Kristie L. Kahl

From 1999 to 2016, testosterone levels have declined in adolescent and young adult men (AYA), according to results presented at the 2020 American Urological Association Virtual Experience

“Overall male testosterone decline can be attributed to multiple etiologies. The United States has an aging population with older males exhibiting lower testosterone levels. Furthermore, overall population has an increase in comorbidities, including diabetes, which may have cause this testosterone decrease nationally,” Soum Lokeshwar, MD, MBA, incoming urology resident at Yale School of Medicine, New Haven, Connecticut, said during a press briefing.

“However, most of these explanations for testosterone deficiency may be attributed to age. This time-dependent decline in testosterone has not been investigated in adolescent and young adult males,” added Lokeshwar, who was at the University Of Miami Miller School of Medicine, Miami, Florida, at the time of the study.

Testosterone deficiency has a prevalence of 10%-40% among adult males, and 20% among AYA men aged 15-39 years, he added. Therefore, Lokeshwar and colleagues hypothesized that serum total testosterone levels will decline in AYA men.

The investigators used data from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2016 to analyze serum testosterone level changes over time in 4045 AYA males. During the study periods, 3 different assays (Biotin-Streptavidin from 1999-2004, IS-Liquid Chromatography from 2011-2012, and High-Performance-Liquid-Chromatography Tandem Mass Spectrometry from 2013 onwards) were used. However, of note, they demonstrate comparable testosterone values with only some additional accuracy in the latest modality, Lokeshwar said.

After controlling for confounders—including year of study, age, race, BMI, comorbidity status, alcohol and smoking use, and level of physical activity—total testosterone was lower among men in the later (2011-2016) versus earlier (1999-2000) cycles (

 < 0.001). Mean total testosterone decreased from 1999-2000 (605.39 ng/dL), 2003-2004 (567.44 ng/dL), 2011-2012 (424.96 ng/dL), 2013-2014 (431.76 ng/dL), and 2015-2016 (451.22 ng/dL; all 

Elevated BMI was associated with reduced total testosterone levels (P < .0001), with the mean BMI increasing from 25.83 in 1999-2000, to 27.96 in 2015-2016 (

 = 0.0006). Lokeshwar noted that even men with a normal BMI (18.5-24.9) had declining total testosterone levels (

Potential causes include increased obesity/BMI, assay variations

According to Lokeshwar, potential causes for these declines could be increased obesity/BMI, assay variations, diet/phytoestrogens, declined exercise and physical activity, fat percentage, marijuana use, and environmental toxins.

“We’ve seen that lower values of testosterone have been associated with increased comorbidities and an increase risk for all-cause mortality. This decline specifically, in these young adult men, with increased obesity may lead to an increase in precocious cancer,” Lokeshwar said, adding such decreases can also result in a lower libido and an increased risk for erectile dysfunction.

“This is especially worrisome in this young adult age group, as many men feel stigma and are less likely to seek care for these low libido and erectile dysfunction.” Lokeshwar added. “Testosterone levels in AYA men are used as the benchmark normal levels for testosterone. This is very scary, because generally, when we think of normal values of testosterone, we treat based upon this age group. This may ultimately lead to the undertreatment of testosterone deficiency, which can have large ramifications and severe consequences.”

1. Patel P, Fantus R, Lokeshwar S, et al. Trends in Serum Testosteron Levels Among Adolescent and Young Adults Men in the United State. Presented at: 2020 AUA Virtual Experience; May 15, 2020. Abstract MP78-01.

Articles

The decline in total testosterone was observed even among men with normal body mass index.

Testosterone levels show steady decrease among young US men

RO7198457, a personalized cancer vaccine, in combination with atezolizumab (Tecentriq) induced showed clinical benefit with a manageable safety profile in patients with locally advanced or metastatic solid tumors, according to phase 1b clinical trial results presented at the AACR Virtual Annual Meeting II.

In dose escalation portion of the study, Juanita Lopez, MB, BChir, PhD, and colleagues administered 8 doses of RO7198457, ranging from 15-50 μg, in weekly and bi-weekly intervals during the 12-week induction stage and every 24 weeks during the maintenance stage plus 1200 mg of atezolizumab on day 1 of each 21-day cycle (n = 132).

To be included in the trial, patients had to be aged 18 or older, with advanced or recurrent solid tumors, a life expectancy of 12 weeks or more, and an ECOG score of 1 or more.

Patients were diagnosed with non-small cell lung cancer, melanoma, renal cell carcinoma, bladder cancer, triple-negative breast cancer, and serial biopsy select solid tumors. The median number of prior therapies was 3 (range, 1-11), which included 39% of patients who received prior immunotherapy. The majority of patients had low levels of PD-L1 expression, including 93% of patients with <5% PD-L1 expression on tumor cells and 79% of patients with <5% expression on immune cells.

The primary end point of the study was safety and tolerability. Secondary end points included maximum tolerated dose (MTD), determining the highest dose with acceptable toxicity, pharmacodynamic activity, and preliminary anti-tumor activity.

The median number of RO7198457 doses received was 8.

In total, 16% of patients discontinued treatment because of progressive disease prior to completing 6 weeks of therapy. Most adverse events (AEs) were grade 1/2, including infusion related reaction/cytokine release syndrome (CRS), fatigue, nausea, and diarrhea. Infusion related reaction/CRS were temporary and reversible. No dose-limited toxicities occurred.

Seven patients (5%) discontinued treatment due to AEs related to the study drugs.

The researchers detected ex vivo T-cell responses in almost 73% of patients (n = 63). There was a median 2.6neoantigen-specific responses (range, 1-9); however, ex vivo data was not available for all vaccine targets because of limited material availability and T-cell fitness, Lopez, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, said during a press briefing held ahead of the meeting.

CD4 and CD8 T-cell responses were detected in 14 patients. Induction of pro-inflammatory cytokines with each dosing appeared to be similar to findings from phase 1a of the trial.

One complete response was observed in a patient with rectal cancer as well as 1 partial response in a patient with triple negative breast cancer (TNBC). The patient with TNBC was previously treated with anti PD-1 therapy and entered the study with visual and lymph node metastasis that all shrank or disappeared after receiving induction treat, Lopez said. “In this patient, we observed the induction and enhancement of 2 new antigen immune responses by ex vivo. One of the de novo CD8 responses was confirmed using MHC multiple analysis with a magnitude of new antigen specific T cells reaching 2.2%,” she added. “At the peak of the response, this patient remains well on study after one and a half years.”

Moreover, preliminary evidence suggested there was infiltration of the vaccine that stimulated T cells in the tumors.

Lopez noted that in vitro stimulation ELISPOT as a more sensitive measure for immune responses to RO7198457 is ongoing.

Neoantigens that arise from somatic mutations can be promising targets for cancer immunotherapy because they are recognized by the immune system as foreign. “Most of these mutated new antigens are not shared between patients,” Lopez said. “Therefore, targeted new antigen specific therapy requires an individualized approach.”

RO7198457, a messenger RNA (mRNA)-based cancer vaccine that is manufactured on a per-patient basis, is produced by sequencing tumor and blood samples and identifying tumor- specific neoantigens. Up to 20 neoantigens are selected for the corresponding mRNA to be generate before being compressed into a liposomal formulation to enable intravenous administration, “preferentially to antigen presenting cells, including dendritic cells in the spleen,” Lopez said.

The mRNA stimulates the immune system and encodes the neoantigens to stimulate an antitumor immune response.

Elaine R. Mardia, PhD, FAACR, co-executive director and endowed chair at the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, commented on the study, commending the unique study design. “Dr. Lopez and colleagues from cancer centers in Europe, Canada, and US conducted a phase 1b clinical trial with a very unique trial design, namely, combining a new antigen mRNA-based vaccine that includes specific targets unique to each patient or combination with atezolizumab,” she said. “The unique trial design that they presented combines dosing of the vaccine with dosing of the anti PDL-1 antibody and differ significantly from the handful of patients that have been described earlier in the literature.”

Lopez JS, Camidge R, Iafolla M, et al. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors. Presented at: AACR Virtual Annual Meeting II; June 22-24, 2020.

The combination of the personalized cancer vaccine RO719845 and the PD-L1 inhibitor atezolizumab showed strong clinical activity across solid tumors, including bladder cancer and renal cell carcinoma.

Personalized cancer vaccine combo induces clinical benefit in advanced solid tumors

Men whose activity exceeded guideline-based exercise levels experienced a decreased likelihood of lower serum testosterone, according to study results presented at the American Urological Association 2020 Virtual Experience.

Richard J. Fantus, MD, from the University of Chicago, explained during a press briefing that the AUA republished guidelines in 2018 stating that all men with testosterone deficiency should be counseled regarding weight loss programs as an initial treatment strategy.

“(Weight loss programs) are relatively inexpensive and safe and reversible,” he added, saying that losing weight can improve a man’s testosterone and improve the signs and symptoms associated with testosterone deficiency.

In 2018, the Physical Activity Guidelines Advisory Committee (PAGAC) set a target activity goal of 500-1000 metabolic equivalent of task (MET) minutes per week.

Using the National Health and Nutrition Examination Survey (NHANES) database from 2011-2016, the researchers evaluated 7597 men between the ages of 18 to 80 who answered the physical activity questionnaire and underwent serum T testing to determine if PAGAC activity thresholds were associated with the likelihood of having low testosterone.

Men were divided into 3 groups of activity levels using PAGAC recommendations: less than recommended (<500 MET minutes/week), recommended (between 500 and 1000 MET minutes/week), and greater than recommended (>1000 MET minutes/week). Activity was categorized as work, recreational, or for transportation, then further divided into vigorous or moderate.

The association between activity level and low T (<300 ng/dL) was analyzed using a multivariable logistic regression controlling for known confounders. Men with prostate cancer were excluded from the study.

The majority of men (n= 4461; 58.7%) accumulated > 1000 MET minutes/week, while 703 (9.3%) met the recommended activity level and 2433 (32%) did not meet the recommended level of activity. Men who did not meet the 500 MET minutes per week tended to be older, with higher BMIs, a higher likelihood of comorbidity, and a higher likelihood of diabetes.

The average testosterone level of the entire cohort was 413.1 ng/dL. Among the entire cohort, lower serum testosterone was detected in 2201 men (29%)-occurring more often in men who were older, obese, had 1 or more comorbidities, and were less physically active.

According to the multivariate analysis, those whose activity exceeded the recommended guidelines demonstrated a significant decrease in the likelihood of lower serum testosterone (OR, 0.631; 95% CI, 0.549-0.72; 

 < .001), compared with men whose activity levels were lower than recommended. Using the same covariates, the researchers found the association between lower activity level and low testosterone to be significant in the obese group of men (

Fantus noted the study was limited by its cross-sectional design, the self-reported activity leading to potential bias, as well as testosterone levels only being measured once and no data reported on participants’ symptoms. However, he added, the study is the largest of its kind with a generalizable cohort.

“Exercise is an important lifestyle modification that should be offered to everyone,” Fantus said. “More is better. Greater than 1000 MET minutes per week has been shown to have numerous additional benefits. That being said, when counseling men regarding low testosterone and exercise, it is incredibly important to really counsel the obese population as exercise, independent of weight loss, may show additional benefits.”

1.      Fantus R. The Association Between Exercise and Serum Testosterone Among Men in the United States. Presented at: AUA 2020 Virtual Experience; May 15, 2020. Abstract PD25-03.

Exceeding exercise guidelines may reduce likelihood of low T in men

Results from the phase III TIVO-3 trial of tivozanib (Fotivda) demonstrated a statistically significant improvement in median progression-free survival (PFS) compared with sorafenib (Sutent), as well as favorable tolerability, in patients with relapsed or refractory renal cell carcinoma (RCC).

These agents were previously evaluated in the frontline setting of this patient population in the phase III TIVO-1 trial, which showed a slight advantage in PFS and response rates for tivozanib; however, overall survival benefit was in favor of sorafenib. In a recent interview with Brian Rini, MD, from Vanderbilt-Ingram Cancer Center, he explained the one-way crossover design of the study was a flaw.

In the phase III TIVO-3 trial – designed to evaluate tivozanib versus sorafenib in patients who had received 2 or 3 prior lines of therapy – the vascular endothelial growth factor tyrosine kinase inhibitor demonstrated a statistically significant improvement in median PFS compared with sorafenib, at 5.6 months versus 3.9 months, respectively. Moreover, 2-year PFS rates were 18% versus 5% in favor of tivozanib.

In addition, response rates were higher and the agent induced durable responses with favorable tolerability.

 about the two trials, and why results from the phase III TIVO-3 trial are key in demonstrating another treatment option for patients with advanced RCC.

TIVO-1, which was done many years ago, was also versus sorafenib. It was a frontline study that showed progression-free survival advantages to tivozanib over sorafenib. It was positive from that sense with a pretty clear progression-free survival advantage, good tolerability. That was all good. Where the problem was is that this study was conducted largely in the Russian Ukraine, and the study design, which was fatally flawed, had a one-way crossover, meaning patients who failed sorafenib could cross over and receive tivozanib. Most of those patients did, and they did quite well, not surprisingly, on tivozanib in that setting. Patients on tivozanib who progressed did not cross over to anything, and in those countries, very little else was available. In essence, it became a study of two sequential TKIs versus just one. While it wasn’t significant, there was a numerical advantage in survival in patients who got the sorafenib-tivozanib sequence. Because of that, the FDA was hesitant to approve the drug and did not approve the drug. Hence, the need for TIVO-3.

There are two main differences (between the trials). One is that TIVO-3 was done in a third- and fourth-line setting, whereas TIVO01 was frontline. Otherwise, the comparator was the same – sorafenib. The results showed a progression-free survival advantage. The absolute numbers are lower, of course, because it’s in a more refractory setting, but similar PFS advantage. There is not a difference in survival. So, there is not a numerical or statistical difference one way or the other. I think this really reaffirms that TIVO-1 was flawed because of that crossover, and when you give patients equal access to subsequent therapies. There was no crossover in either arm in TIVO-3, so patients could go on and get whatever therapy was available, or multiple therapies, in their country. I don’t know the number of patients who had subsequent therapy offhand, but the survival is basically overlapping, which is what we’ve seen in the major trials of VEGF versus VEGF in this refractory setting.

Results from the phase III TIVO-3 trial of tivozanib (Fotivda) demonstrated a statistically significant improvement in median progression-free survival compared with sorafenib (Sutent), as well as favorable tolerability, in patients with relapsed or refractory renal cell carcinoma.

Author | Kristie L. Kahl

Articles

Testosterone levels show steady decrease among young US men

Personalized cancer vaccine combo induces clinical benefit in advanced solid tumors

Exceeding exercise guidelines may reduce likelihood of low T in men

Further Evaluation of Tivozanib Shows Promise for Relapsed, Refractory Renal Cell Carcinoma