Recent advancements in prostate cancer research over the past year

Prostate cancer research

Prostate cancer is the second most commonly occurring cancer in men. More than 1.4 million people were diagnosed with prostate cancer in 2020, according to the World Cancer Research Fund International. While some prostate cancers develop too slowly, to the extent that some people will not need any treatment during their lifetime, some grow very quickly and are likely to spread, according to Prostate Cancer UK.

For those patients who require treatment to prevent the cancer from spreading, current standards of care involve radiotherapy and hormone therapy. In cases where the cancer hasn’t spread beyond the prostate, radical prostatectomy – where the prostate gland is surgically removed – is sometimes recommended. For treating advanced forms of the disease, chemotherapy and steroid tablets – when hormone therapy has stopped working due to treatment resistance – are the go-to forms of treatment.

Over the years, clinical trials, where drug combinations are being tested to potentially cure advanced prostate cancer, have been underway. As we observe Prostate Cancer Awareness Month in September, here are five recent advancements in prostate cancer research over the past year. 

PARP inhibitors: a targeted approach to treating prostate cancer

In recent times, PARP inhibitors have been making headway in treatment research for prostate cancer. These drugs are targeted cancer therapies that halt a group of enzymes known as poly ADP-ribose polymerases (PARP) from repairing the DNA in cancer cells, causing the cells to die.

The U.S. Food and Drug Administration (FDA) approved a new combination drug, which consists of a PARP inhibitor, for the treatment of the most advanced kind of prostate cancer called metastatic castration-resistant prostate cancer (mCRPC).

mCRPC develops at a stage when hormonal therapies, which inhibit testosterone production, stop working. When this occurs, doctors go on to prescribe another class of drugs known as anti-androgens, which are a kind of testosterone blocker. The testosterone hormone feeds the growth of cancer cells, so, curbing its production can slow the development of cancer cells.

One of the drugs that falls under anti-androgens is enzalutamide. In combination with American multinational pharmaceutical Pfizer’s talazoparib – a PARP inhibitor used to treat breast cancer with BRCA mutations – enzalutamide has been successful in trials, which led to the recent FDA approval. The trial had 399 men with mCRPC who were around 70 years of age, separated into a treatment group and placebo group, where in the latter, patients were given enzalutamide with a placebo. These men had previously undergone chemotherapy and other anti-androgen therapy.

It was found that the risk of death declined by 55% with the treatment combination, after a median follow up of nearly one and a half years. Moreover, for those patients who were BRCA-positive, there was an 80% reduction in the progression of the disease.

While the drug combination has been authorized for treating mCRPC, it will not be used to treat other forms of prostate cancer. To add to that, PARP inhibitors tend to cause some serious side effects like anemia. And talazoparib, in particular, can cause a significant drop in cell counts, which must be reported.

More recently, the U.S. gave the green light to multinational pharmaceutical Johnson & Johnson’s AKEEGA, following success in phase 3 trials for the treatment of BRCA-positive mCRPC. AKEEGA, in combination with the corticosteroid prednisone, were found to have caused a 47% reduction for radiographic progression-free survival (rPFS). At the second interim analysis (IA2), with median follow-up at 24.8 months in the BRCA-positive subgroup,  a median rPFS of 19.5 months compared with 10.9 months for placebo and abiraterone acetate plus prednisone (AAP) – a drug combination that has previously shown to increase overall survival in people with mCRPC  – was observed. 

The safety profile was consistent, with some patients experiencing musculoskeletal pain, fatigue, constipation hypertension and nausea. Moreover, 15% of the patients discontinued AKEEGA after experiencing the side effects. 

Earlier this year, another BRCA-positive mCRPC drug was given the FDA nod after it had reaped positive clinical trial results. Pharma giant AstraZeneca’s Lynparza, another PARP inhibitor in the mix, was approved in combination with  abiraterone (Zytiga). This came after the FDA had raised concerns that the “efficacy and safety have not been demonstrated outside of the small population of patients with tumor BRCA mutations and that the addition of olaparib (Lynparza) to abiraterone may cause harm in patients who are definitively negative for tumor BRCA mutations.”

Now, the FDA has authorized a recommended Lynparza dose of 300 mg, twice a day, 1000 mg of Zytiga taken orally once daily, with the latter being paired with prednisolone 5 mg orally, twice daily.

Study investigates novel approach to target aggressive tumors

A study has found the reason why treatable forms of prostate cancers switch to a more aggressive form. Researchers are now uncovering ways to tackle this problem.

Scientists at the Rogel Cancer Center at University of Michigan in the U.S., observed that a specific protein named lysine specific demethylase 1 (LSD1), which is involved in turning genes on and off in cells, including cancer cells, could potentially be why prostate cancers suddenly change form.

The switch, which is termed lineage plasticity, a process that is linked to treatment resistance, is yet to be further understood. However, the role of LSD1 has garnered interest, with potentially promising treatments on the horizon. Research suggested that LSD1 is not only a key factor in the growth of prostate adenocarcinoma tumors – the most common type of prostate cancer that is often treatable – but also has a hand in the progression of neuroendocrine prostate cancer – which is the more aggressive and advanced kind of prostate cancer. 

Employing a technique called RNA interference – a mechanism for gene silencing – the researchers removed the protein from the neuroendocrine prostate cancer cells (in cancer models), which led to the decline in the growth of the cells. What’s more is that when LSD1 was prohibited from interacting with other proteins, it had a greater impact on slowing cancer cell growth. 

“Ultimately, we found that a class of drugs – allosteric inhibitors – that block protein-protein interactions was much more effective in stopping LSD1 and slowing the growth of cancer cells,” said Anbarasu Kumaraswamy, first author of the study. 

Further research showed that the protein turns off the tumor suppressor gene p53, which is supposed to control tumor growth. So, hindering LSD1, resulted in p53 being switched back on. The findings of the study can bring forth  LSD1-targeting clinical trials in advanced prostate cancers. 

Novel biomarkers discovery leads to broader prostate cancer diagnosis measures

Scientists have discovered three new biomarkers that could change the game for prostate cancer diagnosis. 

Research conducted at the University of South Australia (UniSA) looked into a biomarker panel that consisted of the molecules Appl1, Sortilin and Syndecan-1. Appl1 has previously been linked to Treg cell infiltration, Sortilin has been studied as a prognostic biomarker for an aggressive form of breast cancer, and Syndecan-1’s potential to be a molecular marker for triple negative inflammatory breast cancer has also been examined.

When the three biomarkers are used in tandem, it can help doctors differentiate between which patient requires immediate treatment versus whose disease progression needs to be closely monitored, according to the study

“It is anticipated this will lead to long-term improvements in the way prostate cancer is diagnosed and graded,” said Doug Brooks, lead researcher and Professor of Molecular Medicine at UniSA. “The biomarkers are remarkably sensitive and specific in accurately visualizing the progress of the cancer and confirming its grade. This discovery has led to the commercial development of a test designed to determine how advanced and aggressive the cancer is, and whether immediate treatment is needed.”

The tissue-based test is being commercialized by the U.S.-based pathology company Quest Diagnostics in collaboration with Australian cell biology company Envision Sciences. 

New radiopharmaceutical targets prostate cancer cells

Around a third of people who have been diagnosed with metastatic prostate cancer do not respond well to current drugs, highlighting the need for further research in this area. Scientists at the Paul Scherrer Institute (PSI) in Switzerland have developed a drug that aims to change these statistics for the better.

The drug, which is currently being tested on patients in the PROGNOSTICS project, is made up of the isotope terbium-161, a radiopharmaceutical. This class of drugs are radioactive substances that, when it enters the bloodstream, attaches to tumor cells without affecting healthy cells, much like a key in a lock. 

Radiopharmaceuticals carry a radioactive element that emits electrons, which can aid in the destruction of the genetic material in cancer cells. But radiopharmaceuticals currently in the market are unable to attack small tumor cells, making them ineffective. Terbium-161 tackles this issue with its ability to emit electrons that have a range of energies, making its cancer-killing power more targeted. 

The scope of the isotope in eliminating cancer cells has been proven in preclinical studies in mice. Further studies are being conducted in partnership with University Hospital Basel and ETH Zurich, with the project having secured 2 million Swiss Francs ($2.23 million) in funding.

But that’s not all that’s on the radiopharmaceutical turf. In May, U.S-based Convergent Therapeutics was awarded $90 million in funding to advance its lead candidate CONV01-α, for battling advanced prostate cancer. And, Swiss multinational Novartis’ Pluvicto, which got the go-ahead from the FDA last year, has been in the news lately after its shortage led to the FDA quickly authorizing a manufacturing facility to ramp up its production.

Clinical trial shows promising results

The FDA has granted Priority Review to enzalutamide, sold under the brand name XTANDI, for the treatment of mCRPC, along with the hormone therapy leuprolide. This comes after a phase 3 trial was conducted where XTANDI was investigated in combination with the hormone therapy, leuprolide.

The results of the trial showed that the combination of the two drugs significantly reduced the risk of metastasis by 58%, as assessed by the primary endpoint of metastasis-free survival (MFS) in patients with mCRPC with high-risk biochemical recurrence (BCR). 

“The EMBARK study is a phase 3 trial exploring the potential of enzalutamide in patients with non-metastatic hormone-sensitive prostate cancer with high-risk BCR,” said Stephen J. Freedland, director of the Center for Integrated Research in Cancer and Lifestyle and the Warschaw Robertson Law Families Chair in Prostate Cancer at Cedars-Sinai Cancer, and co-principal investigator of the clinical trial. “If approved, we hope to bring a new option to men earlier in the course of their disease.” 

The overall safety profile was consistent, and the most common adverse reactions were fatigue, hot flush, and joint pain (arthralgia).

Moreover, the drug combination brought down the risk of progression of the disease by 93% when compared to  a 67% reduction with the monotherapy (Xtandi), a stark difference, implying that XTANDI would work better paired with leuprolide.

Looking ahead

With more and more research and therapies in the making, with the potential to broaden treatment options for people with prostate cancer, a new class of drugs called protein degraders are gaining traction. Leveraging proteolysis-targeting chimera (PROTAC) technology – capable of targeting unwanted proteins – could be the way to go. And, American biotech Arvinas’ protein degrader – which has shown its potential to shrink tumors in a small subset of patients, based on interim data – might be one to keep an eye on this year. 

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