Taking one-fourth the standard dose of a widely used drug for prostate cancer with a low-fat breakfast can be as effective – and four times less expensive – as taking the standard dose as recommended: on an empty stomach.
The study, a multi-center, randomized, phase-II clinical trial to be presented at ASCO’s 2017 Genitourinary Cancers Symposium in Orlando, FL, found that the 36 patients who took 250 milligrams of the drug with a low-fat breakfast had outcomes that were virtually identical to the 36 patients who took the standard dose, 1,000 milligrams of the drug on an empty stomach.
The finding has significant financial implications. The drug, abiraterone acetate – marketed as ZYTIGA® – now retails for more than $9,000 per month. Even patients with blue-ribbon health insurance can have co-pays ranging from $1,000 to $3,000 per month.
Patients taking abiraterone acetate typically stay on the medication for 12 to 18 months. Since 2011, according to the manufacturer’s website, more than 100,000 patients in the United States alone have filled prescriptions for abiraterone.
If each of those 100,000 patients had taken the drug for 12 months and, theoretically, paid the list price out of pocket but took the lower dose with food, the 75-percent cost reduction could have saved them more than $6 billion.
Seventy-two patients from multiple centers in the United States and Singapore participated in the study. Patients aged 52 to 89 years (median 74) with advanced prostate cancer whose disease had progressed despite standard initial hormonal therapy, were randomly assigned to take the standard dose on an empty stomach or the low dose with breakfast.
The primary objective of the study was to compare the change in blood levels of prostate specific antigen (PSA), a measure of disease burden and progression. Despite a 75-percent difference in dose, there was no difference in abiraterone activity as measured by variation in PSA levels between the two groups of patients. The time to disease progression also was nearly identical for both arms of the study, about 14 months.
Patients who took the drug with food appeared to have an additional benefit. They were less likely to complain about stomach discomfort than those who took the drug as recommended. The drug’s label recommends fasting for 2 hours before and 1 hour after swallowing the medication. Taking the medication with breakfast is therefore logistically easier for patients.
“We know this drug is absorbed much more efficiently when taken with food,” said study director Russell Szmulewitz, MD, assistant professor of medicine at the University of Chicago and a specialist in medical treatment of patients with advanced prostate cancer. “It’s inefficient, even wasteful, to take this medicine while fasting, which is how the drug’s label says to take it.”
“Given the pharmaco-economic implications,” he added, “our results warrant consideration by doctors who care for prostate cancer patients as well as payers.”
Many drugs taken by mouth have a “food effect,” which can alter how the drug is absorbed. Abiraterone has one of the most dramatic food effects. Blood levels of the drug can be up to 17 times higher when taken with a high-fat meal. Taking the drug with a low-fat meal is more predictable. It increases blood levels four to seven fold.
“This is a widely prescribed drug, a mainstay for patients with prostate cancer,” Szmulewitz said. “It is a great medication that has shifted the standard of care.”
Patients with early stage prostate cancer patients are usually treated initially with hormone therapy, drugs that disrupt the production of male hormones such as testosterone, which promotes tumor growth. This can slow or halt progression of the disease.
Over time, however, cancer cells adapt. They develop the ability to grow and spread without relying on hormones, a stage known as castration-resistant prostate cancer. Historically, those patients were treated with chemotherapy, which can have significant side effects.
Abiraterone, approved for treatment of metastatic prostate cancer in April, 2011, added a new layer to the sequence. It “sits between hormone therapy and chemotherapy,” Szmulewitz explained. “It delays disease progression, improves survival and delays deterioration of quality of life.” When its effects diminish, they shift to a similar, competing drug or move on to chemotherapy.
Patients who take abiraterone for prostate cancer should not “conduct such experiments on their own,” Szmulewitz warned. “This was a relatively small study, too small to show with confidence that the lower dose is as effective. It gives us preliminary but far from definitive evidence. Physicians should use their discretion, based on patient needs.”
The study shows that patients with genuine concerns about costs could, with careful guidance and regular follow-up from their doctors, consider the smaller dose taken with a low-fat breakfast. This would enable them to spread the cost of one month’s of pills over four months, a per-patient savings of up to $7,500 each month.
The American Cancer Society estimates that 161,360 men will be diagnosed with prostate cancer in 2017 and 26,730 men will die from the disease. “If we could reduce the cost of medication for this stage of the disease by a few thousand dollars each month simply by having patients take it with food,” Szmulewitz said, “that would be significant.”
In the featured article from the February 2017 issue of The Journal of Nuclear Medicine, researchers document the first-in-human application of a new imaging agent to help find prostate cancer in both early and advanced stages and plan treatment. The study indicates that the new agent—a PET radiotracer—is both safe and effective.
The new agent is a gallium-68 (Ga-68)-labeled peptide BBN-RGD agent that targets both gastrin-releasing peptide receptor (GRPR) and integrin ?v?3. Dual-receptor targeting provides advantages over single-receptor targeting by allowing tumor contrast when either or both receptor types are expressed, improving binding affinity and increasing the number of effective receptors.
Approximately one in seven men will be diagnosed with prostate cancer in his lifetime. In 2017, the American Cancer Society estimates that there will be more than 161,000 new prostate cancer cases in the United States and around 27,000 deaths from the disease. “Although treatable at the early stage, prostate cancer is prone to metastasis,” explain the team of authors, led by Xiaoyuan Chen, senior investigator, Laboratory of Molecular Imaging and Nanomedicine at the U.S. National Institute of Biomedical Imaging and Bioengineering. “An effective and specific imaging method of detecting both primary and metastatic lesions is thus of critical importance to manage patients with prostate cancer.”
This study included 13 patients with prostate cancer (four newly diagnosed and nine post-therapy) and five healthy volunteers. Ga-68-BBN-RGD PET/CT detected 20 bone lesions in seven patients either with primary prostate cancer or after radical prostatectomy. The patients with bone metastases did not necessarily have an elevated prostate specific antigen level. “This result is better than bone scanning with MDP,” Chen notes, referring to the most common radiotracer used today. “MDP bone scans are sensitive but lack specificity because localized skeletal accumulation of Tc-99m-MDP can also be observed in the case of trauma and infection.” No adverse side effects were found during the whole procedure and two-week follow-up, demonstrating the safety of Ga-68-BBN-RGD.
“Compounds capable of targeting more than one biomarker have the ability of binding to both early and metastatic stages of prostate cancer, creating the possibility for a more prompt and accurate diagnostic profile for both primary and the metastatic tumors,” explains Chen.
Looking ahead, Chen says, “Ga-68-BBN-RGD could play an additive role in staging and detecting prostate cancer and provide guidance for internal radiation therapy using the same peptide labeled with therapeutic radionuclides.” He points out that larger-scale clinical investigations are warranted.
A new non-surgical treatment for low-risk prostate cancer can effectively kill cancer cells while preserving healthy tissue, reports a new UCL-led phase III clinical trial in 413 patients.
The trial was funded by STEBA Biotech which holds the commercial license for the treatment.
The new treatment, ‘vascular-targeted photodynamic therapy’ (VTP), involves injecting a light-sensitive drug into the bloodstream and then activating it with a laser to destroy tumour tissue in the prostate. The research, published in The Lancet Oncology, found that around half (49%) of patients treated with VTP went into complete remission compared with 13.5% in the control group.
“These results are excellent news for men with early localised prostate cancer, offering a treatment that can kill cancer without removing or destroying the prostate,” says lead investigator Professor Mark Emberton, Dean of UCL Medical Sciences and Consultant Urologist at UCLH. “This is truly a huge leap forward for prostate cancer treatment, which has previously lagged decades behind other solid cancers such as breast cancer. In 1975 almost everyone with breast cancer was given a radical mastectomy, but since then treatments have steady improved and we now rarely need to remove the whole breast. In prostate cancer we are still commonly removing or irradiating the whole prostate, so the success of this new tissue-preserving treatment is welcome news indeed.”
At the moment, men with low-risk prostate cancer are put under ‘active surveillance’ where the disease is monitored and only treated when it becomes more severe. Radical therapy, which involves surgically removing or irradiating the whole prostate, has significant long-term side effects so is only used to treat high-risk cancers.
Radical therapy causes lifelong erectile problems and around one in five patients also suffer from incontinence. By contrast, VTP only caused short-term urinary and erectile problems which resolved within three months, and no significant side-effects remained after two years.
In the trial only 6% of patients treated with VTP needed radical therapy compared with 30% of patients in the control arm who were under active surveillance. The chances of cancer progressing to a more dangerous stage were three times lower for patients on VTP, and the treatment doubled the average time to progression from 14 months to 28 months.
The trial involved 47 treatment sites from ten different European countries, most of which were performing VTP for the first time.
“The fact that the treatment was performed so successfully by non-specialist centres in various health systems is really remarkable,” says Professor Emberton, who is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. “New procedures are generally associated with a learning curve, but the lack of complications in the trial suggests that the treatment protocol is safe, efficient and relatively easy to scale up. We would also expect the treatment to be far more precise if we repeated it today, as technology has come a long way since the study began in 2011.
“We can now pinpoint prostate cancers using MRI scans and targeted biopsies, allowing a much more targeted approach to diagnosis and treatment. This means we could accurately identify men who would benefit from VTP and deliver treatment more precisely to the tumour. With such an approach we should be able to achieve a significantly higher remission rate than in the trial and send nearly all low-risk localised prostate cancers into remission. We also hope that VTP will be effective against other types of cancer – the treatment was developed for prostate cancer because of the urgent need for new therapies, but it should be translatable to other solid cancers including breast and liver cancer.”
The VTP therapy approach was developed by scientists at the Weizmann Institute of Science in Israel in collaboration with STEBA Biotech, and the European phase I, II and III trials were all led by UCL. The drug used in the procedure, WST11, is derived from bacteria at the bottom of the ocean. To survive with very little sunlight, they have evolved to convert light into energy with incredible efficiency. This property has been exploited to develop WST11, a compound that releases free radicals to kill surrounding cells when activated by laser light.
One of the first people to be treated with VTP was UCLH patient Gerald, a man in his sixties who took part in the latest trial under the care of Professor Emberton. He says:
“When I was diagnosed with early prostate cancer, I had the option of active surveillance but I didn’t want to wait until it got worse so when I was offered a place on the trial I signed up straight away. Some men prefer to delay treatment, but I couldn’t live with the fear of the cancer spreading until it either couldn’t be treated or needed a treatment that would stop me living a normal life.
“The treatment I received on the trial changed my life. I’m now cancer-free with no side-effects and don’t have to worry about needing surgery in future. I feel so lucky to be in this position. I’ve met other men who had surgery – they had to stay in hospital for days whereas I could go home the next day, and one suffered from terrible incontinence which he found very distressing. I had some minor side-effects for a few weeks after the operation, but I’m back to normal now. I am incredibly grateful to Professor Mark Emberton and his team for the excellent care that I received, and I hope that other patients will be able to benefit from this treatment in future.”
The VTP treatment is currently being reviewed by the European Medicines Agency (EMA), so it is likely to be a number of years before it can be offered to patients more widely.
Oral administration of nimbolide, over 12 weeks shows reduction of prostate tumour size by up to 70 per cent and decrease in tumour metastasis by up to 50 per cent
A team of international researchers led by Associate Professor Gautam Sethi from the Department of Pharmacology at the Yong Loo Lin School of Medicine at the National University of Singapore (NUS) has found that nimbolide, a bioactive terpenoid compound derived from Azadirachta indica or more commonly known as the neem plant, could reduce the size of prostate tumour by up to 70 per cent and suppress its spread or metastasis by half.
Prostate cancer is one of the most commonly diagnosed cancers worldwide. However, currently available therapies for metastatic prostate cancer are only marginally effective. Hence, there is a need for more novel treatment alternatives and options.
“Although the diverse anti-cancer effects of nimbolide have been reported in different cancer types, its potential effects on prostate cancer initiation and progression have not been demonstrated in scientific studies. In this research, we have demonstrated that nimbolide can inhibit tumour cell viability – a cellular process that directly affects the ability of a cell to proliferate, grow, divide, or repair damaged cell components – and induce programmed cell death in prostate cancer cells,” said Assoc Prof Sethi.
Nimbolide: promising effects on prostate cancer
Cell invasion and migration are key steps during tumour metastasis. The NUS-led study revealed that nimbolide can significantly suppress cell invasion and migration of prostate cancer cells, suggesting its ability to reduce tumour metastasis.
The researchers observed that upon the 12 weeks of administering nimbolide, the size of prostate cancer tumour was reduced by as much as 70 per cent and its metastasis decreased by about 50 per cent, without exhibiting any significant adverse effects.
“This is possible because a direct target of nimbolide in prostate cancer is glutathione reductase, an enzyme which is responsible for maintaining the antioxidant system that regulates the STAT3 gene in the body. The activation of the STAT3 gene has been reported to contribute to prostate tumour growth and metastasis,” explained Assoc Prof Sethi. “We have found that nimbolide can substantially inhibit STAT3 activation and thereby abrogating the growth and metastasis of prostate tumour,” he added.
The findings of the study were published in the April 2016 issue of the scientific journal Antioxidants & Redox Signaling. This work was carried out in collaboration with Professor Goh Boon Cher of Cancer Science Institute of Singapore at NUS, Professor Hui Kam Man of National Cancer Centre Singapore and Professor Ahn Kwang Seok of Kyung Hee University.
Neem – The medicinal plant
The neem plant belongs to the mahogany tree family that is originally native to India and the Indian sub-continent, but is now also commonly found in Singapore. It has been part of traditional Asian medicine for centuries and is typically used in Indian Ayurvedic medicine. Today, neem leaves and bark have been incorporated into many personal care products such as soaps, toothpaste, skincare and even dietary supplements. Neem seedlings can also be obtained from the Indian flower shops at Campbell Lane and Buffalo Road areas within Serangoon Road in Singapore.
The team is looking to embark on a genome-wide screening or to perform a large-scale study of proteins to analyse the side-effects and determine other potential molecular targets of nimbolide. They are also keen to investigate the efficacy of combinatory regimen of nimbolide and approved drugs such as docetaxel and enzalutamide for future prostate cancer therapy.