefit in patients who got PROSTVAC immunotherapy was in the range of 10 months, approximately, compared with those patients who did not receive PROSTVAC. A phase III trial has been conducted. It has completed accrual, and we are really hoping to see some really good results in the next year or so. That is the immediate future.

We also know that checkpoint inhibitors, such as ipilimumab, nivolumab (Opdivo), or pembrolizumab (Keytruda), which have proven to be very successful in patients with melanoma, lung cancer, and head and neck cancer, have not shown similar successes in a metastatic prostate cancer setting.

Why do you think these immunotherapy agents will likely do better in combination?

What are some ongoing trials in this space you find could be practice changing?

However, we think a combination of these therapies may be more valuable in the future and may yield higher response rates. In fact, many trials are ongoing right now, which are using various combinations of these immunotherapies, such as PROSTVAC with ipilimumab, ipilimumab with nivolumab, and checkpoint inhibitors with targeted drugs. The future is good and is very promising. We just don’t have anything approved yet.That’s a great question. We know that immunotherapy doesn’t, in general, induce PFS benefits or induct objective responses, but it may improve OS. Targeted therapies, on the other hand, are more known to induce objective responses and PFS benefits. Combination of targeted therapy with immunotherapy will have the potential to induce objective responses, PFS benefit, and OS outcomes if they’re used in combination; they act more like synergistic drugs rather than only additive drugs.There are several ongoing trials with immunotherapy. Several trials are combining immunotherapy checkpoint inhibitors with [other agents] including vaccines, targeted drugs, and androgen signaling inhibitors. I’m very excited about the future prospects of these trials. I believe one of these trials, or several of them, will eventually be positive and will improve survival outcomes and quality of life.