Lisette Hilton

Enzalutamide (XTANDI) treatment reduced risk of death in patients with nonmetastatic castration-resistant 

 and rapidly rising prostate-specific antigen (PSA) by 27% compared to placebo, according to research presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Enzalutamide, an androgen receptor inhibitor, is indicated for the treatment of men with castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer. This final analysis of the phase 3 PROSPER study supports enzalutamide and androgen deprivation therapy as the standard of care to improve overall survival in prostate cancer patients before the onset of detectable metastasis.

“This is great news for urologists who see patients with this type of disease. The data are reassuring that patients with nonmetastatic castration-resistant prostate cancer and a rapidly rising PSA have a safe and effective option that improves overall survival by almost 1 year,” according to the study’s lead author Cora N. Sternberg, MD, of Weill Cornell Medicine, New York-Presbyterian in New York City.

The Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer, or PROSPER, is a randomized, double-blind, placebo-controlled, multinational trial of about 1400 men with nonmetastatic castration-resistant prostate cancer. Patients had no evidence of metastatic disease, but their prostate cancer had progressed based on a rising PSA.

Researchers evaluated treating patients with once-daily 160 mg oral enzalutamide and androgen deprivation therapy vs placebo and androgen deprivation therapy.

PROSPER had previously shown enzalutamide resulted in a significant and clinically meaningful lower risk of radiographic progression or death, improvement in metastasis-free survival, of 71% compared to placebo. Overall survival data were immature when the investigators first reported their findings.

In this final overall survival analysis, median overall survival was 67.0 months among men who received enzalutamide compared to 56.3 months in the placebo arm. Sternberg and colleagues reported a median follow up of 48 months. Of 466 deaths, 288, or 30.9%, were in the enzalutamide arm vs 178, or 38.0%, in the placebo group.

Enzalutamide treatment resulted in 11 months of additional survival benefit for patients, according to Sternberg.

“Subsequent antineoplastic therapies were initiated after treatment discontinuation by 310 (33%) men in the enzalutamide arm vs 390 (84%) in the [placebo] arm. This includes patients who crossed over to receive enzalutamide. Median duration of treatment was 33.9 mo vs 14.2 mo with enzalutamide vs [placebo], respectively,” according to the presentation.

Forty-eight percent of men in the enzalutamide arm and 27% in the placebo arm reported grade 3 or higher adverse events, including falls, fatigue, and hypertension. In the enzalutamide arm, 16% of adverse events were drug-related vs 6% in the placebo arm.

“The safety profile was consistent with the established safety profile of enzalutamide. These data should be reassuring to colleagues who are interested in overall survival data and this is a confirmation of metastasis-free survival results,” Sternberg said.

Disclosure: Pfizer and Astellas Pharma funded the trial. Dr. Sternberg has been a consultant to Astellas Pharma, AstraZeneca, Bayer, Incyte, Merck, MSD, Pfizer, Roche, Roche-Genentech, Clovis and Sanofi-Genzyme. For full disclosures, 

Articles

This final analysis of the phase 3 PROSPER study supports enzalutamide and androgen deprivation therapy as the standard of care to improve overall survival in prostate cancer patients before the onset of detectable metastasis.

Enzalutamide reduces risk of death in men with nmCRPC by 27% vs placebo

Apalutamide (ERLEADA) combined with androgen deprivation therapy improves overall survival more than androgen deprivation therapy alone in men with non-metastatic castration-resistant prostate cancer at high risk of metastases, according to results from investigators’ final analysis of the phase 3 Study of Apalutamide in Men With Non-Metastatic Castration-Resistant Prostate Cancer (SPARTAN) trial.

Apalutamide, an androgen receptor inhibitor, became the first FDA-approved therapy for non-metastatic castration-resistant prostate cancer in February 2018. In September 2019, the FDA approved apalutamide for the treatment of patients with metastatic castration-sensitive prostate cancer.

Investigators enrolled 1207 patients in the SPARTAN study, who were randomized 2:1 to receive either 240 mg apalutamide orally once daily in combination with androgen deprivation therapy or placebo once daily in combination with androgen deprivation therapy.

The FDA’s first approval of the drug was based on the primary SPARTAN analysis. Investigators found that in a median follow-up of 20 months, treatment with apalutamide significantly delayed development of metastases, as well as the development of symptoms, according to Eric Small, MD, of the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

Small, the lead SPARTAN study investigator, presented the results of this study during the 2020 American Society of Clinical Oncology Virtual Scientific Program.

“What remained unanswered was whether using a novel androgen receptor targeting agent used early before the development of metastases, as opposed to waiting until metastatic castration-resistant prostate cancer, could prolong life,” Small said. “The answer is yes.”

At their final survival analysis with a median follow-up of 52 months, Small and coauthors found that apalutamide significantly increased overall survival from 59.9 months to 73.9 months. That’s an increase of 14 months in median survival, with a hazard ratio for death of 0.78, with 

“If you correct for the benefits in survival from crossing over from placebo to apalutamide, the increase in survival goes up to 21 months,” he said.

The combination decreased the risk of death by 22%. And treatment with apalutamide and androgen deprivation therapy significantly delayed patients’ time to cytotoxic chemotherapy compared to placebo in combination with ADT, with a hazard ratio of 0.63 and 

“A fair question that is always raised about studies like this where an active agent is used early, is if overall survival is improved not because earlier is better than later, but because the placebo group ends up not getting any active therapy at all. The study ends up being a study of early treatment versus no treatment,” Small said.

That wasn’t the case in SPARTAN, according to Small.

“Over 80% of placebo patients went on to receive active, life-prolonging, FDA-approved therapy. Around 70% of placebo patients went on to receive abiraterone or other life-prolonging therapy at the time of metastases. All 19% of placebo patients who hadn’t yet progressed at the time of study unblinding went on to receive open-label apalutamide. Parenthetically, in addition to prolonging life, apalutamide also significantly delayed the time to chemotherapy use, a secondary end point of the trial,” he said.

Small said that in his estimation, the data are really important to the practicing clinician and an absolute game-changer for patients with prostate cancer.

“We already knew that apalutamide would delay time to metastases. But there was always this gnawing worry that maybe we were burning that bridge, and that it would ultimately disadvantage the patient to use this therapy early. In fact, the results in SPARTAN were exactly the opposite. Early use prolongs life, even when compared to later use. This means that we can use apalutamide in non-metastatic castration-resistant prostate cancer patients with the full confidence that we are prolonging life 

 not ‘burning a bridge’ that we will later regret,” Small said.

Apalutamide’s safety and tolerability were consistent across studies. Median treatment duration was nearly 3 times longer, at 33 months, for patients treated with apalutamide plus androgen deprivation therapy compared to 12 months in the placebo group. The most common adverse reactions in the SPARTAN study, occurring in 10% or less of patients were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, falls, hot flush, decreased appetite, fracture, and peripheral edema.

Disclosures: Janssen Research & Development funded the phase 3 trial. Small has ties to Fortis, Harpoon Therapeutics, Janssen, Beigene, Janssen Oncology, Teon Therapeutics, Tolero Pharmaceuticals, and Merck. For full disclosures, 

Apalutamide (ERLEADA) combined with androgen deprivation therapy improves overall survival more than androgen deprivation therapy alone in men with non-metastatic castration-resistant prostate cancer at high risk of metastases, according to results from investigators’ final analysis of the phase 3 SPARTAN trial.

Apalutamide plus ADT improves OS in men with non-metastatic castration-resistant PCa

U.S. academic centers using the Soltive SuperPulsed Laser System to treat stones are finding it offers several advantages compared with holmium:YAG laser lithotripsy. But more research comparing the two is needed, according to a presentation at the 2019 World Congress of Endourology in Abu Dhabi, United Arab Emirates.

The Soltive SuperPulsed Laser System is a new lithotripsy platform. It is different than holmium:YAG laser technology, which urologists have used for more than 20 years to treat kidney stones, according to presenting author Wilson Molina, MD, professor of urology and director of the Kidney Stone Disease Program at the University of Kansas Medical Center, Kansas City.

Whereas holmium:YAG laser lithotripsy typically uses 200-Î¼m to 365-Î¼m optical laser fibers, the Soltive SuperPulsed Laser System allows the use of 150-Î¼m core-sized fibers. Dr. Molina, along with urologist colleagues from Ohio State University, Columbus, presented a comparison of lithotripsy with a 242-Î¼m core-sized fiber holmium:YAG (AccuMax 200), to the 150-Î¼m core-sized SPTF.

“The thulium fiber platform has an advantage compared to the holmium:YAG in that it’s a portable system, which urologists can plug into a 120-volt outlet. If you can plug in your cell phone, you can plug in the machine,” Dr. Molina said.

Another advantage of the new technology, which the FDA cleared in August 2019, is that it isn’t noisy, according to Dr. Molina.

The Soltive SuperPulsed Laser System offers laser settings that the holmium does not, including high-frequency settings up to 2400 Hz. Urologists could use the Soltive SuperPulsed Laser System for dusting or fragmenting kidney stones, Dr. Molina said.

Soltive laser energy highly absorbed by water

In theory, the Soltive technology should be more effective for stone treatment because the laser's energy is highly absorbed by water.

“The laser energy is emitted at a wavelength of 1,940 nm, which is at the tip of the curve for water absorption. For that reason, it is probably more effective than the holmium laser,” he said.

Because the profile of the beam generated by the Soltive SuperPulsed Laser System is smaller than the beam profile created by the holmium laser, the Soltive SuperPulsed Laser System can use smaller laser fibers-as low as 50 Î¼m, based on bench testing. The holmium laser can only use fibers greater than 200 Î¼m.

“There are three advantages of using smaller fibers. Number one, smaller fibers allow the ureteroscopes to have a better flexion in order to navigate inside the kidney easier. The Olympus 150 µm fiber has greater flexibility and is able to bend to a tighter diameter before thermal breakdown compared to the AccuMax 200. Number two, with small fibers, we have better irrigation during the procedure with better visualization. Third, it potentially delivers energy in a smaller area of the stone, creating fragments that are smaller dust-type fragments,” Dr. Molina said.

Nearly all patients with kidney stones who can be treated with an endoscopic retrograde approach would benefit from the new technology.

“I think this laser could be used for a retrograde approach in patients that have larger stones that cannot undergo the percutaneous approach for reasons such as other comorbidities because it has the potential to be faster in terms of breaking up the stones,” Dr. Molina said.

The drawback to using the Soltive SuperPulsed Laser System is that it's new and has had limited use in a clinical setting, though more data will soon be available through a limited launch of the technology initiated in October 2019 at a total of 15 sites.

“There is some long-term clinical data from a similar technology abroad that is promising. But until we have long-term clinical data that compares with the holmium laser, we cannot make any consistent evaluation,” Dr. Molina said.

Dr. Molina and colleagues have submitted an abstract of the first 25 cases detailing use of the laser to perform the retrograde approach, but it is not yet published. He said researchers have shown so far that the thulium laser is feasible to use and is safe for patients.

Dr. Molina helped to develop the Soltive SuperPulsed Laser System and is a consultant for Olympus.

SuperPulsed thulium fiber laser shows several advantages

Unhealthy eating, like that associated with the Western diet, is associated with notably worse semen quality and less favorable testicular function than healthier eating patterns, according to a study of nearly 3,000 young Danish men published in 

Researchers at Harvard T.H. Chan School of Public Health, Boston performed a cross-sectional study of men in Denmark (median age, 19 to 20 years) who didn’t know their fertility status and had filled out a validated food frequency questionnaire. The authors assessed semen quality and concentrations of total and free testosterone, estradiol, inhibin B, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin. They also studied testicular volume.

“This study is the largest study to date to examine diet pattern with men’s testicular function,” said study co-author Feiby Nassan, ScD, MBBCH, MSc, a research associate at the Harvard T.H. Chan School of Public Health who worked on the study with Niels JÃ¸rgensen, MD, PhD, and colleagues.

Decline of semen quality is a growing concern in men around the world. Total sperm count among men in Western countries fell by 50% to 60% from 1973 to 2011, according to a meta-analysis of 185 studies published in 

Why this is happening is a topic of debate. And while authors are looking at environmental exposures, such as pollution, and behavioral factors, such as smoking and alcohol consumption, they say few have looked at diet quality as a possible cause.

Dr. Nassan and colleagues identified four popular dietary patterns: the largely unhealthy Western diet, with staples such as pizza, processed and red meats, refined grains, and sweets; the generally healthy prudent diet, emphasizing fish, chicken, vegetables, fruit, and water; the traditional Danish open-sandwich pattern, featuring consumption of cold, processed meats, whole grains, mayonnaise, cold fish, condiments, and dairy; and a vegetarian-like pattern, which avoids red meat and chicken and emphasizes vegetables, soy milk, and eggs.

They found that men consuming a Western diet had the lowest total median sperm count at 122 million. Men consuming foods associated with the prudent pattern had the highest median total sperm count at 167. Median sperm counts were 151 million for the vegetarian-like and 146 for the open-sandwich patterns.

Average sperm counts varied within the categories. For example, men in the highest quintile of Western diet consumers had an average 26 million sperm count lower than men in the lowest quintile of Western diet eaters. And those that adhered most to the prudent pattern, the highest quintile, had an average 43 million more sperm than prudent eaters in the lowest quintile.

Men who highly adhered to the open-sandwich pattern had higher counts of motile spermatozoa, while those who consumed a vegetarian-like pattern were more likely to have more morphologically normal spermatozoa compared to men in other dietary categories. Further, men in the highest quintile of Western diet consumers had lower serum inhibin B concentrations and ratios of inhibin B to follicle-stimulating hormone than men in the lowest quintile of Western diet eaters.

Hormone results ‘difficult to explain’

“The hormone results are difficult to explain. Men who had the highest adherence to the Western pattern had higher testosterone concentrations, compared with men with less adherence. But they also had the highest estradiol concentration with unchanged luteinizing hormone levels,” Dr. Nassan said. “This could be due to increased aromatization of testosterone to estradiol and could have resulted in increased negative feedback at the hypothalamic level. If this is correct, this might also explain why follicle-stimulating hormone was not sufficiently higher as a compensation for the lower inhibin B concentration.”

The authors speculated that adherence to the Western diet pattern, at least in part, could lead to reduced hypothalamic activity, which could explain the observed reduction in spermatogenesis, according to Dr. Nassan.

“In addition to this possible explanation, the lower ratio of inhibin B to follicle-stimulating hormone, itself, could also explain a direct adverse effect on the testicles,” she said.

A take-home for urologists, according to Dr. Nassan, is that it may be useful for men’s fertility to follow a generally healthy diet with higher intake of fish, chicken, vegetables, fruit, and water, while cutting back on pizza, French fries, processed and red meats, snacks, refined grains, high-energy drinks, and sweets.

“Patients usually come to your clinics asking those questions about what they should eat and what they should avoid to boost their fertility. Peer-reviewed evidence is limited to answer these questions. This study provides some evidence of the benefits of the generally healthy diet patterns that you could advise your patients to follow-especially the ones whose fertility may need a nudge and may benefit from such diets,” she said.

A limitation of the study is its cross-sectional design, as the authors cannot imply causation from the work.

“However, this does not mean that this association is not important. Many scientific groups, including ours, are working to further study the role of diet and environment on fertility. However, I do not think we have to wait until the perfect controlled blinded clinical trial to happen until we change behavior. In addition, many other studies have suggested consistent results with other health outcomes, so we really have little or nothing to lose if we follow a generally healthy diet,” Dr. Nassan said.

Unhealthy eating, like that associated with the Western diet, is associated with notably worse semen quality and less favorable testicular function than healthier eating patterns, according to a study of nearly 3,000 young Danish men published in JAMA Network Open (2020; 3:e1921610).

Author | Lisette Hilton

Articles

Enzalutamide reduces risk of death in men with nmCRPC by 27% vs placebo

Apalutamide plus ADT improves OS in men with non-metastatic castration-resistant PCa

SuperPulsed thulium fiber laser shows several advantages

Unhealthy diet associated with poor semen quality