Chlormadinone prolongs active surveillance, maintains QoL in men with prostate cancer

Use of the oral antiandrogen chlormadinone at a low dose led to improvements in persistence rate of active surveillance (AS), PSA* and testosterone levels and prostate volume, and quality of life (QoL) in men with low-risk prostate cancer (PCa), the PROSAS study has shown.

Radical prostatectomy (RP) apparently has better survival benefit than watchful waiting for PCa. However, its invasiveness and postoperative complications (eg, urinary incontinence, erectile dysfunction) are major drawbacks. [N Engl J Med 2014;370:932-942; N Engl J Med 2012;367:203-213]

AS bested RP in improving QoL in men with low-risk PCa. [Qual Life Res 2017;26:1635-1645] AS may also help avoid overtreatment. [Eur Urol 2015;67:44-50; World J Urol 2021;39:2491-2497] These suggest that AS should be considered a first-line treatment alternative rather than aggressive curative therapy in this patient setting after evaluating risk and life expectancy, the researchers said.

A total of 143 men with histologically diagnosed PCa were randomized 1:1 to receive either chlormadinone 50 mg/day or placebo. Apart from those indicated in the study protocol, PCa treatments** were disallowed, as was the use of other antiandrogens, 5αRIs***, or any invasive treatment for BPH^#. For those with BPH or difficulty in urination, treatment with α1-blockers and anticholinergics was permitted as needed. [Jpn J Clin Oncol 2021;doi:10.1093/jjco/hyab162]

At 3 years, AS discontinuation rate due to PCa progression was more than twofold higher with placebo vs chlormadinone (49 percent vs 21 percent; hazard ratio [HR], 0.417). This translated to a significantly higher AS persistence rate with chlormadinone vs placebo (76 percent vs 50 percent; p=0.0039). No-cancer-detected rate was also higher with chlormadinone vs placebo (65 percent vs 18 percent).

“These results suggest that antiandrogen therapy with low-dose chlormadinone may prolong AS persistence rate by suppressing PCa progression,” said the researchers.

Compared with placebo treatment, chlormadinone use led to significant reductions in PSA level throughout month 3 to 36 (p<0.0001), as well as in testosterone level (mean, 2.65 vs 5.42 ng/mL; p<0.0001), prostate volume (mean, 23.7 vs 39.0 mL; p=0.0049), and number of positive cores (mean, 0.5 vs 2.1; p=0.0073) at 3 years.

Chlormadinone also outdid placebo in terms of QoL improvement, as reflected by the higher mean EPIC^## urinary summary score with the former vs the latter (94.2 vs 81.5; p=0.0027) at 3 years. A similar trend was seen in the mean EPIC domain-specific subscale scores for function (97.1 vs 86.6; p=0.0161), bother (92.1 vs 77.8; p=0.0030), incontinence (96.1 vs 85.3; p=0.0159), and irritation/obstruction (94.3 vs 81.1; p=0.0038).

“LUTS^### has been shown to affect anxiety in PCa patients undergoing AS. [Therefore,] the QoL improvement with chlormadinone may be related to the LUTS improvement because of the reduction in prostate volume,” the researchers explained.

As for the sexual subscale, mean function score was substantially lower with chlormadinone vs placebo at 3 years (6.8 vs 16.3; p=0.0459). “This was due to a decrease in testosterone levels caused by antiandrogen therapy and is a known effect of chlormadinone,” they said.

Compared with placebo, chlormadinone was tied to a higher incidence of adverse events (AEs; 44 percent vs 12 percent) and serious AEs (6 percent vs 1 percent). The most common AE tied to chlormadinone use was constipation (22 percent) and hepatobiliary disorders (10 percent). These findings mirrored the previously reported safety profile of chlormadinone, said the researchers.

“[Taken together,] in this study, administration of chlormadinone showed reduced positive core count, improved urinary QoL, and increased AS persistency in low-risk PCa patients,” said the researchers. “Since AS maintains QoL compared with other treatments, AS prolongation is considered to contribute to the prognosis of PCa patients.”

“[However,] this study only included patients aged ≥65 years with clinical stage T1c, N0, M0 PCa,” the researchers pointed out. Moreover, the effect of chlormadinone on Gleason score, as well as its longer term efficacy and safety, remain unknown. “The results of this study need to be interpreted with these factors in mind,” they said.