Year : 2020 | Volume
: 36 | Issue : 1 | Page : 6--7
Department of Urology and Kidney Transplant, Medanta the Medicity, Gurugram, Haryana, India
Department of Urology and Kidney Transplant, Medanta the Medicity, Gurugram, Haryana
|How to cite this article:|
Mandhani A. Round up.Indian J Urol 2020;36:6-7
|How to cite this URL:|
Mandhani A. Round up. Indian J Urol [serial online] 2020 [cited 2020 Jan 17 ];36:6-7
Available from: http://www.indianjurol.com/text.asp?2020/36/1/6/274700
Genomic next-generation sequencing has shown that most cancers are heterogeneous, and even in one particular type of cancer, heterogeneity can present at various places. This could be the reason for declining interest in the blanket use of immune checkpoint inhibitors in genitourinary cancers. After initial enthusiasm of rapid approval by the Food and Drug Administration (FDA) to various drugs against programmed cell death receptors PD-1 and its ligand PD-L1, i.e. pembrolizumab and atezolizumab for cisplatin-ineligible patients with metastatic bladder cancer, the FDA has changed its label and now recommends their use in only PD-L receptor-positive tumors.
Immune response is a dynamic process and so is the process of antigen presentation by the tumor. Immune response can happen in more than one way, so we need to gain insight into this immune response. Emerging trends in cancer management suggest that by targeting the constant antigens present on cancer cells with chemotherapeutic agents or radioisotopes, we could open a new frontier of personalized medicine. This emerging field of theranostics looks promising, and a recent study on the use of225 Ac-prostate-specific membrane antigen (PSMA)-617 in metastatic castration-resistant prostate cancer patients in pre-chemotherapy settings has shown the best response ever, even though in a small number of 17 patients only.  The dose was de-escalated from 8–4 MBq for 6 cycles at 2 months interval and the response was assessed by serum prostate-specific antigen [PSA] and68 Ga-PSMA positron-emission tomography/computed tomography scans. PSA decline was seen in 15/17 patients, with ≥90% decline in serum PSA in 82% of patients. This included 41% patients with undetectable serum PSA, who remained in remission for 12 months after therapy. None of the patients discontinued the treatment and none developed xerostomia, a dreaded complication of this therapy. Complete response and remission for 1 year are important yardsticks to measure such outcomes of PSMA-based radioligand therapy, but we need to test whether these benefits can be replicated on a larger scale.
With the widespread use of mirabegron, its safety profile in relation to antimuscarinic (AM) agents such as solifenacin and tolterodine is worth revisiting. In a large integrated clinical database taken from 10 randomized controlled trials of various phases, funded by Astellas Pharma Inc., the safety aspect was discussed in detail. It compared mirabegron (25 and 50 mg) and placebo with various AM agents such as solifenacin and tolterodine extended release (4 mg) in 11,261 patients (placebo, n = 3018; Mirabegron, n = 5244; AM, n = 2999). Although the efficacy was similar with all three, a higher overall frequency of adverse events was reported in older versus younger patients and in women versus men. Adverse events were 21.4% with AM versus 17% with mirabegron. This difference was due to higher incidence of dry mouth, i.e. 8.7% with AM versus 2.7% with mirabegron. New-onset hypertension was slightly higher with mirabegron, i.e. 3.9% versus 3.2%. Mirabegron may be a better option than AM for those aged 75 years and also for elderly patients susceptible to constipation and dry mouth.
Recent evidence has shown that in a newly diagnosed metastatic prostate cancer (also known as metastatic castrate-sensitive prostate cancer; mCSPC), androgen deprivation therapy (ADT) should be combined with one of three agents from among docetaxel, abiraterone, or enzalutamide to improve outcomes. A dilemma faced by clinicians is that of these three, which one should be used first? In a multinational, double-blind randomized trial on 1150 men with mCSPC, enzalutamide (160 mg/day) with ADT was compared with placebo with ADT for radiographic progression-free survival (ARCHES trial). There was significant reduction in progression of disease or death with enzalutamide plus ADT versus placebo plus ADT (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.30–0.50; P = 0.001; median not reached vs. 19.0 months). Although this trial has no survival data to compare with survival data from abiraterone (LATITUDE) or docetaxel (STAMPEDE) trials, reduction in HR for progression-free survival, HR of 0.39, 0.3–0.5, was found to be the highest with enzalutamide. Moreover, complications such as hypertension and hypokalemia are significantly lower with enzalutamide.
This indirectly suggests that there are alternative mechanisms to stimulate androgen receptors despite castrate level of testosterone and complete blockade of receptors rather than that total castration level of testosterone is desirable. This can also be supported by a fact, though in castrate-resistant setting, that abiraterone does not work well if it is given after enzalutamide, but it does so if it is given before enzalutamide.
A randomized trial on 202 patients assigned randomly (1:1) to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (Group A), or the opposite sequence (Group B), has shown that time to second PSA progression was longer in Group A than in Group B (median 19.3 months [95% CI 16.0–30.5] vs. 15.2 months [95% CI 11.9–19.8] months; HR 0.66, 95% CI 0.45–0.97, P = 0.036), at a median follow-up of 22.8 months (interquartile range 10.3–33.4). PSA responses to second-line therapy were seen in 26 (36%) patients. Hence, enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not. Therefore, if the cost of treatment is censored, enzalutamide may be the preferred first-line agent when it comes to a choice between abiraterone and enzalutamide.
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Conflicts of interest:
There are no conflicts of interest.
|1||Parikh RB, Adamson BJ, Khozin S, Galsky MD, Baxi SS, Cohen A, et al. Association between FDA label restriction and immunotherapy and chemotherapy use in bladder Cancer. JAMA 2019;322:1209-11.|
|2||Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, et al.225 Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: A pilot study. Eur J Nucl Med Mol Imaging 2019;46:129-38.|
|3||Chapple CR, Cruz F, Cardozo L, Staskin D, Herschorn S, Choudhury N, et al. Safety and efficacy of mirabegron: Analysis of a large integrated clinical trial database of patients with overactive bladder receiving mirabegron, antimuscarinics, or placebo. Eur Urol 2020;77:119-28.|
|4||Khalaf DJ, Annala M, Taavitsainen S, Finch DL, Oja C, Vergidis J, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: A multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol 2019;20:1730-9.6|
|5||Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, et al. ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2019;37:2974-86.|