Vogelzang Disputes 'Weak' Guideline Rating for Sipuleucel-T

Nicholas J. Vogelzang, MD

In a recent guideline for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) shared their thoughts on the implementation of six drugs approved since their previous recommendations were issued in 2007, as well as on older drugs.

In addition to recommending, with moderate strength, that androgen-deprivation therapy (ADT) be used indefinitely in these patients, the guideline also shares suggestions for the use of the six newer drugs concurrently with ADT.

Among the newer agents is the immunotherapy sipuleucel-T (Provenge). The guideline gives this drug a weak recommendation in the setting in which it was FDA-approved in 2010: for the treatment of asymptomatic and minimally symptomatic patients with mCRPC. As part of their rationale for the weak recommendation, the guideline authors explain that sipuleucel-T offers improved survival and low toxicity, but an unclear effect on quality of life. In addition, the guideline suggests that sipuleucel-T offers moderate benefit and low harm, with moderate evidence strength.

“Although controversies have been raised in editorials regarding the conduct of clinical research of this product, based on the trial results, it remains an option that may reasonably be discussed with patients who have a low symptom burden,” the guideline states.

An autologous cellular immunotherapy, sipuleucel-T targets prostatic acid phosphatase (PAP) as a means of boosting a patient’s immune system in the fight against cancer. The drug is tailor-made by using leukapheresis to collect immune cells (autologous antigen-presenting cells) from a patient’s own blood; the cells are then exposed to a protein (PAP linked to immune-cell activator granulocyte-macrophage colony-stimulating factor) and returned to the patient intravenously, according to the FDA, which notes that the product also contains T cells, B cells, natural killer cells, and other cells.¹

The panel that wrote the ASCO/CCO guidelines considered data from the phase III IMPACT trial of sipuleucel-T,² which demonstrated that men treated with the drug survived a median of 4.1 months longer than those in the control arm. Median overall survival was 25.8 months, versus 21.7 months, for a 22.5% reduction in risk (P = .032).

The guideline authors pointed out that there was no difference between the drug and placebo in the areas of prostate-specific antigen (PSA) level, objective disease progression, or grade 3 to 5 adverse events, and that quality of life information was not reported in the trial.

To gain insights about the use of sipuleucel-T in this population of men, and to seek an expert opinion about the position taken on the drug in the guideline, Urologists in Cancer Care spoke with Nicholas J. Vogelzang, MD, site research leader at the Comprehensive Cancer Centers of Nevada and a member of the US Oncology Network. A collaborator on the IMPACT trial, Vogelzang uses sipuleucel-T regularly in patients and gives lectures about the treatment on behalf of its developer, Dendreon.

UCC: How frequently, and in which types of cases, do you give sipuleucel-T—and why?

Vogelzang: I’ve treated about 150 men with Provenge so far, and I recommend it to every one of my prostate cancer patients who have metastatic disease.

We don’t fully understand how Provenge works, so I can’t say that it’s working well. But we know it works better when PSA is low, and we’ve done a lot of studies to show a profound upregulation of the immune system by the drug.

I have anecdotal cases, such as a patient, a veterinarian from Utah, whose PSA became very low with a combination of [the immunotherapeutic vaccine] Prostvac followed by Provenge. But I’m not counting on that happening regularly. I have other patients whose PSAs keep rising rapidly. That’s frustrating to the doctor and the patient, but it doesn’t mean I’m not going to try Provenge on everyone appropriate for the therapy.

I believe Provenge is an important component of managing prostate cancer. It certainly beats chemotherapy, Zytiga [abiraterone], or Xtandi [enzalutamide] in terms of side effects. That’s why I do not understand the guideline’s comments about quality of life. Anyone who has used the therapy understands that it’s ideal for older patients. It prolongs survival at a very low physical cost, and is fully reimbursed with few out-of-pocket costs to the patient.

What is your opinion of the ASCO/CCO guideline’s “weak” recommendation that physicians administer sipuleucel-T to men with mCRPC who are asymptomatic or minimally symptomatic?

I thoroughly disagree with the strength of that recommendation. There were three randomized trials of sipuleucel-T, two small and one large. The FDA mandated that the endpoint should be survival, and it met that endpoint. I see no reason to call the evidence weak. The only reason for the “weak recommendation,” I think, is because there’s a pervasive PSA-driven bias. Doctors just don’t believe a drug works unless PSA drops. They think that PSA is an adequate surrogate, but in this immunotherapy world, it is not.

The other issue that might make it weak, at some level, is that Provenge is not available outside the US.

The guideline mentioned that “controversies have been raised in editorials regarding the conduct of clinical research of this product.” What were the guideline authors referring to?

That was an editorial in the Journal of the National Cancer Institute by Marie L. Huber, and co-written by Chris Parker, [MD], from the [Royal Marsden in the] UK, that challenged some of the findings from the IMPACT trial.³ That article was robustly refuted by Philip Kantoff, [MD, of Harvard Medical School], in a subsequent editorial.⁴

There was another controversy when Maha Hussain [MB ChB, of the University of Michigan Health System] and Howard Scher [MD, chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center,] suggested that the FDA should not approve Provenge on the basis of two small randomized phase II trials.⁵ In fact, they were correct when they said we should wait for the results of a large phase III trial.

Both these controversies continue to be dredged up by the naysayers. However, they miss the key point: Immunotherapy of cancer is an exciting and effective modality. We must continue to study and use it to help our patients today.

A supplement to the ASCO/CCO guideline looks at the cost of the medications available for mCRPC. Sipuleucel-T is cited as the most expensive (the comparison was made using prices for a 30-day period for oral drugs, or for one infusion or cycle in the case of parenteral drugs). Do you think that might affect doctors’ willingness to use it in patients?

The problem is that it’s front-loaded. You pay $100,000 for a 5-week treatment, but when you look at enzalutamide, the average person is on it for 12-18 months for over $8000 a month. I cannot understand why there is a focus on monthly costs versus total costs.

I tell patients it’s my job to give them every available therapy. The average patient with prostate cancer gets 10 to 15 different therapies for the disease. Some are very expensive and some are very cheap. We don’t criticize leuprolide or goserelin for being expensive, yet those drugs cost about $1000-2000 a month for the duration of the patient’s life. Surgical orchiectomy is far cheaper, is one simple procedure, and lasts also for the duration of the patient’s life. If you wanted to make cost the primary issue in treating patients, you could argue that we’d save a lot of money rapidly if we simply required surgical castration.

You were involved in the recent launch of a trial (NCT02237170) designed to uncover more about the mechanism of sipuleucel-T. Why do you feel this trial is important, and what are its endpoints?

The trial is being conducted by Matthew Galsky [MD, assistant professor of Urology] at Mount Sinai Hospital, and it is considering a novel way to look at the immune system using an array of immune cytokines and cells. Provenge is a focus—particularly effects on T cell function.

Recently, there has been research into the value of B cell activation by Provenge, and Emmanuel Antonarakis [MBBch] and Chuck [Charles] Drake, of Johns Hopkins School of Medicine, reported on eosinophils as a predictive response marker. The appearance of eosinophils is a clue that the immune system is being activated by Provenge. In addition, there is interest in the concept of antigen spreading—showing that, with the use of Provenge, T cell activity against one antigen on a prostate cell begins to activate other T cells that spread to attack other antigens on the prostate cells.

The immune system is an amazingly adaptable responder, and just because we don’t have an entirely clear idea how it works doesn’t mean it doesn’t work. People who ignore it are missing an opportunity.

Ultimately, we don’t know what our T cell repertoire is able to do against prostate cancer. Our T cells have enormous potential, and can recognize and destroy thousands of viruses, bacteria, fungi, and other invaders of our body. It’s very hard to measure the cells that, for example, are responsible for us being immune to polio—they circulate at extremely low levels, and to even detect them is a major technological task. So it is not surprising that it is hard to find a T cell clone that is able to recognize and suppress prostate cancer.

We can extrapolate that to the work done by Steve Rosenberg [MD, PhD, of the National Institutes of Health] on CARs [chimeric antigen receptors], where they can isolate and expand one clone of T cells which are then able to literally lyse all leukemia cells in kids with advanced, completely resistant leukemia. If a T cell is that powerful when it is heavily amplified, and if you understand that Provenge is just beginning to tweak the T cells, it’s no wonder we have a long way to go. Provenge is a first-generation technique, but you can see the potential for second-generation therapies.

What’s next for sipuleucel-T?

A phase III trial that’s almost done is called PROSPECT. It is examining the Prostvac vaccine in a three-armed trial (NCT01322490) looking at overall survival in patients who take Prostvac with or without adjuvant GM-CSF, compared to those taking placebo.

The protocol specifies that Prostvac be given to Provenge-naïve patients. In practice, I try to give Provenge after Prostvac to all my patients. In that small way I am giving two lines of immunotherapy to my patients. I can’t do a randomized phase III trial of the combination, but if the Prostvac trial is positive, it will open up the potential to study the two agents in combination and in sequence. If we see activity of the PD-1/PD-L1 agents in prostate cancer, someday we may see triple immune therapy for patients with mCRPC.

References

1. FDA. Vaccines, blood & biologics: questions and answers — Provenge. US Department of Health & Human Services website. http://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm210037.htm. Posted September 24, 2013. Accessed September 30, 2014.
2. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. NEJM. 2010;363(5):411-422.
3. Huber ML, Haynes L, Parker C, Iversen P. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. JNCI. Published online January 9, 2012.
4. Kantoff PW, Higano CS, Small EJ, Whitmore JB, Frohlich MW, Schellhammer PF. Re: interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. JNCI. 2012;104(14):1107-1109.
5. Goldberg P. Biostatician Thomas Fleming warns against approval of cancer vaccine. The Cancer Letter. 2007;33(17):1-4.