latest research on metastatic prostate cancer

More Treatment Options Emerging for Some Men with Metastatic Prostate Cancer

June 19, 2019 , by NCI Staff

Enzalutamide and apalutamide block the androgen receptor (AR) on cancer cells, blunting androgen's (A) ability to fuel prostate cancer growth.

On September 17, 2019, the Food and Drug Administration approved apalutamide (Erleada) for men with metastatic, castration-sensitive prostate cancer. The approval was based on the results from the TITAN trial, which showed that apalutamide combined with androgen deprivation therapy (ADT) improved overall survival and radiographic progression-free survival compared with ADT alone. Further details on the trial results are discussed in the article below.

The treatment landscape for metastatic prostate cancer is shifting and expanding yet again, according to new findings from two large clinical trials presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO).

The ENZAMET trial tested the drug enzalutamide (Xtandi) and the TITAN trial tested apalutamide (Erleada) in men whose cancer is still responsive to hormone-suppressing therapies—also called castration -sensitive prostate cancer. In both trials, combining the respective drugs with the androgen deprivation therapy (ADT) substantially improved how long men lived overall and how long they lived without their cancer getting worse.

Results from both trials were also simultaneously published in the New England Journal of Medicine .

Enzalutamide and apalutamide are already approved by the Food and Drug Administration to treat prostate cancer that no longer responds to therapies that reduce levels of the hormone androgen , known as hormone-resistant (or castration-resistant) disease. Those approvals are expected to expand based on these new data.

From a treatment perspective, the trials’ findings now mean that “there are more treatment options for patients,” said William Dahut, M.D., the clinical director in NCI’s Center for Cancer Research , who specializes in treating prostate cancer but was not involved in either study.

Speaking at the ASCO meeting, Tanya Dorff, M.D., head of the genitourinary cancers program at the City of Hope Comprehensive Cancer Center in California, agreed. The trials also confirm the value of intensifying treatment in men with hormone-sensitive metastatic prostate cancer, Dr. Dorff said, “rather than being reserved for castration-resistant patients.”

In Five Years, a Major Treatment Shift

In men diagnosed with metastatic hormone-sensitive prostate cancer, the cancer is typically driven to grow and spread by androgens that are produced largely in the testes. For many years, treatments that block androgen production have been a mainstay for men initially diagnosed with metastatic prostate cancer.

Starting in 2014, that began to change after a large clinical trial showed that adding the chemotherapy drug docetaxel to ADT improved how long men with hormone-responsive disease lived . Shortly after, another clinical trial showed that adding abiraterone (Zytiga) to ADT also improved survival in these men, although primarily in men with many metastatic tumors , known as high-volume disease.

However, docetaxel, which works by directly killing cancer cells, can have substantial side effects, and some patients aren’t healthy enough to tolerate it. And abiraterone—which blocks androgen production throughout the body—can also cause side effects, including those that affect the liver. It also has to be given in combination with the steroid prednisone, which carries its own toxicity.

Enzalutamide and apalutamide block the androgen receptor on cancer cells, blunting androgens’ ability to fuel prostate cancer growth. The drugs’ efficacy in hormone-resistant metastatic prostate cancer led researchers to test them in men with less advanced disease. The goal was to see if they could “provide more complete reduction of androgen signaling” in hormone-responsive prostate cancer cells, explained Kim Chi, M.D., of the BC Cancer Agency in Vancouver, a lead investigator on the TITAN trial.

Doing so, Dr. Chi said during a presentation of the TITAN data at the ASCO meeting, might help stave off the typically inevitable development of hormone-resistant cancer, which is more difficult to treat and a key driver of prostate cancer deaths.

Improving How Long Patients Live

The ENZAMET trial—funded in part by the drug’s manufacturer, Astellas Pharma, as well as government health agencies in Canada and Australia—enrolled more than 1,100 men (largely outside of the United States) with hormone-sensitive metastatic prostate cancer. The men were randomly assigned to ADT combined with enzalutamide or with any of three other androgen-blocking drugs.

At a median follow-up of nearly 3 years, men who received ADT plus enzalutamide had a 33% reduced risk of death , with 80% still alive compared with 72% of men treated with ADT plus another antiandrogen drug, reported the trial’s lead investigator, Christopher Sweeney, M.B.B.S., of the Dana-Farber Cancer Institute.

Men in the enzalutamide group also had better clinical progression-free survival  (PFS), which the research team defined as the time until the return of disease-related symptoms, the detection of new metastases on imaging scans , or the initiation of another cancer treatment for prostate cancer, whichever came first. At 3 years, 63% of men in the enzalutamide group were alive without clinical progression of their disease, compared with 33% in the standard treatment group.

Although enzalutamide appeared to be effective regardless of whether men had high- or low-volume disease, one apparent differentiating factor was planned early treatment with docetaxel. Nearly half of the men in both treatment groups received early treatment with docetaxel and, for those men, enzalutamide was not associated with longer overall survival .

Side effects and serious side effects were more common in men treated with enzalutamide, including increased blood pressure and fatigue. In men who also received docetaxel, the rate of peripheral neuropathy was more than tripled in the enzalutamide group. Seven men treated with enzalutamide experienced seizures, compared with no men in the standard treatment group, and overall more than twice as many men receiving enzalutamide stopped treatment (33 versus 14).

From the standpoint of efficacy, similar results were seen in the TITAN trial with apalutamide. Funded by the drug’s manufacturer, Janssen Pharmaceuticals, the trial enrolled more than 1,000 men with hormone-sensitive metastatic prostate cancer, with participants randomly assigned to receive ADT along with a placebo or ADT plus apalutamide.

At 2 years of follow-up, approximately 82% of men who received ADT plus apalutamide were still alive , compared with 74% in men treated with ADT plus placebo, for a 33% reduction in the risk of death. The trial’s other primary measure was the amount time men lived without evidence on imaging scans that their disease had progressed, known as radiographic PFS. At a median follow-up of nearly 2 years, men treated with ADT plus apalutamide had a 50% improvement in radiographic PFS than men treated with ADT alone.

Rash was one of the most common side effects among men treated with apalutamide, with more than a quarter experiencing this problem. For most men, the rash did not cause symptoms, but it was still the primary reason for men stopping apalutamide treatment, Dr. Chi said.

The drug also appeared to be effective across different subgroups of patients, including men with low-volume and high-volume cancer. At the time of the last analysis of the data, Dr. Chi noted, approximately two-thirds of men in the apalutamide arm were still taking the drug.

How to Choose?

More treatment options also require clinicians and patients to make more decisions. In the case of enzalutamide and apalutamide, Dr. Dahut said, both drugs “may be particularly good choices for men with low-volume disease, who might shy away from docetaxel” due to concerns about side effects.

Unlike docetaxel, which must be administered intravenously in the hospital, enzalutamide, apalutamide, and abiraterone are oral drugs that can be taken at home, so they also offer greater convenience for patients. On the other hand, many patients tolerate docetaxel quite well, Dr. Dahut noted, and it’s given for a fixed duration, not continuously like the other drugs.

Cost might also be a consideration when it comes to the three hormone therapy drugs, explained Michael Carducci, M.D., who specializes in treating prostate cancer at Johns Hopkins University Sidney Kimmel Cancer Center.

“Our underinsured patients have struggled to cover the cost of these medications,” he said.

Speaking during an ASCO session on the TITAN findings, Dr. Carducci added that other factors, such as age, can influence treatment decisions. When older patients “hear about some of the side effects [of these drugs], they don’t want to feel old or frail,” he said. So while they are willing to undergo ADT, “the idea of adding more therapy … remains a problem.”

Researchers are continuing to identify potential biomarkers or specific clinical factors that can identify which patients might be the best candidates for a given treatment, Dr. Dorff noted. In the meantime, she said, clinicians “will need shared, informed decision making with our patients.”

And although there is the possibility of combining these different treatments, she stressed, “combinations have not yet proven to be beneficial and should not be offered outside of a clinical trial.”

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A new study illuminates the therapy resistance of metastatic prostate cancer

Bone metastases are devastating developments of cancers that originate in other organs. In the case of metastatic prostate cancer, bone metastases represent an incurable, painful, and often deadly development, killing more than 30,000 American men every year. Unlike many other tumor types, metastatic prostate cancer responds poorly to immune-based therapies, but a new study published in Cancer Cell and originating in part from Harvard Stem Cell Institute (HSCI) labs, has uncovered a key mechanism for why such therapies fail to work, potentially leading the way to a breakthrough in the treatment of this devastating disease.

This study began in 2015, when a multi-disciplinary team of doctors, surgeons, researchers, and bioinformaticians from HSCI, Massachusetts General Hospital (MGH), and Harvard Medical School (HMS) assembled to address the question: “Why does prostate cancer so commonly spread to the bone and why can’t we treat it with immune therapy?” The team focused on bone marrow, where the immune system is generated and where prostate cancer establishes its metastases.

“Given that all blood and most immune cells are being made in the bone marrow, it has been unclear why metastases to bone respond so poorly to immune therapies,” said Gerald and Darlene Jordan Professor of Medicine at Harvard University and HSCI Co-Director David Scadden M.D .

Using samples from patients whose prostate cancer had spread to the bone marrow of their spines, the team looked for how metastatic tumor evaded these usually effective therapies. The tumor, they found, were able to bias the differentiation of normal hematopoietic stem cells towards an abnormal inflammatory myeloid population.

“We found that a group of immune cells, called myeloid cells, have distinctive features when metastatic cancer cells are present,” explained Scadden, a professor in the Harvard Department of Stem Cell and Regenerative Biology. “They send a signal that turns off the immune attack of T cells.”

Specifically, the bias created by the tumor led to generation of myeloid-derived suppressor cells (MDSC), which are capable of inhibiting the normal T-cell response against the tumor within the bone marrow. Because immune therapies rely on this defensive T-cell response, these abnormal cells effectively rendered such treatments useless.

The team then looked at how to counter this response. Generating a mouse model of disease, they demonstrated that by blocking the interaction between the MDSC and T-cells the dysfunctional relationship between them could be broken, “re-awakening” the T-cell immune response against the tumor and improving animal survival. This work identified specific molecules, CCL20 and its receptor CCR6, as key regulators of the immune-suppressing effect that can be targeted to improve immune targeting of prostate cancer metastases in bone. The study points to a possible new approach for patients with metastatic prostate cancer.

“We showed that interrupting that signal releases the brake and the immune system can go after tumor cells enough to extend the lifespan of animals,” said Scadden. “There are agents that have been tested in humans in other settings which target the ‘off’ signal. This work supports testing them in metastatic prostate cancer.”

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April 16, 2024

10 min read

New Prostate Cancer Treatments Offer Hope for Advanced Cases

Major discoveries during the past 10 years have transformed prostate cancer treatment, enabling it to proceed even for the most advanced form of the disease

By Marc B. Garnick

David Cheney

D eciding how to diagnose and treat prostate cancer has long been the subject of controversy and uncertainty. A prime example involves prostate-specific antigen (PSA) testing, a blood test for a telltale protein that can reveal cancer even when the patient has no symptoms. After its introduction in the early 1990s, PSA testing was widely adopted—millions of tests are done in the U.S. every year. In 2012, however, a government task force indicated that this test can lead to overtreatment of cancers that might have posed little danger to patients and so might have been best left alone.

While arguments for and against PSA testing continue to seesaw back and forth, the field has achieved a better grasp on what makes certain prostate cancers grow quickly, and those insights have paved the way for better patient prognoses at every stage of the disease, even for the most advanced cases. A prostate cancer specialist today has access to an enhanced tool set for treatment and can judge when measures can be safely deferred.

The importance of these advances cannot be overstated. Prostate cancer is still one of the most prevalent malignancies. Aside from some skin cancers, prostate cancers are the most common cancers among men in the U.S. Nearly 270,000 people in America will be diagnosed with prostate cancer this year, and it is the fourth most common cancer worldwide. Fortunately, the vast majority of patients will live for years after being diagnosed and are more likely to die of causes unrelated to a prostate tumor.

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At its most basic level, prostate cancer is a malignancy that occurs in the prostate gland, which produces fluid that mixes with sperm from the testicles to make semen. The prostate is located in front of the rectum, below the bladder and above the penis, and cancer in the gland has four major stages.

Early on, localized tumors show no evidence of extension beyond the prostate gland. A second, “regionally advanced” form of the disease remains close to the prostate. Then there are metastatic prostate cancers, which spread outside the gland to other parts of the body. Treatment of tumors in this category has benefited from improved diagnostic imaging tests. In fact, with these tests, cancer specialists have characterized the fourth category, oligometastatic prostate cancer, a disease stage on a continuum between localized prostate cancer and more broadly dispersed metastatic disease. Major discoveries in the past 10 years have transformed the way we approach each type of prostate cancer, and these advances are likely to continue for decades to come.

The first treatment steps for people with localized cancer involve risk stratification. Through this process, a physician gauges the likelihood of a cancer’s being eliminated or cured by local treatment (usually surgery or radiation) and, if it does abate, of its returning. A physician determines the risk based on PSA results, physical examination of the prostate gland and inspection of cells from the biopsied tumor.

The right course of action for a patient with elevated PSA levels continues to undergo constant revision. Until five to seven years ago, a physician evaluated a person with high PSA by feeling their prostate gland for potentially cancerous abnormalities. Invariably, the next step would be a needle biopsy—an uncomfortable procedure in which the physician obtains snippets of prostate tissue through the rectum.

But we now have a way to biopsy through the perineum—the area between the back of the scrotum and the anal-rectal area. Thanks to technical improvements, it can be done in an outpatient setting without general anesthesia or sedation. The technique reduces the patient’s risk of infection and need for antibiotics because it doesn’t disrupt the bacterial flora in the rectum. In a recent study, researchers compared outcomes in patients who underwent a trans­rectal biopsy and received antibiotics with those for people who had a transperineal biopsy with minimal to no antibiotics. They found the two approaches comparable in terms of complications from infections.

Even more exciting is the prospect of eliminating biopsies altogether. When a patient has an abnormal PSA value but their rectal examination shows no obvious evidence of cancerous deposits, physicians can now use magnetic resonance imaging (MRI) to look at the prostate and surrounding tissue. MRI scans are best for identifying clinically significant cancers—those that, if left untreated or undiagnosed, could eventually spread. MRI can also uncover more extensive cancer spread or tumors in unusual locations such as the front of the prostate.

Another benefit of MRI procedures is that they identify fewer clinically insignificant cancers—those that are unlikely to cause problems and might best be left alone. In this case, failure to detect certain cancers is a good thing because it spares people unnecessary treatment. In some medical centers in the U.S. and many in Europe, a physician will perform a biopsy only if the MRI scan does reveal evidence of clinical significance. Studies that have compared the two diagnostic approaches—routine biopsy for all patients with elevated PSA levels versus biopsies based on abnormal MRI findings—found they are similarly effective at detecting clinically significant cancers.

Once a patient is diagnosed with prostate cancer, what happens next? For decades the debate over treatment has been just as contentious as the debate over diagnosis. Fortunately, new research from the U.K. has provided some clarity. Investigators there studied several thousand people with elevated PSA levels whose prostate biopsies showed cancer. These patients were randomized to receive surgical removal of the cancerous gland, radiation treatments or no active treatment at all. At the end of 15 years of comprehensive follow-up, about 3 percent of patients in each group had died of prostate cancer, and nearly 20 percent in each group had died of unrelated causes.

Based on the results of this study and others, more people are now being offered “active surveillance” after a prostate cancer diagnosis, in which treatment is either delayed or avoided altogether. Careful monitoring of patients who have not undergone surgery or radiation is becoming more common; it is now being extended even to those with more worrisome tumors. The monitoring involves a range of measures: PSA testing every three to six months, physical examination of the prostate gland and assessment of the patient’s urinary symptoms. Those tests are followed by repeat biopsies at increasing intervals, as long as there are no significant pathological changes.

If a cancer is identified as having either intermediate- or high-risk features, doctors need to track its progression, usually with bone scans using radio­­pharma­ceut­i­cals and with abdominal-pelvic computed tomography (CT) scans, which may show any spread in the areas to which prostate cancer most often metastasizes. Unfortunately, these techniques are not sensitive enough to reliably detect cancer in structures less than a centimeter in diameter, such as lymph nodes. Consequently, small areas of metastatic disease may go undetected. These cases are said to be “understaged.”

Understaging can now be studied through more precise diagnostic testing. Typically patients whose disease is understaged are not treated until the cancer becomes detectable through symptoms such as urination problems or pain. The disease then may require intensive therapies, and there is less of a chance of long-term remission. One technology that can help address understaging is advanced scanning that combines radiodiagnostic positron-emission tomography (PET) with CT.

These scans can detect molecules commonly found in prostate cancer cells, such as prostate-specific membrane antigen (PSMA). If PSMA is present outside the prostate gland, such as in pelvic lymph nodes, the affected areas can be identified, and a plan can be made for targeted radiation treatments or surgical removal.

Let’s consider how PET-CT scanning can be used in clinical practice. One of my patients, a 68-year-old man, was diagnosed with prostate cancer that was localized but had high-risk features. The traditional diagnostic bone and CT scans did not show any evidence of cancer spread outside the prostate. A PET-CT scan for PSMA, however, did reveal the presence of several small deposits of cancer cells in well-defined areas of the pelvis, indicating the cancer had spread to the lymph nodes. This finding prompted treatment that included radiation therapy in the prostate gland and the cancerous lymph nodes, as well as androgen-deprivation therapy (ADT), a treatment that reduces levels of testosterone, the hormone that enables prostate cancer to grow and progress.

The more precise identification of small tumor deposits in a limited number of pelvic lymph nodes—diagnosed as oligometastatic prostate cancer—enabled a new use for an old technology in oncology called metastasis-directed therapy (MDT), which targets cancer-containing lymph nodes or bony areas with radiation. At times, surgical removal of the abnormal lymph nodes may also be incorporated into MDT. Recently published studies on the use of MDT in conjunction with conventional treatments show, in some cases, long-term remission lasting through years of follow-up. Until recently, such a scenario was unthinkable for people whose prostate cancer had spread to their lymph nodes. My patient had the PSMA scan and MDT, as well as a relatively short course of ADT. He is cancer-free for now.

Precise identification of small metastatic deposits has other positive benefits. ADT has for decades been the mainstay for treating many forms of prostate cancer. Patients must continue the therapy for years, sometimes for the rest of their lives. Side effects of ADT are similar to those experienced during menopause. In fact, “andropause” is the term that captures the effects of ADT. Lower levels of testosterone are accompanied by a multitude of symptoms, including but not limited to loss of libido, erectile dysfunction, weight gain, hot flashes, bone loss, cognitive impairment, mood changes, diminished energy, and worsening of preexisting heart and vascular problems.

Studies of MDT for oligometastatic prostate cancer have raised the question of whether ADT could be delayed, administered for a shorter duration or even omitted in patients who otherwise would have required it. By strategically deploying traditional forms of localized treatment—usually surgery to remove the prostate gland or radiation—with added MDT for oligometastatic disease, doctors can significantly shorten the duration of ADT or potentially eliminate it. Such an approach would have been difficult to imagine five years ago. Longer-term follow-up studies will help scientists determine whether some people diagnosed in this fashion can go into an extended remission.

F or advanced forms of prostate cancer that have spread to other parts of the body, ADT has been the main treatment. Physicians historically have generally recommended surgical removal of the testicles—the primary source of testosterone—or the administration of other hormones that block the production and action of testosterone. In the mid-1980s I was involved with research on drugs called luteinizing hormone–releasing hormone analogues that lowered testosterone by shutting off the signal in the brain that instructs the testicles to make testosterone. Today newer agents have been added that further lower and block testosterone’s action.

The goal of prostate cancer treatment at later stages is to eliminate multiple sources of testosterone. As noted earlier, testosterone in the body comes predominantly from the testicles; the adrenal glands also produce a small amount. But prostate cancer cells can evolve to produce their own androgens. Testosterone and its active form, dihydrotestosterone (DHT), traverse the membranes of prostate cancer cells and interact with androgen receptors in the cytoplasm, a cell’s liquid interior. The receptors then transport DHT to the nucleus, where it instructs the cancer cell to grow, replicate and spread.

Traditional ADT does little to affect either the production of testosterone by the adrenal glands or androgen-producing prostate cancer cells, and it doesn’t block the activity of androgen receptors. But new approaches to ADT may address these shortcomings. Drug combinations that affect all these processes have substantially improved survival in people with metastatic prostate cancer—and, more important, patients are able to tolerate these more intensive treatment programs.

Instead of just one drug to decrease testosterone, new standards for treatment prescribe combinations of two or even three drugs. In addition to traditional ADT, there are medications such as do­cetaxel, a chemotherapy, and other new drugs that can block the production of testosterone by the adrenal glands or cancer cells or stop it by interfering with the activity of androgen receptors. All these drug combinations have resulted in meaningful improvements in survival.

Yet another therapy for advanced disease involves the identification of PSMA-expressing cancer cells that can be targeted with pharmaceuticals designed to deliver radioactive bombs. An injectable radiopharmaceutical can be delivered selectively to these cells, leaving healthy cells mostly unaffected. This therapy, lutetium-177-­PSMA-617 (marketed as Pluvicto), has been approved by the U.S. Food and Drug Administration for the treatment of prostate cancer that has become resistant to other forms of ADT and chemotherapy. It is likely to become an important therapy for even earlier stages of prostate cancer.

Genetics and genomic testing of patients and cancers have also helped in the quest for improvement of symptoms and longer survival. Some genetic mutations that are known to increase the risk of breast and ovarian cancer have also been associated with a heightened risk of prostate cancer. Testing for such mutations is becoming much more common, and patients who have them can be treated with specific therapies that block their deleterious effects, leading to better outcomes.

An understanding of the type of mutation is also critical—for both patients and their family members. Germline mutations are inherited from a patient’s biological parents by every cell in the body. These mutations can be passed along to the patient’s children. A somatic mutation, in contrast, is not inherited but develops in the cancer itself. Targeted therapies designed specifically to correct the effects of either germline or somatic mutations have produced significant improvements in patient longevity. Some of the most commonly recognized cancer mutations—either somatic or germline—are those in BRCA genes, which have been associated with early-onset breast and ovarian cancer.

When researchers studied cancer in families with BRCA mutations, they uncovered many cases of prostate cancer. This finding led to the discovery that BRCA mutations appeared in both men and women in these families. The mutations change the way DNA is repaired, introducing defects that can result in cancer formation. Drugs have now been developed that treat cancers linked to the BRCA mutations. Several such drugs—those in a class called poly­(ADP-ribose) polymerase (PARP) inhibitors—have recently received FDA approval for use as a treatment in people with these mutations. This research has led to more widespread genetic testing of patients with prostate cancer and, when germline mutations are found, family genetic counseling.

All these advances have occurred over the past decade—an incredibly short interval in the context of cancer oncology. Current options for early-stage prostate cancer enable physicians and patients to feel more at ease with conservative choices rather than immediate interventions with negative side effects. For patients whose cancers are advanced at initial diagnosis or progress and become metastatic, the treatment of oligometastases now often leads to long-term remission and requires fewer treatments with harmful systemic side effects. For those with more widespread metastatic disease, their cancer can now be managed with improved therapeutics based on a better understanding of disease biology. These new strategies have begun to transform this once rapidly fatal disease into a chronic condition that people can live with for years or even for their full life expectancy.

Marc B. Garnick is Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston. He is editor in chief of Harvard Medical School’s 2024–2025 Report on Prostate Diseases.

Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology

Affiliations.

• 1 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
• 2 2Stanford Cancer Institute.
• 3 3Indiana University Melvin and Bren Simon Comprehensive Cancer Center.
• 4 4Yale Cancer Center/Smilow Cancer Hospital.
• 5 5Vanderbilt-Ingram Cancer Center.
• 6 6Duke Cancer Institute.
• 7 7Mayo Clinic Comprehensive Cancer Center.
• 8 8The University of Texas MD Anderson Cancer Center.
• 9 9Fred Hutchinson Cancer Center.
• 10 10Dana-Farber/Brigham and Women's Cancer Center | Mass General Cancer Center.
• 11 11UT Southwestern Simmons Comprehensive Cancer Center.
• 12 12City of Hope National Cancer Center.
• 13 13Memorial Sloan Kettering Cancer Center.
• 14 14Prostate Health Education Network (PHEN).
• 15 15Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute.
• 16 16Abramson Cancer Center at The University of Pennsylvania.
• 17 17Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
• 18 18Roswell Park Comprehensive Cancer Center.
• 19 19University of Wisconsin Carbone Cancer Center.
• 20 20The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
• 21 21UC San Diego Moores Cancer Center.
• 22 22University of Michigan Rogel Cancer Center.
• 23 23O'Neal Comprehensive Cancer Center at UAB.
• 24 24Moffitt Cancer Center.
• 25 25UCLA Jonsson Comprehensive Cancer Center.
• 26 26UCSF Helen Diller Family Comprehensive Cancer Center.
• 27 27University of Colorado Cancer Center.
• 28 28University of California San Francisco, Patient Services Committee Chair.
• 29 29The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.
• 30 30Fred & Pamela Buffett Cancer Center.
• 31 31Huntsman Cancer Institute at the University of Utah.
• 32 32UC Davis Comprehensive Cancer Center.
• 33 33Fox Chase Cancer Center.
• 34 34National Comprehensive Cancer Network.
• PMID: 37856213
• DOI: 10.6004/jnccn.2023.0050

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

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The Research Institute of McGill University Health Centre (RI-MUHC) has enrolled this week the first patients to take part in an early-stage, multi-centre clinical trial of Actinium-225, a radioactive isotope used as a treatment for metastatic prostate cancer. The RI-MUHC is proud to be selected as the first site worldwide to launch this new clinical trial, which introduces a promising new therapy in precision medicine for patients who have exhausted all other options in the treatment of their disease.  

The third leading cause of cancer-related-death in men, prostate cancer will affect approximately 1 in 8 Canadian men during their lifetime and cause the death of one in 30, according to the Canadian Cancer Society.  

Led at the RI-MUHC by Dr. Ramy Saleh, Medical Oncologist at the MUHC’s Cedars Cancer Centre and Medical Director, Oncology, at the Centre for Innovative Medicine (CIM) at the RI-MUHC, the study will evaluate the safety (i.e. the drug’s ability to act without adverse effects) and tolerability (i.e. the subject’s ability to withstand adverse effects) of Actinium-225, which works by targeting the prostate-specific membrane antigen (PSMA).  

PSMA, which is found in more than 80 per cent of patients with metastatic prostate cancer, is highly expressed in prostate tumoral cells, but is very little present in the rest of the body. Actinium-225 binds to PSMA receptors, finds the cancer cells and emits radiation to kill them by breaking their DNA strands. A potential advantage of this targeted mode of action is the sparing of healthy organs.

“We are very excited to be testing Actinium-225 and to be the first centre in the world to start this clinical trial,” says Dr. Saleh. “It’s a great satisfaction for our team because it’s the result of our sustained efforts to bring the latest therapeutic advances to our patients.”

The experimental treatment, developed by the US company POINT Biopharma, will be administered by intravenous injection to 50 patients with metastatic castration-resistant (mCRPC) or biochemically recurrent (BCR) prostate cancer, for whom standard of care treatments have failed. Different doses will be tested and patients will be followed for five years to monitor any side effects.

In addition to assessing the safety of the drug for patients, the study will monitor how the drug interacts with tumours and healthy organs, find out if it is well tolerated, and determine the right dose that could be used in future studies.

“Other clinical trials have shown that similar treatment with drugs that target PSMA can reduce prostate cancer tumour burden and potentially improve prognosis. So, although we don’t know if the drug we’re studying will improve the health of our patients, we see this trial as our best hope,” adds Dr. Saleh, who is also Medical Director of the Phase 1 Research Unit at the CIM, Investigator in the Cancer Research Program at the RI-MUHC and Assistant Professor in the Gerald Bronfman Department of Oncology at McGill University.

Clinical trials: the path to better health outcomes  

Research is essential to improve cancer treatments and survival rates. Phase 1 clinical trials are a critical part of research, because they can determine whether to continue or stop development of a new drug.

Established in 2018, the Phase 1 Research Unit at the CIM is dedicated to providing high-quality care to its cancer patients while supporting the drug development process. One of the distinguishing elements of the unit is its state-of-the-art facilities and equipment, which allow for precise and efficient study conduct. In addition, the unit often works with a multidisciplinary team of experts to ensure comprehensive and robust clinical trial designs.  

“This world first confirms that the RI-MUHC, by fostering collaboration between its researchers and industry experts, has established a leadership position in Canada’s clinical trials ecosystem. The Centre for Innovative Medicine not only brings the latest experimental therapies to patients, but also attracts the most innovative pharmaceutical companies, both nationally and internationally, at every stage of clinical trials,” says Dr. Louise Pilote, Director (interim) of the CIM and Deputy Director of the RI-MUHC.

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