Category: 2018

OncBioMune Pharmaceuticals will soon start a Phase 2 clinical trial of its investigational vaccine ProscaVax in men with early-stage prostate cancer under “active surveillance”. ProscaVax consists of a combination of the PSA protein produced by the prostate gland with the cytokines interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF). [Cytokines are molecules that participate in immune responses.] This will be the first time that prostate patients will be treated with a vaccine rather than waiting for disease progression or being exposed to more invasive treatment options that frequently are accompanied by unpleasant side effects such as incontinence and/or impotence. Scientists will evaluate whether the vaccine leads to a change in prostate cancer progression compared to patients on “active surveillance” in which disease progression is monitored before other strategies such as surgery or radiation therapy are considered. PSA doubling time and adverse effects will also be assessed.

Treatment arm-patients will start with a 4-month induction period, being given six (6) doses of ProscaVax at weeks 1, 2, 3, 7, 11, and 15. This period will be followed by maintenance injections once every month and alternating between low-dose IL-2 alone and the ProscaVax vaccine for six months.

OncBioMune reported results of a Phase 1a/1b study in January, 2018 showing that ProscaVax reduced tumor growth in 70% of recurrent prostate cancer patients after a minimum of 31 weeks of treatment. This result added to previously reported positive safety data. Trial results at 19 weeks of treatment also found that ProscaVax stopped disease progression in 80% of patients.

The single-site trial is expected to finish in August, 2022. It will be conducted at Beth Israel Deaconess Medical Center in Boston, MA and includes the Dana-Farber Cancer Institute. Information about this trial was published in the July 16th, on-line edition of Prostate Cancer News Today to which readers of this website are urged to subscribe.

In catching up on some news from a few months ago, I realized that much had been written recently about treating men with an early stage of advanced  prostate cancer. So here is some information in addition to the following posts; The FDA Approves Apalutamide for Some Men with Prostate Cancer; and  Xtandi Extends Metastasis-Free Survival in Hormone-Resistant Men with Rising PSA according to Phase 3 Study.

Over the course of prostate cancer progression, there can come a time during which the cancer is progressing, but there are no treatments known to improve survival.  One of these “empty spaces” is when men who are being treated with androgen deprivation therapy (ADT) see their PSA levels begin to rise (indicating the cancer has become resistant to ADT and is starting to grow again), but no metastases are visible yet on scans.  This clinical state is termed “non-metastatic hormone-resistant prostate cancer” (non-metastatic CRPC).  Many of these men will ultimately go on to develop metastases and lethal prostate cancer.  Until today, there were no other options and these men often just continued to receive ADT despite its diminishing benefit.

At the 2018 ASCO Genitourinary Cancers Symposium, held February 8-10 in San Francisco, California, results from two randomized phase 3 clinical trials, SPARTAN and PROSPER, may have filled this empty space.  Enzalutmide (Xtandi®) and Apalutamide (Erleada®; ARN-509) are two highly similar hormonal treatments that when added to ADT (or whatever treatments were already being used) were found to significantly delay the onset of metastases and several other measures of cancer progression in men with non-metastatic CRPC.

In the PROSPER trial, investigator Maha Hussain, MD (Northwestern University), tested the addition of enzalutamide vs. placebo in 1,401 non-metastatic CRPC patients who were continuing to receive ADT despite a rapidly rising PSA.  Enzalutamide was found to delay the time to metastatic disease by 22 months on average, compared with placebo.

In the SPARTAN trial, investigator Eric Small, MD (University of California, San Francisco), tested the addition of apalutamide vs. placebo in 1,207 non-metastatic CRPC patients with rapidly rising PSA,  in addition to whatever treatment the men were already receiving (mostly ADT). Apalutamide was found to delay the time to metastatic disease by over 24 months on average.   The full results from the SPARTAN study were simultaneously published in the New England Journal of Medicine.

This could be amazing news for patients with CRPC. “We don’t yet know if either apalutamide or enzalutamide increases the survival duration in these patients, although early indication is in that they will,” said Philip Kantoff, MD, Chairman of the Department of Medicine at Memorial Sloan Kettering Cancer Center, who led the discussion on the trials at the Symposium.  “Patients do need to be aware that these treatments when used early, can cause greater treatment exposure and greater chance for toxicity including a small chance of unexplained death.  Nonetheless these trials may change practice patterns in a major way and provide treatment opportunities for men with no current effective therapies.”

These two treatments are highly similar oral medications, differing chemically by only a single atom.  They have since been separately licensed and developed by different pharmaceutical companies, namely Astellas Pharma (enzalutamide) and Janssen (apalutamide).  Apalutamide is a new medicine, whereas enzalutamide is already FDA-approved for metastatic CRPC.  Both of these treatments are now under review by the FDA for use in non-metastatic CRPC, and decisions – and the change in practice that will accompany an FDA approval — are expected very soon.

For additional information, see the Prostate Cancer Foundation Feb. 28th Newsletter.

I realize this is somewhat old news but I’d like to share it anyway. On February 14, the Food and Drug Administration (FDA) approved apalutamide (Erleada) for men with prostate cancer that has not spread (non-metastatic) and is resistant to standard hormone therapy, also called androgen deprivation therapy (ADT). In the clinical trial that led to its approval, treatment with apalutamide decreased the risk of metastasis or death by more than 70% compared with placebo.

In the phase 3 trial (dubbed SPARTAN) that led to the FDA approval, men with hormone-resistant prostate cancer and no metastatic disease detectable by standard imaging tests were randomly assigned to receive apalutamide or placebo in addition to ongoing ADT. All participants were at high risk of metastasis based on rapidly rising prostate-specific antigen (PSA) levels. The study was sponsored by Janssen Pharmaceutical Companies, the manufacturer of apalutamide.

The median length of time from the start of treatment to when tumors spread (metastasis-free survival) or the patient died was 16 months in the placebo group and 40 months in the apalutamide group. Men treated with apalutamide also went longer without worsening symptoms of cancer progression. Even when their cancer progressed on apalutamide and they went on to receive another therapy, these men had longer time to progression with the subsequent treatment than men in the placebo group. The median length of time patients were alive after the start of treatment (overall survival) was 39 months for those who received placebo and had not been reached at the time of the study analysis for those who received apalutamide. An early analysis suggests that apalutamide may reduce the risk of death from prostate cancer, but longer patient follow-up is needed before the researchers can confirm this.

Apalutamide is the first drug to be approved by FDA based on an improvement in metastasis-free survival. Traditionally, most approvals are based on an improvement in progression-free survival or overall survival.

“These are very dramatic results and, in many ways, exceeded our expectations,” said lead investigator Matthew Smith, M.D., Ph.D., of Massachusetts General Hospital Cancer Center.  “We’re learning that using hormone therapy earlier in men with prostate cancer can delay metastasis and probably improve survival. But the balance of benefits and potential side effects will need to be evaluated on a patient-by-patient basis,” said William Dahut, M.D., head of the Prostate Cancer Clinical Research Section of National Cancer Institute’s Center for Cancer Research (NCI-CCR).

While apalutamide—and, potentially, enzalutamide (Xtandi)—gives men with non-metastatic hormone resistant disease a new treatment option, this patient population may decrease in the future, Dr. Dahut noted. That’s because traditional imaging techniques such as a CAT scan may not be able to detect tiny metastatic tumors, he explained. But a technique being used in research studies called molecular imaging  can catch smaller tumors. If molecular imaging tests become part of clinical care, more men with prostate cancer might be classified as having metastatic disease. “It’s highly likely that apalutamide would be active in men with metastatic hormone-resistant prostate cancer, Dr. Dahut speculated. Trials to evaluate apalutamide in this patient population are already underway, Dr. Smith noted.

For additional information, see the March 8th, 2018 NCI Cancer Currents blog.

Related blogs describing apalutamide were published on this website. See February 16th, 2018 and  November 10th, 2017 posts.

 

Men with nonmetastatic, castration (hormone)-resistant prostate cancer (CRPC) and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. Currently, only one recently approved treatment, Erleada® (apalutamide), is available to these patients. Xtandi®, an androgen receptor inhibitor, is an approved treatment for metastatic CRPC patients. It has been shown to delay disease progression and prolong these patients’ overall survival.  In a recent article published in the June 28th, 2018 issue of the New England Journal of Medicine, researchers hypothesized that enzalutamide (Xtandi®), which prolongs overall survival among patients with metastatic, hormone-resistant prostate cancer, could also delay metastasis in men with nonmetastatic, hormone-resistant prostate cancer and a rapidly rising PSA level. In this double-blind, phase 3 PROSPER trial, asymptomatic men with nonmetastatic, hormone-resistant prostate cancer and a PSA doubling time of 10 months or less and who were continuing androgen-deprivation (hormone) therapy received enzalutamide (at a dose of 160 mg) while men receiving only placebo and standard hormone therapy were randomized in a 2:1 ratio. The primary end point of the study was metastasis-free survival, the length of time a patient lives without cancer spreading or until death from any cause. Secondary goals included extension of the time to PSA progression and to the first use of a subsequent anticancer chemotherapy, patients’ overall survival, and safety.

A total of 1401 patients (median PSA doubling time, 3.7 months) were enrolled. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group. The time to the first use of subsequent chemotherapy was longer with enzalutamide treatment than with placebo (such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months.) At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. So median overall survival had not been reached. However, the researchers noted that more patients receiving the combination therapy died without detectable development of metastasis than was seen in the placebo group. In these patients, no trend regarding the cause of death was found, and only two deaths were considered to be related to Xtandi treatment. The researchers noted that these patients were elderly, with a median age of 80 years in the Xtandi group and 81 years in the placebo group, and they had a high burden of other coexisting conditions. Subsequent follow-up and additional interim analysis are expected to clarify the benefits of Xtandi® in patients’ overall survival in the PROSPER study.

Conclusions from this PROSPER clinical trial indicated that in men receiving the combination therapy the time a patient remained alive and metastasis-free was significantly extended by nearly two years (21.9 months), the time to PSA progression by almost three years (33.3 months), and the time to the first use of chemotherapy by nearly two years (21.9 months), compared to single standard therapy. In men with nonmetastatic, hormone-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, (NCT02003924).

As mentioned above, these findings were recently published (“Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer”) in the New England Journal of Medicine and also summarized in the July 5th Prostate Cancer News Today. (I strongly encourage readers to subscribe to this valuable email resource.)

 

The National Cancer Institute (NCI), the largest institute of the National Institutes of Health (NIH), recently posted a short (3-4 minute) but very illustrative video showing and describing three ways how our immune system fights cancer. These methods include: a) non-specific immune stimulation, as illustrated in bladder cancer; b) T-cell transfer therapy, somewhat similar to how Provenge works against prostate cancer; and, c) immune checkpoint inhibitors, such as Keytruda and Opdivo, currently the subject of many combinatorial clinical trials against several types of cancer including prostate cancer. This video appeared in the July 11th, 2018 e mail edition of Cancer Information Highlights from the National Cancer Institute, nci@updates.cancer.gov to which one can subscribe at www.cancer.gov.

The following is bad news for men in England with advanced prostate cancer. The rationale behind making this drug unavailable to men was cost. If anyone here in the US recommends we switch to the British system of health care, this should serve as a wakeup call against it. The therapy as described in the link below has been approved in the USA on the basis of two major clinical trials.

Janssen’s medication Zytiga (abiraterone) was recently rejected as a first-line treatment for newly diagnosed advanced prostate cancer on the National Health Service (NHS) in England following an initial draft recommendation from the National Institute for Health and Care Excellence (NICE). The negative recommendation means Zytiga won’t be made routinely available for men with newly diagnosed metastatic prostate cancer. As it is recommended now, Zytiga will only be prescribed through the NHS for these men once standard hormone treatment or chemotherapy has failed.

In two recent Phase 3 trials – STAMPEDE and LATITUDE – first-line therapy with Zytiga along with steroids and hormone therapy was found to  reduce the chance of cancer recurrence and improve survival, compared to hormone therapy alone. Patients were all at high risk of their disease spreading, and treated earlier, before their disease become resistant to standard hormone therapy. After three years, 83 percent of patients taking Zytiga, prednisolone, and hormone therapy remained alive, compared to 76 percent in the control arm. Also, the combination reduced the risk of disease worsening or death by 71 percent.

LATITUDE  included men with prostate cancer whose cancer had already spread at the time of diagnosis but who had yet to receive hormone treatment. The LATITUDE trial compared patients treated with standard hormone therapy to those treated with hormone therapy plus Zytiga and the steroid prednisone. The combination reduced the risk of death by 38 percent.

“Two clinical trials published last year provided compelling evidence of the huge potential benefit of abiraterone [Zytiga] for these patients,” Sir Harpal Kumar, chief executive of Cancer Research UK, said in a press release, expressing his disappointment.

NICE highlights its key reasons for not recommending the therapy because it couldn’t accurately estimate the drug’s cost-effectiveness based on the data submitted.  NICE concluded they could only recommend drugs that are clinically effective and show value for money compared to current treatment options. In this case, abiraterone has fallen short.  Janssen can now submit additional data to help NICE resolve these questions and review the revised data later this summer, before a final decision is made.

Following this draft recommendation, the Institute of Cancer Research (ICR) also expressed disappointment that Zytiga will not be made available to these patients as a first-line treatment, at least for now. The ICR is now calling for urgent discussions about the data supporting the drug’s effectiveness earlier in treatment as well as the drug’s price.