provenge

Hi Mr. Kayak,
I'm responding to this thread for the first time, I read your post where you were trying Provenge at the earliest possible time and had superior results. A PSA of <2, which I would call great. So as not to repeat my signature too much, I was placed on Lupron until it failed me six years later, then we went to ADT2 by adding Casodex for 18 months then it failed me with a PSA of 4.6. This is when we went to Provenge. I had two small bony mets and that's all so to me, this was sort of the first possible.

The Provenge was done Sept-Oct. 2013. Unfortunately my PSA only continued to rise, it is now 47 after 10 months. I just wanted you to have this info about the sometimes adverse changes after Provenge. I am not saying they were caused by Provenge, only that they occurred . . . Q

Post Edited (quincy17) : 9/28/2014 11:01:36 AM (GMT-6)

Sipuleucel-T Helps ADT Boost Prostate Cancer Immunity
Beth Fand Incollingo
Published Online: Thursday, August 28, 2014
Emmanuel S. Antonarakis, MBBCh

Sipuleucel-T (Provenge) is effective when given either before or after androgen deprivation therapy (ADT) in men with biochemically recurrent prostate cancer (BRPC) who face a high risk of developing metastases, a study has found.

The study demonstrated that tumor specific T-cell responses and broad‐based immune responses were augmented with both strategies, but investigators are still uncertain about which sequence is superior, said lead author Emmanuel S. Antonarakis, MBBCh, assistant professor of Oncology at Johns Hopkins Medicine. The preliminary clinical data, reported in the phase II STAND study, were presented this spring during the annual meeting of the American Society of Clinical Oncology (ASCO), in Chicago.

The results were in direct opposition to those presented at last year’s meeting, Antonarakis said. In 2013, after 2 to 4 weeks of follow-up, investigators concluded that sipuleucel-T was most helpful when administered after ADT. Now, after at least 6 months of follow-up, Antonarakis said, evidence seems to be pointing to sipuleucel-T before ADT as the strategy of choice, although he cautioned that one important test of immune response conflicts with that idea.

“Our conclusion is that the jury is out,” Antonarakis said. “We simply don’t know what all this means. We need to have information about metastasis-free survival before we can determine whether these immune responses that we think might mean something actually mean something. In the next 6 to 12 months, we’ll present mature data on PSA [prostate-specific antigen] progression and metastasis-free survival in these patients, none of whom had evidence of metastatic disease when they enrolled.”

He added that “We do studies to figure out and confirm or dispel our preconceived hypotheses, and this is an important lesson about having long-term follow-up and not making conclusions based on a short amount of follow-up.”

The STAND study was the first to look at the combination of sipuleucel-T and ADT in patients with no metastases; the patients all were hormone therapy-naive, Antonarakis said.

Sipuleucel-T is an autologous cellular immunotherapy targeting prostatic acid phosphatase (PAP), approved by the FDA for the treatment of patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. The investigators studied the drug in men with BRPC because these patients have a low disease burden and minimal immune tolerance. The authors noted that ADT has been shown to enhance anti-tumor immunity and augment the effects of cancer immunotherapies.

In the trial, 68 men with testosterone ≥200 ng/mL, a PSA doubling time of ≤12 months, and no metastases were randomized 1:1 to receive sipuleucel-T first, followed by ADT starting 2 weeks after the third dose of the immunotherapy (arm 1), or sipuleucel-T initiated after 3 months of ADT (arm 2). In all, the men received 3 doses of sipuleucel-T and 12 months of the ADT leuprolide (Lupron). The primary endpoint was cellular immune response to target antigen PA2024 measured via the ELISPOT test, the authors wrote. Secondary endpoints included humoral and cytokine responses, product parameters, clinical efficacy, and safety, they said.

The data they reported at ASCO comprised results for 65 men followed for 9 months or more after their final injection of ADT. In arm 1, which started treatment with sipuleucel-T, 10 of 32 men, or 31.3%, achieved undetectable prostate-specific antigen (PSA) (<0.02 ng/mL) and testosterone (<0.35 ng/mL) 9 months after their last ADT injection, the investigators reported in an abstract. In arm 2, the cohort that started treatment with ADT, 14 of 33 men, or 42.4%, achieved those goals in the same time period, the authors reported in the abstract, noting that 4 men in the 65-patient evaluable group developed PSA progression.

“We looked at T-cell responses using ELISPOT, which tells you how many activated CD8-specific T cells you have in response to a vaccinating antigen, in this case PA2024. It turned out that, with a follow-up of 6 months, T-cell responses as measured by ELISPOT in patients who got sipuleucel-T first and then ADT were better,” Antonarakis said. “The second thing we did was to look for antibodies against PA2024 using an ELISA test. At 15 months of follow-up, antibodies against PA2024 were higher in patients who received the sipuleucel-T first, which seems to suggest that sipuleucel-T before hormonal therapy was better, although that is the opposite of what we reported a year ago. The third thing we looked at was cytokines, proteins that immune cells make, and, surprisingly, they were higher in patients who received hormonal therapy first.”

Even without knowing which works best, Antonarakis emphasized that the study demonstrated that either sequence will work to increase the anti-tumor immune response in this population of patients.

“Overall,” he said, “anti-tumor immune response in all three of the tests are increased when you give hormonal therapy plus sipuleucel-T in patients that have biochemically recurrent prostate cancer without metastases.”

Adverse events occurred with similar frequency in each arm, with chills, headache, and fatigue the most frequent in both. Four and 7 patients, in arms 1 and 2 respectively, experienced grade 3 adverse events, and there were no grade 4 or 5 events, the authors reported in their poster.

www.onclive.com/publications/urologists-in-cancer-care/2014/august-2014/sipuleucel-t-helps-adt-boost-prostate-cancer-immunity/1

Jim,

That should kick it....good for you...love the combination therapies...wish I could join you on the Provenge...

Quincy,

That's what I find odd with Provenge...they say you can't base its success by PSA...but is that short term, long term, or what? At some point we need to react to a rising psa don't we? There just doesn't seem to be a good marker for how well Provenge is working on a case by case basis.

Which clinical trial?

Jerry

Quincy17,

So sorry to hear that your PSA is rising. Challenge with Provenge - PSA usually continue to rice in many patients after treatment (l 49packard) but in some cases it can fall ( for example Todd1963, Samham55)but it is happened no often . Provenge hasn't impact on progress of disease, but the most important it is has strong data of OS; with Provenge you are longer live. It turns out that if the PSA is low when you start, the magnitude of benefit seems to be larger.
I see you have serious case ( G-9). Many patients uncomfortable with rising PSA and ask their doctors to start other therapy right away, but some patient, by advice of their doctors , wait 6-12 months and give Provenge time to work better . You said your PSADT is slowdown ( it is one of visible benefit of Provenge) .

In my previous post from 8/24/2014 I posted figure how immunotherapy may alter tumor growth rates, thereby improving survival. Immunotherapy administered earlier would potentially have a greater effect on survival than immunotherapy administered later . Also the effect on survival could be enhanced when used in combination with other therapies and can enhanced other therapy. Those with more favourable baseline factors such as low PSA – may benefit the most from Provenge treatment, and provide a rationale for immunotherapy as an early treatment strategy in sequencing algorithms for mCRPC. I hope your doctor already has plan for your next step and I will keep you in my prays.

LupronJim,

I read with big interest your detailed information about your treatment It will be interesting to see " abscopal effect". While this phenomenon is extremely rare, its effect on the cancer can be stunning, leading to the disappearance of malignant growths throughout the entire body. Such success has been described for a variety of cancers, including melanoma, lymphoma, and kidney cancer. Scientists suggest that the effect may depend upon activation of the immune system. "Abscopal effect"findings support the idea that radiation may help stimulate the immune system to fight cancer. At this time, T-cells and dendritic cells are believed to play a primary role.

I hope you read my post from 3/9/2014 by Dr. M. Scholz.( I see you have oncologist from Prostate Oncology (Scholz/Lam).
Dr. Scholz words:"Considering that radiation seems to enhance the anti-tumor immune response, boosting this immune response even further with an immunotherapy like Provenge* is an attractive idea to test in a larger group of patients in a formal clinical trial. It’s logical to consider that that radiation and Provenge together will cause a greater anticancer immune effect than either method by itself."

Provenge has many trials with other treatments ( Zytiga, Xtandi, Xofigo radiation therapy and others;I posted about them ). You can
see it here:
clinicaltrials.gov/ct2/results?term=Sipuleucel-T&Search=Search

I will follow your posts with big interest and keep you in my thoughts, hopping that you have "Abscopal effect".

Just new article Today:"Enzalutamide + Sipuleucel-T Gives Immune Boost in mCRPC"
Beth Fand Incollingo
Published Online: Monday, September 1, 2014
Daniel P. Petrylak, MD

"Sipuleucel-T (Provenge), an immunotherapy tailor-made for men with metastatic castration-resistant prostate cancer (mCRPC) using their own white blood cells, is just as potent if it is manufactured while a patient is taking enzalutamide (Xtandi), and the two drugs seem to boost immunity more effectively when administered together, according to preliminary data from a phase II study.

The early results of the ongoing STRIDE trial, or study P12-2, were published in conjunction with abstracts from the Annual Meeting of the American Society of Clinical Oncology, held this spring in Chicago, Illinois.

Sipuleucel-T is an autologous cellular immunotherapy; enzalutamide is an androgen receptor inhibitor. Both are approved for the treatment of men with mCRPC, authors Quinn et al pointed out.

“Given the lack of potential cross resistance and data suggesting that androgen ablation may potentiate the immunotherapeutic effects of vaccines, combining these agents may be a beneficial treatment approach for mCRPC,” the authors hypothesized.

In the study, patients with asymptomatic or minimally symptomatic mCRPC received sipuleucel-T with enzalutamide dosed at 160 mg per day for 52 weeks. The men were randomized 1:1 to either the concurrent arm of the trial, in which enzalutamide was started 2 weeks before sipuleucel-T was initiated, or the sequential arm, in which enzalutamide was begun 10 weeks after sipuleucel-T was initiated.

The primary endpoint was the peripheral T cell immune response to the immunizing antigen PA2024, and an exploratory endpoint was time to prostate‐specific antigen (PSA) recurrence. As of January 14, 2013, 22 patients had been enrolled, with 6 (3 in each arm) having completed sipuleuel-T treatment, the authors reported.

Investigators found no differences in product potency between trial arms.

“The median cumulative CD54 upregulation (a measure of antigen‐ presenting cell [APC] activation) was 35.3 vs 26.6 and CD54+ cell counts were 1.9 vs 1.8 x109 in arms A and B, respectively,” the authors wrote. “In all patients, APC activation was greater at infusion 2 vs 1 indicating an immunologic prime boost. Pre‐ and post‐culture cellular composition did not differ between the arms.”

The authors concluded that sipuleucel-T can be manufactured while a patient is taking enzalutamide without a change in the drug’s anticipated potency, and that, when given concurrently with enzalutamide, sipuleucel-T is delivered with an “immunologic prime boost.”

www.onclive.com/publications/urologists-in-cancer-care/2014/August-2014/Enzalutamide--Sipuleucel-T-Gives-Immune-Boost-in-mCRPC

My best Hope

A little titbits From PCRI2014 ( special about Provenge);

Basics treatment Principles relapsed and advanced disease:

- PSA rise after ]surgery or radiation should trigger disease reevalution and timely therapy;

- Use the latest imaging technology;

Combination therapy ( rather than sequential therapy ) may improve results.

One of the Tool for cancer dormancy- Provenge, ;


Strategic Principles Guiding Treatment

- Complete remission matter;

- intelligent Drug Combinations rather than Sequential Drug use ;

-attention to managing side effects,

- General Health issues must be addressed.

Characteristics of successful Combination therapy:

- Agents with different mechanisms of action
1/100 vs
1/100 x 1/100 = 1/10,000
1/100 x 1/10,000 = 1/1,000 ,000

- Toxicities should not overlap;

- drugs interaction need to be avoided;

-Principles apply where ever resistance to treatment is a problem- Cancer, AIDS and tuberculosis .

Zytiga and Xtandi before Provenge closes a Window of Opportunity !

Other Provenge tricks:

- With radiation- The Abscopal Effect;

-Follow Provenge immediatly with Zytiga or Xtandi, why wait for Psa to rise;

- Add investigational Yervoy ( Now available at UCSF ) . ( It is in trial with Provenge)

Best to give immune therapy at start of ADT.

Yervoy ( investigation therapy ) risk at high dosages.

Dr. Myers thinks Xtandi and Zytiga shouldn't be combined.


But for me the most interesting part was when Dr. Hussain was asked by Dr.Mark Moyad about her not endorsing Provenge and death threats. Her answer was that at that time there was only good OS. The PSA, Radiografic scans didn't improve and it would be hard to judge efficacy. She invoked Saddam Hussain ( she grow up during his regime )and in my opinion played victim card and thus covered her own cruelty (towards PC patients) and deception. ( Meanwhile MU Medical Centre one of the lieder in Medical oncology and where Dr. Hussain works still doesn't offer Provenge to its patients ! )

It bring back some memory to me.
Dr. M. Hussain Dr. H. Scher and play big role to reject Provenge in 2007 by FDA, and in fact Dr. Scher had many conflicts and also voted against approval.
The truth is, it was Drs.Pazdur, Scher, and Hussain who put the 'fix' in and derailed Provenge in 2007 when, at the time, there were no alternatives for the men with advanced prostate cancer to whom Provenge was addressed.

Here Scher said (transcript of the Advisory Committee 2007 ):

"..The truth is, it was question does this drug prolong life, I just don't know at this point in time. So I start thinking, you know wearing my physician's hat, obviously I feel extremely frustrated when there are no options to offer patients. So if I start thinking, am I denying a potentially useful agent to men who clearly need it, the answer is unfortunately I don't know. So I say well, what if we think that this really should be available, start thinking about the number of agents that are currently under development. There's now issues of 1 prioritization...
... I think we are really poised at the beginning of what will be hopefully an outstanding era of immunotherapy. I think there is sufficient evidence demonstrated which justifies the definitive study, and obviously there are investors in that who concurred, but I think it does not meet the -- as the question was phrased, to establish the efficacy. I think this is still an open question...
... Personally I have no experience with this agent, so I'd just like to ask the clinicians who have used it, we
all understand the difficulties assessing time-to-progression and how it does not associate with survival as we are currently
measuring it..."

Here Dr. Hussain said (transcript of the Advisory Committee 2007 )::

"...Yes, I can’t help but feel that there is an inconsistency in the FDA position on what would be or would not be accepted for a registration purpose.So here we heard that survival is an endpoint that is accepted. That’s not an issue. That’s not a problem. In my two years on ODAC, I am left with the impression that, in a disease where there’s never been surrogacy demonstrated, a progression-free survival will not be accepted, or time-to progression is not accepted."

What has always bothered me, and still bothers me, is the fact that Drs. Scher and Hussain never should have been seated on the Provenge Advisory Committee panel. Both of their waiver requests were flawed. That is, I think there is evidence to support the contention their waiver request significantly under-reported their COIs. Also Drs. Scher and Hussain were put on the Advisory Committee by Dr.Pazdur (no doubt. with some nefarious manoeuvring), and both voted “No.”

First of all, survival ( OS) is the gold standard. Drs.Scher and Hussain admitted seeing the survival. Provenge has always shown survival, and in the worst case scenarios. Their conflicts stood out and they showed they were for all whom they worked for and represented.

Do the math. There was no other viable option and a minimum of 90,000 patients would be denied an opportunity to live longer healthy productive lives. ( from 2007 to 2010 when Provenge finally was approved and 30,000 prostate cancer patients die each year.)
Some few of those 90,000 appeared before the panel that day and entered pleas for their lives that did not go unheeded by the Advisory Committy. Many others wrote similar supplications.All but four (four with personal illegally-undeclared conflicts of interest) on the panel voted to recommend FDA Approval after the entire panel had voted unanimously that Provenge was an utterly safe and virtually side-effects-free therapy.

Between 2007 and 2010, almost 100,000 men lost their lives to prostate cancer. Many would have benefited from access to Provenge under Conditional approval. Where is their justice? Who speaks for them?

Then there was the year long CMS fiasco ( 2010-2011). The "informal inquiries" CMS received and the investigation that they started about payment for Provenge ( first time such investigation by CMS in history of any drug). A year long delay because doctors were told they might not be reimbursed. CMS launched its year long Provenge investigation.

it looks like Provenge never had a brake. What a tragedy !


On March 2008 Theodore J. Cohen, Ph.D well known advocate for Provenge sent 2 dozen, white roses in memory of the Provenge AC meeting on March 29, 2007.. here he wrote in his memory to Dr. 'Andrew.von Eschenbach. Here his email"

"Dr. von Eschenbach…
It was I who sent you the 2 dozen, white long-stem roses. They were meant as a sign of mourning for the overturned, overwhelming recommendation to approve Provenge for end stage prostate cancer (17-0 on safety, 13-4 on the basis of substantial efficacy) by your own Advisory Committee. They also were meant to call attention to the egregious COIs attendant to Drs. Scher and Hussain, which have yet to be fully investigated and vetted by your agency and HHS. Theodore J. Cohen, Ph.D"

Between 2007 and 2010, almost 100,000 men lost their lives to prostate cancer. Many would have benefited from access to Provenge under Conditional approval. Where is their justice? Who speaks for them?

Just recently read article "Former FDA head says biotech business model 'is basically falling apart'" from Aug 25, 2014, :
"Andrew von Eschenbach, commissioner of the FDA for more than two years until January 2009, said in an interview Friday that as a result of FDA demands, drug trials have become too large and expensive...He said the FDA needs to allow for more drugs to be approved conditionally based on evidence from measurable substances in the body that show they work, called biomarkers. He also said the agency needs to do a better job laying out the approval process for new products ...“You want to get the right drugs to the right patients at the right time, he said. “We have the tools to do that, but we need to regulatory environment to allow it.”

What a hypocrisy ! The same person who had lead role in rejection of Provenge ( he was Head of FDA at that time) .

www.bizjournals.com/boston/blog/bioflash/2014/08/former-fda-head-says-biotech-business-model-is.html?page=all

There is interesting book " Story of Dendreon". Here some interesting from it:

"...Meanwhile, the Prostate Cancer Foundation snubbed its nose at Dendreon. And in April, 2007, Dr. Howard Scher, who was an executive and director of ProQuest, and the chairman of the Prostate Cancer Foundation’s “Therapeutic Consortium”, spearheaded an unprecedented lobbying effort to convince the FDA to reject Dendreon’s treatment – the first time in history that the FDA had gone against an advisory panel’s recommendation to approve a drug for terminally ill patients. This lobbying effort had the support of government officials who have ties to Michael Milken. ""

Here about threats to some doctors :

"...Essentially identical stories appeared in the Philadelphia Inquirer, the New York Times, the Boston Globe, the Seattle Times, and on CNBC. Every one of these media outfits portrayed Dendreon’s supporters as potentially dangerous lunatics. Every one of them stated unequivocally that Dr. Scher had been “threatened.” Yet, not one of them specifically described the threats, and as far as I can ascertain, there were no “threats.”

One more interesting quote from this book:

"... In December 2007, three U.S. Congressmen — Mike Michaud (D-Maine), Dan Burton (R-Indiana) and Tim Ryan (D-Ohio) — called on the House Commerce Committee to investigate why the FDA failed to approve Dendreon’s treatment for prostate cancer. Referring to Dr. Scher and his ally, Dr. Hussain, the lawmakers said in a letter that “there are reasons to believe that serious ethics rules were violated by two FDA advisory panel members in their decision [to vote and lobby against Dendreon] and that these violations played a role in the subsequent FDA decision not to approve Provenge at this time.”
A bipartisan group of 12 additional Congressmen eventually signed on to the request for an investigation. And in February 2008, as outrage over this scandal spread through the medical community, a group of seven respected doctors, calling themselves “Physicians for Provenge” wrote a letter to the ranking members of the House Commerce Committee, suggesting that the investigation should urgently proceed."

This investigation never was started.

Read more about tragedy of Provenge :


www.deepcapture.com/wp-content/uploads/story-of-dendreon.pdf

My best Hope

Thanks for all the very helpful info, Hope. That cleared up a lot of my questions on Provenge and made me happy that I started when I did. I assume by early you mean at a low PSA count, mine was 4.7, which was about as low as the trial I was in would accept. I do not think that Provenge is the cause of my rising PSA, there is probably some other mechanism at work. I'm just doing my due diligence here, searching every possible avenue for the answer . . . Q

Quincy17,
It is so wonderful you could receive Provenge , when your PSA was < 5.
I posted many times on this board that patients with lower (≤ 22.1 ng/mL) versus higher (> 134 ng/mL) baseline PSA values not only generally lived longer, but also achieved a greater benefit with Provenge.
The estimated improvement in median survival with vs control Provenge as 13.0 months in the lowest baseline PSA quartile and 2.8 months in the highest quartile.
Furthermore, the risk of death for patients in the lowest baseline PSA quartile was reduced by 49%, compared with 16% for patients in the highest PSA quartile.( from The phase III IMPACT trial of Provenge that supported the approval of sipuleucel-T for the treatment of patients with mCRPC by FDA in 2010 ).
Patients with a lower disease burden may have a more robust immune system due to less tumor-mediated immunosuppression and fewer prior immunosuppressive treatments, as well as having more time to allow the immune system to mount an effective response . So we can see that patients with low PSA – may benefit the most from Provenge, and provide a rationale for immunotherapy as an early treatment strategy in sequencing algorithms for mCRPC.

Here Dr. James L. Gulley, the chair of the Department of Urology at Thomas Jefferson University, words:" There’s data suggesting that if in the group of patients with the lowest PSA on the Phase III study, those patients did substantially better getting the Provenge than the placebo in that group. That difference was about 13 months in the lowest group of patients, so it could be that a subset of patients, a part of the patients who have lower disease, may actually have more benefit than patients with more advanced disease. It’s harder for immune system to work with the more advanced disease... When we have talked about this in think tank sessions, we thought how are we going to sequence this all if somebody has no symptoms and their PSA is just kind of slowly going up, would we give them Provenge first? The answer is a lot of us have said yes, maybe Provenge first and then after that then follow that with Xtandi and then ride that for as long as we can and then maybe Zytiga, and on down the line."


LupronJim,
In my respond to Quincy17, I just explain what it mean " Window of Opportunity ". Early or late, mostly of patients are starting to progress and have more advanced disease and will have less benefit from Provenge or even disqualify from this treatment if progress rapidly and become systematic.
It is unbelievable that you could receive your Provenge with such low PSA ( I read about your bike ride ! ). I notice that this year more patients with PSA so low like yours ( example Kayak808 ) have Provenge and its very good sign that more doctors give this treatment.

Does bias against Provenge still continue ? Yes, read this article ( meanwhile Drs. Pazdur, Scher and Hussain have big influence at the ASCO ):

"Vogelzang Disputes ‘Weak’ Guideline Rating for Sipuleucel-T ( Provenge)

Beth Fand Incollingo
Published Online: Friday, October 3, 2014
Dr. Nicholas J. Vogelzang

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.[/re]

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. 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. "

www.onclive.com/publications/urologists-in-cancer-care/2014/october-2014/vogelzang-disputes-weak-guideline-rating-for-sipuleucel-t/3

My best Hope

This morning my Provenge reinfusion #2 had to be rescheduled due to a manufacturer error with the cell collection #2 from Friday Oct 3.

Has anyone else ever had this problem with Dendreon?

The vendor has been very good on financial reimbursements for travel expenses, and I am not expecting any problems with that.

I had been hoping to leverage the abscopal effect with Provenge #2 right before today's start of SBRT #1 of 5 and Provenge #3 of 3 right after SBRT #5 of 5.

There is no consensus on best timing for abscopal effect. So I gave it my best shot with new schedule

I am rescheduling the SBRT #2-5 to get them closer to my new Provenge #2 on Oct 17-20.

Dr King was OK with this revised timing:

Mon OCt 6 SBRT #1 @ 1:45 PM as scheduled

Fri OCt 10 SBRT #2 @ 1:45 PM

Mon OCt 13 SBRT #3 @ 1:45 PM (will also attend my mentor Tall Allen's suport group meeting that night)

Fri Oct 17 SBRT #4 @ 2:30 PM and Provenge cell collection #2 in Van Nuys (would have been #3)

Mon OCt 20 SBRT #5 @ 2:30 PM, and Provenge Infusion earlier that day (Would have been #3 which is now Oct 31-Nov 3)

Dr King at UCLA also said the very low bowel dosage was because of a perfect storm of optimal anatomy and visceral fat and that I should have no long term issues from that.

The first fraction took 30 minutes and included 4 rotations of the RapidArc equipment with 8 Gy to postate and 5 Gy to the pelvic lymph nodes at a summary level with a much more discrete plan for the radiation techs.

So far no ill effects but it has only been 12 hours.

LupronJim

Thanks, Hopeneverdies.

Here's another article on the abscopal effect by Dr Scholz

prostate-cancer.org/abscopal-effect/

You are right, in overall scheme of things the Dendreon Mfg error is just a bump in the road.

I was able to reschedule my SBRT from Mon-Wed-Fri-Mon-Wed starting Oct 6 to spread it out such that the last two SBRT's wee coincident with the Provenge #2 redo by doing Mon-Fri-Mon-Fri-Mon Oct 20.

So SBRT #4 was a week ago Friday Oct 17 the afternoon after my morning Lukapharesis and SBRT #5 was last Monday Oct 20 the afternoon after my successful morning Infusion.

No one is quite sure exactly what timing makes most sense, so I was happy with the revised timing.

In fact at the end of the Scholz article I linked is the mention of a clinical trial in AZ by Dr. Steve Fnkelstein. It's not an identical case as the trial deals with spot radiaiton and C-11 Acetate scans after Provenge but I called him. They are doing the Provenge two weeks after the SBRT which is what my Provenge #3 of 3 ends up being after the reschedule.

So far minimal side effects, some occasional urgency so wearing a pad as insurance that generally stays clean all day, but better dafe than sorry.

The SBRT itself was a breeze, 5 fractions @ 8 Gy each so a total of 40 Gy which is only half of the 79 - 81 Gy IMRT total. So in theory which I hope never becomes necessary, while IMRT offers no redo's to same area, with SBRT I can get a second bite of the apple.

Dr Chris King at UCLA was able to keep to dosage to the rectum very low due to favorable anatomy and visceral fat.

I go from FL back to LAX next weekend and wrap up the Provenge treatmemts. Still working with Dendreon to get the trip expenses reimbursed since they are due to the Dendreon Mfg error.

The Patient Access Netrowk foundation has been great and has already granted two $2,500 grants to offset my prior three weekend trips.

LupronJim

Recently I read interesting scientific article from Yale Journal of Biology and Medicine

"Yale J Biol Med. Dec 2014; 87(4): 481–489.
Published online Dec 12, 2014.
PMCID: PMC4257035
Focus: Vaccines

Anti-Cancer Vaccines — A One-Hit Wonder?

Immunization against common bacterial and viral diseases has helped prevent millions of deaths worldwide. More recently, the concept of vaccination has been developed into a potentially novel strategy to treat and prevent cancer formation, progression, and spread...

To date, the only therapeutic anti-cancer vaccine that has been licensed for use in clinical practice is sipuleucel-T (Provenge), which is used for the treatment of prostate cancer...

The milestone that sipuleucel-T has provided in the timeline of anti-cancer vaccine development should not be underestimated and really provides hope for further therapeutic anti-cancer vaccines making it into clinical practice in the future. With exciting new tools in biomedical research such as next-generation sequencing, more and more potest ntial TSA and TAA candidates are now being identified with anti-cancer vaccines currently in various stages of clinical trials development and testing. Therefore, the question is: Can any of these new developments reach the milestone-setting heights of sipuleucel-T?...

The notion of a vaccine that could be used to treat and offer lifelong protection against cancer has travelled a long path since it was first proposed. Along the way, many obstacles have had to be overcome and while there are still many hurdles in the way, the first few anti-cancer vaccines recently have made their way into clinical practice. Of this small handful, one is a therapeutic vaccine (sipuleucel-T) that is used to treat prostate cancer, whereas the others are preventive vaccines against virus-causing cancers. The licensing and approval of these vaccines has forged the way for other vaccines currently being developed and in various stages of clinical trials testing...

Overall, the state of anti-cancer vaccines looks promising. With a few anti-cancer vaccines currently in clinical practice and several more currently in phase III clinical trials, the future certainly looks bright for the once much-maligned concept. The question however still remains: Has a revolution truly begun or are anti-cancer vaccines just a one-hit wonder?"

www.ncbi.nlm.nih.gov/pmc/articles/PMC4257035/

Up to day we see that there is only one immunotherapy - Provenge and prostate cancer patients have this weapon in their arsenal.

All this "amazing promise" of new cancer immunotherapy (for example checkpoint targeted immunotherapy) is just " amazing promise".

Many of them are still in infancy ( preclinical or In phase I clinical trials in men with measurable metastatic CRPC )and nobody know if they will be successful. It will take maybe 5-20 years to see if it is a real deal.
One of them is Yervoy( ipilimumab)- immune modulator that works by breaking tolerance and stimulating the immune system so that it can recognize and attack the prostate cancer.It fail after chemo, waiting for result before chemo ( sometimes in 2015 ) I think doctors sceptical about its success, even Dr.Wolchok ( one of lead investigator and creator ) thinks Ipilimumab activity would be limited to melanoma, renal cancer ( AACR 2014). Prostvac jast finish enrolment for men in metastatic, castration-resistant prostate cancer (mCRPC) and I think we should see result in about 1-2 years.
I don't hold my breath about Prostvac. Just recently study was published from small trail for men with a rising PSA after first-line therapy. For me it wasn't impressive ( for example increasing the average PSA doubling time by just 2.4 months).

On 10/07/2013 I posted :
"I more convince now it will be no partner for selling drug, it will be ''dirty" buy out or company will be driven to bankruptcy. It will be miracle if Dendrion will stay independent.
What will happened: or Provenge will become foundation of care for HRPC ( after the biggest robbery buy out in history ) or it will be put on the shelf like Bexxar therapeutic for lymphoma, by GlaxoSmithKline."

www.healingwell.com/community/default.aspx?f=35&m=2487796&p=9

As we see my prediction is happened and now we will see how it will develop in future.

If you want to know how often business is done in biopharmaceutical industry I recommend to read :
" The Empire of Edge
How a doctor, a trader, and the billionaire Steven A. Cohen got entangled in a vast financial scandal.
By Patrick Radden Keefe"

www.newyorker.com/magazine/2014/10/13/empire-edge

And of course don't forget to read ( if you didn't read yet) :

" Michael Milken, 60,000 Deaths, and the Story of Dendreon " ( then you can undestant why was so much negativity about Provenge)

/www.deepcapture.com/wp-content/uploads/story-of-dendreon.pdf

I am optimistic and believe early or late justice will be serve for those who work so hard to bring this company down and try to deprive patients from Provenge.

But back to Provenge, just remember:

-- Provenge treatment effect appeared greater with decreasing baseline PSA:
</=22 PSA - median survival ( OS)- 13 months; the OS hazard ratio- 0.51; Not 4.1 months, but 13 months at the median or better[ (IMPACT trail data )
Estimated 3-year survival in the lowest PSA quartile was 62.6 % for Provenge patients and 41.6 % for control group, representing a 50 % relative increase;

- crossover effect:64 % from placebo group choose frozen Provenge, adjusted model showed almost 8 months OS without crossover;( impact trial data );

-THE IMMUNE RESPONSE FROM PROVENGE CONTINUES WELL BEYOND THE DATE OF infusion and supports our understanding of how PROVENGE works over time.( Protect trial data);

- treatment with Provenge results in a humoral antigen spread that correlates with improved outcomes. In the antigen spread process, following treatment induced cell lysis, the immune response broadens overtime resulting in the activation of multiple cancer-related antigens, which extends the immune response.Provenge treatment resulted in humoral antigen spread that was associated with improved OS ( IMPACT trial data) ;

- tumor biology rules: the faster growing tumors will lead to reduced survival. immunotherapy may slow the tumor growth rate over time;

- Provenge alters trajectory of PSA and significantly prolongs PSADT in HRPC and works by altering disease velocity;

-- screen for metastasis with Na/F scan ( if possible);


Merry Christmas , Happy holidays and Happy New Year !

My best Hope

Every time I see Hopeneverdies spend so much time keeping us current on Provenge I feel obligated to give an update.

Of course there is no cotrol group to prove whether the abscopal effect is working for me or not, but so far with SBRT ended 10-20-14 and Provenge ended 11-02-14, still no side effects.

Initial PSA was <0.01 and latest one was =0.01.

Since PSA has never been a very reliable indicator for me, my medical oncologist Jeffrey Turner in Marina del Rey CA and I agreed to monitor nadir +1 rather than nadir +2 and do a new round of scans if or when it eventually gets to PSA >1.

My hope for moment is that PSA remains low until 9 months after I re-started Zytiga on 8-26-14 and I can begin IHT to redscover a libido.

Trusitng that the Provenge will prolong any PSA increases and make the SBRT, Zytiga and Lupron more effective.

LupronJim

Hope - This is the first time I recall seeing this statement: " it really has to be used for bone-only mCRPC".

That makes it sound like Xofigo in that it only works for bony mets not for LN involvement.

In my case I was originally misdiagnosed by rural Florida imaging firm with bony mets but F18 Sodium by Dr Fabio Almeida proved I never had bony mets and C-11 Acetate showed I did have 3 micro LN's all contained in pelvic area.

If the above statement is valid, I guess it can't hurt but may not have helped unless the abscopal effect comes into play on bone mets too small to show up on scans, or bone mets in path of the SBRT also not visible on scans.

My PSA post the final SBRT fraction on 10-20-14 and the final Provenge on 11-03-14 remains undetectible and if that contnues until I have been on Zytiga for 9 months, I will begin IHT on Memorial Day 2015.

Thanks for all the research you do and share on Provenge.

LupronJim