Janssen-Biotech has submitted a new drug application to the Food and Drug Administration (FDA) for apalutamide (ARN-509) to treat non-metastatic hormone-resistant prostate cancer. Apalutamide is an oral androgen receptor inhibitor that blocks the action of testosterone in prostate cancer cells. (Whether ARN-509 differs in its mechanism of action from enzalutamide [Xtandi] is not known to this website at this point.) The drug had been tested in the Phase 3 SPARTAN clinical trial in men with non-metastatic hormone-resistant cancer who have a rapidly rising prostate specific antigen (PSA), despite receiving continuous androgen deprivation (hormone) therapy (ADT). The primary objective of the trial was to assess metastasis-free survival, or the time from randomization to first evidence of confirmed metastasis (the spread of cancer cells to another part of the body). Janssen revealed that patients receiving ADT plus apalutamide lived significantly longer without metastasis, compared to those receiving ADT plus a placebo. But the company did not disclose any further details. The hope is to treat men with prostate cancer earlier in the disease course before the cancer has metastasized.
Studies have estimated that between 10 and 20 percent of patients diagnosed with prostate cancer might develop the hormone-resistant form within about five years. Moreover, metastatic hormone-resistant prostate cancer is associated with deterioration in quality of life and few therapeutic options. For details about the FDA approval process, see the following link.
In December 2016, when I first embarked on my latest course of prostate cancer treatments, it seemed logical to me to treat the cancer first by stimulating my immune system; therefore, Provenge® (sipuleucel-T) was my first choice. That course of three treatments were administered quite readily. Immediately after receiving Provenge®, I was unexpectedly made aware (from a former NCI colleague as I may have written in an earlier blog), of the National Cancer Institute (NCI) clinical trial in which I am currently participating wherein I receive the vaccine Prostvac and the monoclonal antibody therapy nivolumab (Opdivo®). Nivolumab, an immune checkpoint inhibitor, is already approved for the treatment of several other cancers, including melanoma, bladder cancer, head and neck cancer, and Hodgkin’s lymphoma. Laboratory studies have shown that immune cells found within tumors often overexpress (over-produce) the protein PD-1 which is targeted by nivolumab, and which prevents those immune cells from recognizing and attacking the cancer cells. (For more information on how nivolumab works, see the May 15th, 2017 post.) So at this point, I am fully engaged in the NCI biweekly trial.
As a Christian, I continuously seek God’s plan for all aspects of my life certainly including my now 22-year old battle with prostate cancer. God and Jesus (in that still small voice) have reinforced the message to me on several occasions that they are very much involved in my disease and treatment which I have previously described on this website. But I am human; doubt and lack of faith in God’s Word and His promises periodically creep in. I generally start each morning by spending twenty minutes or so reading Bible passages as cited in 2-3 daily devotional books. A few days ago, as I was quietly meditating and praying, I asked God “am I really on the right track here with this trial or am I just deluding myself? Is this really part of Your plan for me?” Many clinical trials don’t work out as positively as researchers had hoped they would. In many trials, only a small subset of patients experience positive results. I thought “could I be engaging in wishful-thinking, that this trial would be overall successful and that Prostvac and Opdivo® would retard my cancer specifically? After all, I had been involved in biomedical research at NCI for over fifteen years before retirement, therefore this trial has an excellent chance of success right? Is this really where you want me at this time, Lord?” From my heart, I asked God to show me if I am following the right therapeutic path or not.
After pleading my case to God and embarking on the day, I immediately checked my e mails and, there again was a totally unexpected article from the National Cancer Institute. The October 23rd NCI article stated that “on September 22, the Food and Drug Administration (FDA) granted accelerated approval to the immunotherapy drug nivolumab (Opdivo®) for some patients with advanced liver cancer (hepatocellular carcinoma).” This is in addition to the cancer types in which nivolumab had already produced some positive responses and in the current trial, it is being paired with a specific prostate cancer vaccine. The message I perceived was that God was telling me again to stay the course, “you are where I want you to be.” Do I believe I will be cured? Physicians say no, but God is certainly able to heal me if it is His will. Whatever the case, I will be content and fully trust in His overall game-plan. I have nowhere else to go for such divine wisdom, love and care. Periodically, as I have needed and asked for, God has given me these confirmatory signposts as I travel this journey. I believe this was another such marker. If you are not sure if you have a personal relationship with God in your life, see the following section. (To be continued).
For men with metastatic, hormone-resistant prostate cancer, treatment with Taxotere (docetaxel) and prednisone has been shown to improve survival. But few treatment strategies are available if this first-line therapy fails. Second-line therapy of anti-cancer agent Jevtana with the steroid medicine prednisone is currently used, with favorable data reported in 2010. However, new options are still needed to improve patients’ survival.
In the international AFFINITY trial, researchers assessed whether adding custirsen to Jevtana after failure with first-line Taxotere would improve survival in the overall patient group and within subgroups with poor-prognosis. Recent results from the AFFINITY Phase 3 trial shows that combining custirsen (OGX-011) with Jevtana (cabazitaxel) and prednisone does not improve survival of metastatic hormone-resistant prostate cancer (PC) patients who progressed after prior Taxotere (docetaxel) treatment.
Custirsen inhibits the production of clusterin, a stress-induced glycoprotein (a protein with a carbohydrate attached to it) that prevents cell death. Levels of clusterin are increased in some forms of cancer, including prostate cancer. Importantly, clusterin has been associated with treatment resistance.
Therefore, in light of the results above, treatment with Jevtana and prednisone “remains the standard of care for patients with metastatic hormone-resistant prostate cancer progressing after Taxotere chemotherapy. For details see the following link.
Patients with low-to-intermediate prostate cancer who receive low-dose permanent brachytherapy, a type of radiation therapy, have excellent outcomes in the long run, according to data recently presented at the American Society for Radiation Oncology (ASTRO) 2017 Annual Conference. At nine years of follow-up, only a minority — 11-14 percent — of patients treated with either iodine-125 (I-125) or cesium-131 (Cs-131) brachytherapy had seen their cancer return, as assessed by a rise in PSA levels.
Brachytherapy is a relatively new cancer treatment that implants small radioactive seeds directly into a patient’s tumor. This ensures that radiation is delivered specifically to a cancer site while sparing healthy surrounding tissues. The seeds used in brachytherapy may be composed of diverse radioactive compounds. Cesium-131 seeds, in particular, have unique attributes that are seen to shorten treatment time and reduce common prostate side effects.
Results published in The International Journal of Radiation Oncology, Biology and Physics in August 2017 showed that patients treated with cesium-131 seeds have shorter recuperation periods, recovering their urinary, bowel, and sexual functions quicker than with other brachytherapy solutions. Iodine-125 seeds are also being used. Results found that the relapse-free survival rate was similar in both groups: 89% in the I-125 arm and 86% in the Cs-131 arm.
Together with the prior data, the findings support the use of low-dose permanent brachytherapy as a viable therapeutic option for localized and lower-risk prostate cancer patients.
As described in recent website blogs, utilizing one’s immune system to combat cancer (immunotherapy) is at the cutting edge of prostate cancer research and cancer research in general. I am personally familiar with an on-going National Cancer Institute (NCI) clinical trial combining the prostate cancer vaccine Prostvac and the checkpoint inhibitor antibody Opdivo® (nivolumab), currently approved by the FDA for the treatment of non-small cell lung cancer. On October 12th, it was reported that the National Institutes of Health (NIH), the nation’s medical research agency announced a partnership with eleven leading biopharmaceutical companies to accelerate the development of new cancer immunotherapy strategies. This Partnership for Accelerating Cancer Therapies (PACT), a five-year public-private research collaboration totaling $215 million is part of the Cancer Moonshot. PACT will initially focus on efforts to identify, develop and validate robust biomarkers — standardized biological markers of disease and treatment response — to advance new immunotherapy treatments that harness the immune system to attack cancer.
NIH, the nation’s medical research agency, includes 27 Institutes and Centers of which the National Cancer Institute (NCI) is the largest. NIH is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.
New immunotherapies have resulted in dramatic responses in certain cancer cases. They have also been the focus of intense investment by biopharmaceutical companies seeking to provide new options for patients who do not respond to other cancer therapies, but they don’t work for all patients. Development and standardization of biomarkers to understand how immunotherapies work in some patients, and predict their response to treatment, are urgently needed for these therapies to provide benefit to the maximum number of people.
The biopharmaceutical companies are expected to contribute $55 million over the five years while NIH will contribute $160 million. For more information and for the companies involved, see the following link. For more information about NIH and its programs, visit www.nih.gov
An independent Data Monitoring Committee (DMC) recommended that the Phase 3 PROSPECT study of Prostvac in men with metastatic hormone-resistant prostate cancer (mCRPC) should be discontinued due to inadequate results. Prostvac did not improve overall survival. The PROSPECT trial (NCT01322490) was a randomized, double-blind, and placebo-controlled Phase 3 trial that included 1,298 mCRPC patients from 200 sites in 15 countries. These men had minimal or no symptoms associated with their mCRPC. The trial evaluated whether Prostvac, alone or in combination with granulocyte macrophage colony-stimulating factor (GM-CSF), could improve overall survival compared to a placebo. GM-CSF is a cytokine or signaling molecule that can also stimulate the immune system. It stimulates the production of granulocytes and monocytes, two types of cells in the immune system that are important for fighting infections.
Previous studies evaluating more than 2,000 participants suggested that Prostvac immunotherapy was well-tolerated. In a Phase 2 trial, this immunotherapy showed potential in prolonging survival in men with advanced prostate cancer. However, the interim analysis for the Phase 3 PROSPECT trial suggested that Prostvac may not be as effective as hoped. It is hoped that combination therapies including Prostvac may be more effective. Copenhagen, Denmark-based Bavarian Nordic’s hopes of salvaging Prostvac now rest on whether it can boost the effect of other immuno-oncology agents, notably Bristol-Myers’ PD-1 and CTLA-4 checkpoint inhibitors Opdivo and Yervoy. Publicly, Bavarian Nordic has not given up hope that the cancer vaccine can complement these drugs. For further details, see the Sept. 15th FierceBiotech article and Sept. 21st Prostate Cancer News Today.
Prostvac had been in late stage Phase III development (PROSPECT trial) for metastatic, hormone-resistant prostate cancer patients who are either asymptomatic or minimally symptomatic. It is a therapeutic pox virus cancer vaccine directed at PSA-producing cells. It is administered with or without GM-CSF (granulocyte macrophage colony-stimulating factor, a protein secreted by immune system cells that functions as a white blood cell growth factor. Prostvac immunotherapy (administered by s.c. injections) is intended to trigger a specific and targeted immune response against prostate cancer cells and tissue by using virus-based immunotherapies that carry the tumor-associated antigen PSA (prostate-specific antigen) along with 3 natural human immune-enhancing costimulatory molecules collectively designated as TRICOM (LFA-3, ICAM-1, and B7.1 When PSA-TRICOM is presented to the immune system in Prostvac, cytotoxic T lymphocytes (CTLs) are generated that may recognize and kill PSA-expressing cancer cells.
This website has been covering Prostvac development for several years. See blogs posted August 5th, 2014 and May 15th, 2017 among others.
Editorial note: I am writing some of this post while awaiting Hurricane Irma to pass my home directly in about 1-2 hours.
Opdivo® (nivolumab) and the prostate cancer vaccine Prostvac are being combined in a National Cancer Institute clinical trial described in posts on this website dated May 15th and August 7th, 2017. Bristol Myers Squibb and Clovis Technology will collaborate to assess the combination of Opdivo® (nivolumab) and the PARP inhibitor, Rubraca (rucaparib) in Phase 2 and 3 clinical studies in patients with different cancer types, including prostate cancer.
The companies plan to launch a Phase 2 study to investigate the safety and effectiveness of the combination treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). All studies are expected to begin before the end of 2017.
“We are very enthusiastic about studying Rubraca and Opdivo® in combination, and the potential to create new treatment options for patients with multiple tumor types, as well as for patients beyond those with BRCA mutations,” according to Patrick J. Mahaffy, Clovis Oncology’s president and CEO. “This substantial clinical collaboration in ovarian, triple-negative breast and prostate cancers represents a significant effort by Clovis and Bristol-Myers Squibb to realize that potential,” he said.
Cancer cells are constantly multiplying, but the division process is sometimes associated with errors that may cause their death, such as DNA breaks. If cancer cells repair these breaks, they survive and keep multiplying.
Rubraca is an oral inhibitor of PARP proteins (PARP-1, PARP-2, and PARP-3), which are involved in DNA repair. By inhibiting these proteins, Rubraca prevents cancer cells to repair their DNA. Indeed, previous studies have shown that PARP inhibition promotes inflammation, cell death, and increases the action of T-cells within tumors.
Opdivo® acts upon a protein called programmed cell death-1 (PD-1), which inhibits the immune system’s ability to detect cancer cells. By inhibiting PD-1, Opdivo® restores the body’s capacity to activate the anti-tumor response and fight cancer cells. Because of its potential role as an enhancer of the immune system’s response, Opdivo® is under evaluation in a broad range of clinical trials across all phases in a variety of tumor types. For more information, see the following.
Additional results involving Opdivo® include an article published September 11th in MedlinePlus describing research suggesting that Opdivo® — a drug that works with the immune system to fight melanoma — is more effective than the current standard of care for patients who’ve had surgery to remove advanced tumors. In addition, an August 17th post from the National Cancer Institute Current Contents stated that the Food and Drug Administration has approved Opdivo® for patients with metastatic colorectal cancer that has one of two specific genetic features and whose disease has progressed after chemotherapy.
I have been on a vacation but am now resuming publishing pertinent posts.
As has been written before, several potential side effects accompany hormonal therapy for prostate cancer. A MedlinePlus e mail received today from the National Institutes of Health (NIH) National Library of Medicine discussed the potential heart risk posed by early hormone suppression treatment of prostate cancer. The take-home message from a new study is that “patients with localized prostate cancer should be followed to minimize the health effects of androgen-deprivation therapy on the cardiovascular system,” said study author Reina Haque, a researcher with the Kaiser Permanente Southern California Department of Research & Evaluation. The advice given is that “patients should consider heart-healthy lifestyle changes, and physicians should actively monitor the patient’s health for early signs of heart disease.”
In recent years, there’s been an expansion in use of hormone-suppressing treatment for prostate cancer. The treatment was previously restricted to advanced prostate tumors, but now it’s being given to a growing number of men with early stage prostate cancer that has not spread to other parts of the body. However, the safety and effectiveness of androgen-deprivation therapy for these men hasn’t been investigated, the study authors said.
In the new study, researchers assessed outcomes for more than 7,600 men with early stage prostate cancer. The investigators tracked the men for up to 12 years, starting when they were diagnosed between 1998 and 2008. The researchers factored in certain heart risk factors — things such as overweight/obesity, history of smoking, diabetes, high blood pressure or if they required heart medications. The study found the men with early stage prostate cancer who did not already have heart disease, but who received hormone-depleting treatments had an 81 percent higher risk for heart failure. Meanwhile, those who already had heart disease when they received the anti-hormone treatment also had a greater risk for heart rhythm problems, including a 44 percent increased risk of an irregular heartbeat. These men were also three times more likely to develop “conduction disorder,” which occurs when electrical impulses to the heart are interrupted.
The findings allow men with localized prostate cancer to consider the positive and negative effects of androgen-deprivation therapy and discuss it with their physicians. “If they move forward with the therapy, patients should work with their physicians to adjust their lifestyle to reduce the risk of cardiovascular disease.”
On May 15th, this website posted information about a Phase 1-2 clinical trial sponsored by the National Cancer Institute (NCI) of the National Institutes of Health (NIH). The proposed therapeutic regimen initially consisted of the NCI vaccine Prostvac, and two antibodies, ipilimumab (Yervoy®) and nivolumab (Opdivo®). However, toxic events recently surfaced in the use of ipilimumab in several patients necessitating its removal from this particular NCI trial. In addition, a website post dated April 11th, 2017 cited the lack of activity of ipilimumab as a sole agent in prostate cancer clinical trials. However, it was proposed that ipilimumab might be more useful in combination immunotherapy.
The Food and Drug Administration (FDA) has cleared a cooling cap—a device designed to reduce hair loss during chemotherapy—for use by patients with any kind of solid tumor. FDA initially cleared the device, the DigniCap® Scalp Cooling System, for patients with breast cancer in 2015. The expanded clearance of DigniCap is for “reducing the frequency and severity of hair loss” in adult patients with solid tumors who are receiving chemotherapy types and doses that are associated with this common side effect.
Scalp cooling, which has been used in Europe for several decades, is thought to prevent hair loss by reducing blood flow to hair follicles. Cooling the scalp causes blood vessels to constrict, which may limit the amount of chemotherapy drug that reaches hair follicles.
The DigniCap system uses a tightly fitted cap in which cold liquid circulates to cool the scalp before, during, and after chemotherapy. This cap, which is connected to a machine that regulates the cooling process, is covered by an outer cap, made of neoprene, that acts as an insulator.
The average total cost of scalp cooling ranges between $1,500 and $3,000 per patient, depending on the number of cycles of chemotherapy. Insurance does not currently cover scalp cooling treatments, according to the maker of DigniCap, Dignitana Inc., of Sweden.
For the full article, see the following link published by the National Cancer Institute.
