Category: Treatment Information

The U.S. Food and Drug Administration (FDA) has granted priority review to Clovis Oncology’s application seeking approval of Rubraca (rucaparib) for treating men with recurrent metastatic castration (hormone)-resistant prostate cancer (mCRPC) and BRCA mutations.

Clovis submitted its application to the FDA in November, 2019. The priority review status will shorten Rubraca’s regulatory review for this indication to six months from the standard 10 months.

Nearly 12% of men with mCRPC have a mutation in the BRCA1 or BRCA2 genes, which are involved in DNA repair. These tumors rely on other DNA repair mechanisms — including those involving PARP enzymes that act as DNA damage sensors — to survive and grow. Thus, treatments that block PARPs’ activity (PARP inhibitors), such as Rubraca, are particularly effective in BRCA-mutated tumors. Rubraca is already approved for the treatment of several gynecologic tumors carrying BRCA mutations, and as a maintenance therapy regardless of BRCA mutations.

Rubraca’s new application was supported by data from the TRITON2 Phase 2 trial (NCT02952534), which is evaluating its safety and effectiveness in up to 360 mCRPC patients with mutations in BRCA genes or in other 13 DNA repair genes known to increase susceptibility to PARP inhibitors.

Besides eligible mutations, participants must have experienced disease progression after at least one but no more than two previous androgen-receptor targeted therapies and one prior taxane-based chemotherapy for their castration-resistant disease.

TRITON2’s main goals were to assess overall response rates in men with measurable disease, and the proportion of men who saw a reduction in the levels of prostate-specific antigen (PSA) — a biomarker of prostate cancer — after treatment. Secondary goals included duration of response, time to disease progression or death, overall survival, and safety measures.

Early positive data from TRITON2 led to Rubraca’s breakthrough therapy designation by the FDA for the treatment for mCRPC patients with BRCA mutations, a status intended to accelerate the therapy’s development and review. As of Feb. 28, 2019, 190 patients (98 with a BRCA mutation) had received Rubraca, with a median follow-up of 13.1 months. Among patients with BRCA mutations, results showed that 43.9% of those with measurable disease responded to treatment, and that 60% of these responses lasted at least 24 weeks. Also, 52% of patients had a confirmed PSA response (deemed as a 50% or greater reduction in PSA levels), which lasted a median of 5.5 months.

Rubraca’s safety profile was consistent with prior reports from TRITON2 and other trials, with the most common adverse events being fatigue (55.3%), nausea (49.5%), anemia (37.9%), decreased appetite (27.9%), transient increase in liver enzymes (24.7%), constipation (24.7%), vomiting (22.1%), and diarrhea (21.1%).

The preceding was an excerpt from Prostate Cancer News Today, Jan. 16th by Dr. Marta Figureiredo.

The National Cancer Institute (NCI) is sponsoring a clinical trial at many locations comparing two types of radiation therapy, stereotactic body radiation therapy (SBRT) with intensity-modulated radiation therapy (IMRT). The former is administered in less than two weeks while the latter is given in five weeks. The aim of the trial is to compare cure rates and side effects. The following video by Dr. Mark Scholz, Executive Director of the Prostate Cancer Research Institute (PCRI) describes the trial now recruiting patients.

Delivering higher doses of radiation therapy over a shorter time period — an approach called stereotactic body radiation therapy (SBRT) — does not worsen side effects in men with localized prostate cancer, compared to conventional radiation therapy, a Phase 3 trial shows. The study also suggests that SBRT delivered through the CyberKnife System is less toxic for the genitourinary system than conventional linear accelerators used for this kind of radiation therapy. The research was published in an article in the journal The Lancet Oncology.

Accuray’s CyberKnife is a robotic system that delivers SBRT to the prostate and other organs. This approach involves very high doses of radiation over a smaller number of treatment sessions compared to conventional radiation therapy. As the prostate can move unpredictably during the course of treatment, tracking its position and correcting the radiation delivery site are key. CyberKnife offers continual imaging and automatic beam delivery corrections through its Synchrony technology, which helps increase treatment efficacy and spare healthy tissue, according to the company.

The international, Accuray-funded PACE-B Phase 3 trial (NCT01584258) was designed to compare SBRT to conventional radiation therapy in men who were ineligible for surgery, had low or intermediate risk cancer, and to determine if the CyberKnife system provided any benefits over other SBRT delivery systems. Patients assigned to SBRT received five sessions over one or two weeks, while those on conventional radiotherapy had either 39 sessions over eight weeks, or 20 sessions over four weeks. The trial included 874 men and took place in the U.K., Ireland, and Canada. In both groups, 90% of the patients had intermediate-risk prostate cancer.

Clinical assessments and patient-completed questionnaires showed that SBRT and conventional radiation therapy resulted in similar levels of acute gastrointestinal and genitourinary side effects over three months. No treatment-related deaths occurred in either group. The researchers also found that moderate or worse genitourinary side effects were less common in CyberKnife users (12%) than in non-users (31%). Gastrointestinal side effects were similar in both groups. In a news release, researchers said the results are “promising, and for the first time show in a large patient group that giving five large doses of SBRT is safe in the short term.” Of note, eight of the study’s authors received grants and/or personal fees from Accuray.

The above information first appeared in the Oct. 3rd e mail edition of Prostate Cancer News Today, by Jose Marques Lopes, Ph.D.

The U.S. Food and Drug Administration (FDA) has approved Erleada (apalutamide) for the treatment of men with metastatic, castration (hormone)-sensitive prostate cancer (mCSPC), or those whose cancer still responds to androgen deprivation (hormonal) therapy (ADT).

The decision is based on the double-blind TITAN Phase 3 trial (NCT02489318), as it showed that adding Janssen’s Erleada to ADT significantly extended both overall survival and progression-free survival (PFS) – the period without cancer progression –, which were the trial’s primary goals. Based on results from the SPARTAN clinical trial, Erleada had already been approved in 2018 as a treatment for patients with non-metastatic (localized) castration (hormone)-resistant prostate cancer in both the United States and the European Union.

Compared to ADT and a placebo, treatment with Erleada and ADT reduced the risk of death by 33%, and the likelihood of disease worsening (as assessed by radiography) or death by 52%. After a median follow-up of 22.7 months, 84% of the patients on Erleada and ADT reached the two-year mark alive, compared to 78% of those on ADT and placebo. In this indication, Earleada decreased the risk of cancer spreading or death by 72 percent compared to a placebo, and delayed the cancer’s metastasis by more than two years. The frequency of serious adverse events was 19.8% for Erleada and 20.3% for placebo.

Erleada is an oral therapy that targets the androgen receptor, blocking its activation by androgens such as testosterone. Its chemical structure and mode of action are similar to that of enzalutamide (Xtandi). In turn, ADT, a mainstay of prostate cancer treatment, reduces the amount of androgens in the body.

TITAN included 1,052 mCSPC patients regardless of extent of disease and of being newly diagnosed or having been treated with up to six cycles of docetaxel (taxotere). It was funded by Johnson & Johnson-owned Aragon Pharmaceuticals and Janssen Research and Development (also owned by Johnson & Johnson). The study’s findings were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine.

“Prostate cancer is more difficult to treat once it spreads, and for patients with castration (hormone)-sensitive disease, it is clear that androgen deprivation therapy (ADT) alone is often not enough,” Kim Chi, principal investigator in TITAN and medical oncologist at BC Cancer-Vancouver, said in a press release. “Results from the TITAN study showed that, regardless of the extent of disease, patients with metastatic castration-sensitive prostate cancer have the potential to benefit from treatment with Erleada in addition to ADT.”

Most information in this post appeared in the September 19th, 2019 Prostate Cancer News Today by Jose Marques Lopes, Ph.D.

Tumors with large numbers of prostate cancer cells with mutations in DNA repair genes (e.g. BRCA1 and 2) are easier to target using prostate-specific membrane antigen (PSMA) therapies, and patients with these tumors are more likely to respond to this potential treatment’s use, a study found and published in European Urology.

PSMA is a membrane protein often found at very high levels on the surface of prostate cancer cells, especially among those forming castration (hormone)-resistant prostate cancer (CRPC) tumors, an aggressive form of the disease that no longer responds to hormone therapy.

For that reason, PSMA has become a promising target of researchers working to develop a new class of medications that combine an anti-PSMA antibody with a radioactive moiety. Such medications, like lutetium (Lu)177-PSMA, use the anti-PSMA antibody to specifically spot and deliver the radioactive lutetium-177 conjugate to prostate cancer cells which produce PSMA in large amounts.

But this type of targeted radiation therapy does not work for all patients, and the rates of those failing to respond have amounted to about 30% in studies. Between 30% to 60% of patients with metastatic CRPC (mCRPC) treated with these therapies, however, have reported reductions of more than 50% in PSA levels (a biomarker of prostate cancer).

Prior studies used antibodies that target the intracellular (not the surface) part of PSMA, which has no clinical value for estimating PSMA levels. A team of investigators at the Institute of Cancer Research in London set out to characterize the levels of PSMA found specifically on the surface of prostate cancer cells — called membranous PSMA (mPMSA) — in a group of men with mCRPC. Because mutations in DNA repair genes lead to a high genetic variability within a single tumor, researchers also examined if these mutations affect PSMA levels and could be used to guide PSMA-directed therapies.

The study involved two groups of patients: a test group of 60 patients who provided mCRPC tissue samples, including 38 people with matched, castration (hormone)-sensitive prostate cancer (CSPC) diagnostic samples; and a confirmation group of 10 patients whose tumors contained a high number of mutations in DNA repair genes.

Despite the high degree of variability in membranous PSMA levels evident among different patients and even between samples obtained from the same patient, high levels of mPSMA at diagnosis generally associated with greater cancer aggressiveness (based on the Gleason score) and poorer patient survival.

In addition, researchers found that membranous PSMA (mPSMA) levels tended to be higher in metastatic hormone-resistant prostate cancer samples compared to hormone-sensitive samples, or samples from patients whose tumors respond to hormone therapies.

Investigators also found that mPSMA levels were more than four times higher in tumors containing numerous mutations in DNA repair genes, compared to those with no mutations. These findings were confirmed in the second group of study patients.

Testing for DNA repair defects was a good indication of which tumors had high levels of PSMA — and so would be expected to respond to these PSMA-targeted therapies like lutetium-177-PSMA. Identifying patients with DNA repair mutations could be useful in design of clinical trials to identify likely responders to PSMA treatments. (I was recently informed that genetic testing for DNA repair mutations is commercially available from the company Invitae.)

For additional details see the Aug. 22 Prostate Cancer News Today.

Men with metastatic hormone-resistant prostate cancer (mCRPC) given Lynparza® (olaparib), a breast and ovarian cancer treatment, lived a clinically meaningful longer time without disease progression or death compared to those given standard treatment with Xtandi® (enzalutamide) or Zytiga® (abiraterone) in a Phase 3 trial. These eligible patients had a mutation in one of 15 DNA repair genes involved in the homologous recombination (HR) pathway. Specifically, these positive benefits were seen in patients with mutations in BRCA1, BRCA2, or ATM, the most common among HR gene mutations; the first two are also strongly linked with familial breast and ovarian cancers. Overall, HR mutations occur in approximately 25% of men diagnosed with mCRPC.

The multicenter, open-label PROfound study (NCT02987543) compared the efficacy and safety of Lynparza® to that of Xtandi® (from Astellas and Pfizer Oncology) and Zytiga® (from Janssen) in mCRPC patients whose disease had progressed while on these newer hormone treatments.

Lynparza®, an oral PARP (poly ADP-ribose polymerase) enzyme inhibitor marketed by AstraZeneca and Merck, is intended to prevent cancer cells from repairing their DNA errors, thereby causing their death. It is approved for some breast and ovarian cancers.

Patients in PROfound were treated with 300 mg twice daily of Lynparza®, or investigators’ choice of Xtandi® (160 mg daily) or Zytiga® (1,000 mg daily, plus prednisone). Lynparza’s safety and tolerability results were generally consistent with previous trials. The PROfound trial is expected to fully conclude in February 2021.

“This is the only positive Phase 3 trial of any PARP inhibitor in metastatic hormone-resistant prostate cancer, where the need for new, effective therapies is high,” according to José Baselga, AstraZeneca’s executive vice president, Oncology R&D. “The PROfound trial also demonstrates the potential value of genomic testing in this at-risk patient population.”  Roy Baynes, senior vice president, head of global clinical development and chief medical officer at Merck Research Laboratories, said trial results “represent the potential for a new, oral, and targeted treatment option for this patient population.”

Lynparza® is being tested in other prostate cancer trials, including the international PROpel Phase 3 study testing the addition of Lynparza® to Zytiga® as a first-line treatment of mCRPC patients who have not been given chemotherapy or newer hormonal agents (NCT03732820). PROpel is currently enrolling up to 720 men at sites across the U.S., Canada, Europe and elsewhere.

The material above was summarized from an article appearing in Prostate Cancer News Today, August 12, 2019 to which an e mail subscription is highly recommended.

 

Additional note on how PARP inhibitors work. DNA is damaged thousands of times during each cell multiplication cycle, and that damage must be repaired, including in normal as well as in cancer cells (which multiply and grow faster than normal cells). Otherwise, if DNA damage is not repaired, cells may die due to this damage. BRCA1, BRCA2 and PALB2 are proteins in cells that are important for the repair of double-strand DNA breaks by the error-free homologous recombinational repair, or HRR, pathway. PARP1 is a protein that is important for repairing single-strand breaks (‘nicks’ in the DNA). Drugs that inhibit PARP1 cause multiple double strand DNA breaks to form in this way, and in tumors with BRCA1, BRCA2 or PALB2  mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don’t replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair system operating, which allows them to survive the inhibition of PARP by drugs like Lynparza®.

 

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.

The ENZAMET trial enrolled more than 1,100 men 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 enzaluatamide had a 33% reduced risk of death, with 80% still alive compared with 72% of men treated with ADT plus another antiandrogen drug. 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 (taxotere). 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.

From the standpoint of efficacy, similar results were seen in the TITAN trial with apalutamide (Erleada). 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.

What factors would influence the choice of treatments? In the case of enzalutamide and apalutamide, Dr. William Dahut, clinical director of the National Cancer Institute’s Center for Cancer Research 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. Other factors such as insurance costs may also affect treatment choice.

For additional details, see the following article published June 19th, 2019 on line by the National Cancer Institute (NCI) Cancer Currents Blog.

A recent study presented on May 3-6 at the American Urological Association’s 2019 Meeting found that treating metastatic, hormone-resistant prostate cancer (mCRPC) patients (who had not received chemotherapy) with Xtandi (enzalutamide) leads to better survival outcomes and lower healthcare costs than Zytiga (abiraterone acetate).

While therapies that lower male sex hormones (testosterone) — required for prostate cancer to survive and grow — are a mainstay of therapy for advanced prostate cancer, most patients will eventually acquire resistance to such approaches. This often happens because the cellular receptor for these hormones, called the androgen receptor, becomes constantly active, even in the absence of androgens. Therapies that inhibit the androgen receptor — such as Pfizer and Astellas’ and Xtandi and Janssen’s Zytiga — have largely improved the overall survival of prostate cancer patients, and are now approved for mCRPC patients in the U.S. and Europe. However, which treatment brings the most benefits or the lowest healthcare costs has not been addressed.

In this study, researchers performed a retrospective study to compare the overall survival and healthcare costs associated with these two second-generation androgen receptor inhibitors. They examined data from 3,174 adult men with mCRPC who had not received chemotherapy for at least one year before starting treatment with either Xtandi or Zytiga. Patients had been treated between April 2014 and March 2017, and their data were recovered from the Veterans Health Administration (VHA) database. Overall, 1,945 patients, mean age 73, received Zytiga, while Xtandi was administered to the remaining 1,229 patients, mean age 74.

After examining outcomes of these patients, researchers found that those on Xtandi lived for a median of 30 months, compared to 26 months for Zytiga. This represented a significant 17% reduction in mortality risk with Xtandi. Xtandi-treated patients also required fewer outpatient visits — both overall and cancer-related — than those treated with Zytiga, indicating that Xtandi led to a reduced use of medical resources. In line with this, Xtandi patients had fewer healthcare costs than Zytiga patients. In total, a patient treated with Xtandi would have a monthly healthcare cost of $8,085, compared to $9,092 for Zytiga. Prostate cancer-related costs were also lower for Xtandi — $6,321 versus $7,280.

Thus, researchers concluded that “chemotherapy-naive mCRPC patients treated with Xtandi had better survival, significantly lower resource use and healthcare costs than patients treated with Zytiga.”

The above appeared in the e mail Prostate Cancer News Today, May 16th, 2019.

Treatment with the radioactive molecule lutetium-177-PSMA-617 (LuPSMA), which binds to the prostate-specific membrane antigen, is a potential therapeutic strategy for patients with metastatic castration (hormone)-resistant prostate cancer (CRPC), results from a Phase II pilot study suggest.

Prostate-specific membrane antigen (PSMA) is found at high levels in prostate cancers, particularly in patients with hormone-resistant disease — a form of cancer that no longer responds to hormone therapy and continues to progress. More research is assessing the potential of using agents that target this protein to deliver radioactive compounds directly into cancer cells. The LuPSMA molecule is composed of an anti-PSMA antibody bound to the radioactive compound Lutetium-177. Its safety and efficacy are being assessed in a pilot Phase 1/2 study by researchers at the Peter MacCallum Cancer Centre, Melbourne, Australia.

The trial enrolled 50 metastatic CRPC patients whose tumors were positive for the PSMA factor. Their cancer had progressed after standard treatments, including hormone therapy and chemotherapy, and they were offered four doses of LuPSMA, each given six weeks apart. Participants had rapidly progressing disease, taking 2.6 months to double their PSA levels — a marker of prostate cancer. Most patients had received the chemotherapies docetaxel (Taxotere; 84%) and  cabazitaxel (Jevtana; 48%). Hormone therapy with Zytiga (abiraterone), Xtandi (enzalutamide) or a combination of both had been given to 90% of patients.

The study’s primary goals were to measure the number of patients whose PSA levels dropped and the treatment’s toxicity. Additional objectives included imaging responses, time patients lived without disease worsening, overall survival, and quality of life scores.

Investigators reported a reduction in PSA levels by at least 50% in 64% of patients, including 44% who experienced a reduction of at least 80%. Among the 27 patients with measurable disease at the study’s start, 56% experienced a partial or complete tumor reduction. The median time patients lived without disease worsening — measured through a rise in PSA levels — was 6.9 months. Their median overall survival was 13.3 months. A total of 14 patients received additional LuPSMA doses after their disease progressed. In nine of these patients (64%), PSA levels reduced by at least 50%. The most common side effects were dry mouth, nausea, and fatigue. Serious side effects were rare and included abnormally low levels of platelets and anemia, both detected in 10% of cases.

Overall, these early findings confirm the “high response rates and low toxicity with LuPSMA in men who had progressed after standard therapies,” even “in patients who subsequently progressed and were administered further LuPSMA,” the researchers wrote. “These results have provided the basis for randomised controlled trials currently underway,”

These findings were shared in a poster presented at the  2019 Genitourinary Cancers Symposium, Feb. 14–16 in San Francisco.

Results from a Phase 3 clinical trial reveal that adding the androgen receptor inhibitor darolutamide to androgen deprivation (hormone) therapy (ADT) extends by 22 months (from 18.4 months to 40.4 months) the time men with hormone-resistant prostate cancer live without metastasis and without increasing the incidence of adverse events. The treatment also extended survival, time to pain progression, time until chemotherapy was needed, and kept patients alive and progression-free for longer periods than ADT alone, researchers reported.

The investigational drug darolutamide can help delay the spread of prostate cancer to other parts of the body in men with non-metastatic, hormone-resistant disease, according to results from the ARAMIS clinical trial. In addition, trial results showed that the drug appears to lack some of the side effects seen with similar drugs used to treat men with this form of prostate cancer.

Until recently, there had been no effective treatment options for patients with non-metastatic, hormone-resistant prostate cancer. These men have prostate tumors that continue to grow even after receiving androgen deprivation (hormone) therapy (ADT)  to keep androgen (testosterone) levels in the body extremely low or undetectable. But over the last 2 years, two drugs have been approved by the Food and Drug Administration (FDA) to treat this form of the disease and some researchers expect that, based on the results of this new trial, darolutamide may be next.

The darolutamide findings, from an interim analysis of the ARAMIS clinical trial, were published in the New England Journal of Medicine and presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco on February 14.

The drug has a very favorable safety profile. The incidence of side effects was generally similar between the darolutamide group and the placebo group, noted study coauthor Karim Fizazi, M.D., Ph.D., of the Gustave Roussy Institute, University of Paris, who presented the results in San Francisco. Darolutamide was not associated with a higher incidence of side effects such as seizures, falls, fractures, cognitive changes, or hypertension. The ARAMIS climical trial results “strongly support the use of darolutamide” in patients with non-metastatic, hormone-resistant prostate cancer, said William Dahut, M.D., head of the Prostate Cancer Clinical Research Section of the National Cancer Institute’s (NCI) Center for Cancer Research.

Darolutamide, jointly developed by Bayer and Orion, belongs to a class of oral drugs called androgen (testosterone) receptor inhibitors.  It prevents the binding of testosterone to the androgen receptor on a cell, thus blocking signals that prostate cancer cells require to grow and proliferate. In the body, these agents compete with androgens for binding to the androgen receptor, which reduces the ability of androgens to promote the growth of prostate cancer cells.

In 2018, the Food and Drug Administration (FDA) approved both apalutamide (Erleada) and  enzalutamide (Xtandi) for men with non-metastatic, hormone-resistant prostate cancer. In the clinical trials that led to these approvals, the drugs were shown to improve the median time from random assignment until the tumor spread or the patient died—known as metastasis-free survival—in men with this form of prostate cancer. Treatment with both drugs, however, was associated with side effects related to the central nervous system, including fatigue, falls, and cognitive changes. In both trials, treatment with the respective drugs more than doubled metastasis-free survival compared with men who received a placebo: 40 versus 16 months in the apalutamide trial and 36.6 versus 14.7 months in the enzaluatmide trial.

The ARAMIS trial, which was sponsored by Bayer and Orion Corporation—the co-developers of darolutamide—included men whose prostate-specific antigen (PSA) levels were rising at a rate that has been associated with an increased risk of metastasis and death in previous studies. Metastasis-free survival was the primary endpoint of the trial; secondary endpoints included overall survival and the amount of time until a patient’s pain worsened.

The randomized trial included more than 1,509 men with non-metastatic, hormone-resistant prostate cancer whose PSA levels were rapidly rising while receiving hormone therapy. These men were considered to be at increased risk of having the disease spread to other parts of the body. All participants received ADT plus either darolutamide or a placebo. At a median follow-up of 17.9 months, the median metastasis-free survival was 40.4 months for patients receiving darolutamide plus ADT, compared with 18.4 months for patients receiving placebo plus ADT. The risk of metastasis or death from any cause was reduced by 59%. While more than half of patients were alive at the time of the analysis, the interim analysis pointed toward a 29% reduction in the risk of death for patients taking darolutamide. Also, the treatment extended the time patients lived without disease progression — 36.8 months versus 14.8 months — representing a 62% reduction in the risk of disease worsening or death. The 3-year overall survival rates were 83% in the darolutamide group and 73% in the placebo group, the researchers found. The median overall survival has not yet been reached in the study. The median amount of time until a patient’s pain got worse was longer in the darolutamide group than in the placebo group (40.3 months versus 25.4 months). It lowered the risk of needing a chemotherapeutic medication by 57%. The time to first skeletal event — such as radiation therapy to the bone, bone fractures, spinal cord compression, or bone surgery — was also longer with darolutamide.

Darolutamide has a different chemical structure than apalutamide and enzalutamide whose structures as similar, which the study authors believe may explain why it has fewer side effects. Darolutamide basically does not penetrate the blood-brain barrier, whereas apalutamide and enzalutamide do. The low incidence of central nervous system-related side effects seen in the trial was consistent with its rodent studies. Side effects likely to be related to the drug reaching the central nervous system include fatigue, dizziness, cognitive impairment, and seizures, according to the researchers. There was no detectable difference in the incidence of these side effects between patients treated with darolutamide and those who received a placebo, he added, noting that patients with a history of seizures were not excluded from the trial. In the trial, fatigue was the only side effect that occurred in more than 10% of participants in either group. A low incidence of side effects is particularly important for men who do not have symptoms of the disease, researchers noted. The percentage of participants who stopped taking either the drug or the placebo because of side effects was similar, i.e. about 9%.

In the coming years, researchers and patients hope to learn more about patient preferences for darolutamide, enzalutamide, and apalutamide. For example, an ongoing clinical trial is comparing two of these androgen receptor inhibitors, darolutamide and enzalutamide in men with metastatic hormone-resistant prostate cancer to determine which drug patients prefer based on their responses to a questionnaire. Patients will first take one drug and then the other. In the meantime, darolutamide has already received Fast Track designation by the U.S. Food and Drug Administration for the treatment of non-metastatic, hormone-resistant prostate cancer patients.

The information above appeared in the National Cancer Institute (NCI) e mail periodical, NCI@updates.cancer.gov, dated March 15th, 2019.