【2021 EAU】Research progress on apatamide

*Only for medical professionals to read for reference.
The 36th European Association of Urology (EAU) Conference in 2021 will be held online from July 8th to 12th.
Among them, prostate cancer is a high-risk disease for men worldwide, with about 300 articles Research reports
.

As a new research hotspot, a new generation of non-steroidal AR inhibitor apatamide has appeared frequently at international conferences in recent years.
Next, I will share with you the three research results related to apatamide in this EAU conference.

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Abstract P0845 The results of the high and low tumor burden subgroups of the final analysis of the TITAN study of apatamide [1] The TITAN study is a multi-center, randomized, double-blind, controlled, prospective global phase III clinical study aimed at exploring apatamide +ADT and placebo (PBO) + ADT for the efficacy and safety of patients with metastatic hormone-sensitive prostate cancer (mHSPC)
.

In May of this year, the final analysis results of the efficacy and safety of the TITAN study were officially published in the Journal of Clinical Oncology (JCO)
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The results showed that at a median follow-up of 44 months, compared with placebo, apatamide combined with ADT reduced the risk of death in patients by 35%.
After excluding the influence of cross-entry factors, apatamide can reduce mHSPC patients 48 % Risk of death [2]
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At this EAU conference, the prognosis of high tumor burden (HV) and low tumor burden (LV) patients receiving apatamide treatment in the final results of the TITAN study was updated
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The definition of high tumor burden: 1) visceral metastasis and ≥1 bone metastases; or 2) ≥4 bone metastases, one of which is outside the spine or pelvis
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At baseline, the proportion of patients with high tumor burden was 63%, and the proportion of patients with low tumor burden was 37% (apatamide group: HV n=325, LV n=200; control group: HV n=335, LV n=192 )
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The results showed that apatamide can significantly prolong the rPFS of patients with high tumor burden and low tumor burden
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Among them, the risk of imaging progression of patients with high tumor burden was reduced by 48% compared with the placebo group, and the risk of imaging progression of patients with low tumor burden was reduced by 64% (Figure 1)
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Figure 1 TITAN study high and low tumor subgroup rPFS results From the OS results, the use of apatamide treatment in patients with high tumor burden can reduce the risk of death by 30%.
After excluding the effects of cross-entry patients, this risk can be reduced.
Reached 39%; patients with low tumor burden were treated with apatamide, and the risk of death was reduced by 47%.
Similarly, after the effects of cross-entry were excluded, the benefit was more significant, and the risk of death could be reduced by 66% (Figure 2)
.

Figure 2 TITAN study high and low tumor subgroup OS results The results of other study endpoints all show that compared with placebo, apatamide: 1.
Significantly prolong the time to CRPC in patients with high tumor burden and low tumor burden, reducing 60% and 77 respectively % Risk of progress
.

2.
Significantly prolong the time to PSA progression for patients with high tumor burden and low tumor burden, reducing the risk of progression by 68% and 85%, respectively
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3.
From the results of PSA response, patients with low tumor burden treated with apatamide, the ratio of PSA ≤ 0.
2 ng/mL can reach 83.
5%, which is much higher than 43.
2% in the placebo group; the same in the apatamide group The proportion of patients with high tumor burden was also much higher than that in the placebo group (58.
2% vs 24.
8%)
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The above results indicate that regardless of whether mHSPC patients have high tumor burden or low tumor burden at baseline, they can all get significant benefits from treatment with apatamide
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 V41 Prognostic results of robotic radical prostatectomy after neoadjuvant apatamide treatment [3] The NEAR study is a phase II study that explores the treatment of neoadjuvant apatamide with robotic radical prostatectomy for the treatment of high-risk localized prostate cancer.
The clinical trial (NCT03124433) updated the prognosis of patients in this study at this EAU conference
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The study included 25 patients with moderate or high-risk localized prostate cancer who underwent robotic radical prostatectomy after receiving 240 mg of apatamide daily for 12 weeks
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Study outcomes included patient-reported outcomes, PSA changes, pathological and radiographic changes
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The results showed that after the use of neoadjuvant apatamide, the positive rate of surgical margins was significantly lower than that of the center's previous radical surgery alone, which was only 12% (previously 42.
9%)
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84% of patients reached the lowest PSA value less than 0.
03ng/ml after radical surgery
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In addition, the median blood loss was 200ml, the median catheter indwelling time was 8 days, and the median hospitalization time was 2 days.
These data are comparable to the previous data of only radical surgery
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In terms of patient reporting outcomes, the QLQ-C30 quality of life score with neoadjuvant apatamide remained stable
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The above results show that the use of neoadjuvant apatamide therapy can ensure significant short-term benefits on the basis of ensuring the quality of life of patients, and we look forward to long-term benefits in the future
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Abstract P0437 The role of apatamide and autophagy inhibitors in a human prostate cancer xenograft mouse model [4] In previous in vitro experiments, it was found that the up-regulation of autophagy is the survival of prostate cancer cells in anti-tumor therapy with apatamide Therefore, this study explored the autophagy response of using apatamide (APA) alone and in combination with the autophagy inhibitor ChI in an in vivo model
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The study used castrated nude mice and divided them into four groups after xenotransplantation of human prostate cancer cells.
They were the control group, the apatamide group (10 mg/kg), and the autophagy inhibitor ChI group (10 mg/kg).
And apatamide (10 mg/kg) combined with autophagy inhibitor ChI (10 mg/kg) group
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The tumor weight, size, histological analysis, western blot (WES) and immunofluorescence results of the samples were evaluated after 2 weeks and 3 weeks of culture
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The results showed that the tumor weight of the APA+ChI treatment group was lower than that of the control group, APA group and ChI group (APA+CHI 203.
2, APA 320.
4, ChI 337.
9, and control group 380.
4)
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The APA+ChI treatment group showed decreased expression of ATG5, Beclin 1, and LC3
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In addition, Ki67 nuclear staining was detected in all samples, but compared with the control group (100%), the staining in APA + Chl (58%) was reduced
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The above results indicate that the combined use of apatamide and the autophagy inhibitor Chl can significantly enhance its anti-tumor effect, and may provide patients with a new combination therapy in the future
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 Implications 1.
As a new generation of non-steroidal AR inhibitors, apatamide can block the combination of androgen and AR, block the androgen-AR complex from entering the nucleus and block the AR complex from DNA Combining three mechanisms of action to inhibit androgen signaling pathway [6]
.

Following the approval of NM-CRPC indications in China in 2019, new indications for mHSPC were approved last year.
Among them, the TITAN study at the mHSPC stage has recently been released with final analysis results, and the final OS analysis results have shown that Apa Tamide can significantly reduce the overall risk of death of mHSPC patients by 48% [2]
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For the formulation of treatment strategies for mHSPC patients, clinicians may consider stratified treatment of high and low tumors or high and low risks based on the research results of CHAARTED and LATITUDE
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The Titan study of the EAU conference's hierarchical analysis of tumor levels has given us a different direction of thinking
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First of all, for mHSPC patients with high tumor burden, due to the rapid disease progression, if only ADT treatment is used, previous studies have shown that patients will progress in about 8 months [7], which is also the same as the control group patients in the TITAN study who progressed to CRPC at 8.
3 months The situation is the same
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Therefore, for such patients, clinicians usually choose a new type of endocrine treatment represented by apatamide
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Secondly, for mHSPC patients with low tumor burden, domestic experts will routinely consider traditional CAB treatment based on the stratified treatment concept and previous clinical experience.
However, the EAU guidelines in 2021 pointed out that the 5-year survival benefit of traditional CAB compared with simple ADT is weak ( <5%)[8], so traditional CAB is no longer recommended as the standard treatment for mHSPC
.

Combined with the data from the low tumor load group of the TITAN study, apatamide can bring patients a 64% reduction in the risk of imaging progression and 66% of the risk of death, and it can deeply reduce the PSA of patients.
This result suggests We, even for patients with low tumor burden, first-line treatment with apatamide can bring significant benefits
.

2.
Patients with localized prostate cancer usually undergo radical prostatectomy.
For patients with high-risk characteristics, preoperative androgen blockade therapy may help reduce tumor burden and increase the possibility of complete resection
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In the past, neoadjuvant ADT was often used for treatment, but studies have shown that neoadjuvant ADT does not bring PSA recurrence-free survival and tumor-specific survival benefits [9], so the EAU guidelines do not recommend neoadjuvant ADT treatment before surgery [8]
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However, the direction of neoadjuvant therapy has not been abandoned by clinicians.
ADT combined with more powerful new endocrine therapy can reduce androgen levels to a greater extent and improve anti-tumor efficacy.
This is also one of the current research hotspots related to prostate cancer
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The initial results of the NEAR study at the 2019 EAU conference showed that neoadjuvant apatamide can significantly reduce the residual tumor burden [10]
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The latest results of the NEAR study also indicate that neoadjuvant apatamide has significant short-term effects including PSA and reducing the positive rate of resection margins.
Then whether it can bring sustained long-term benefits to patients, we also look forward to the ongoing three The PROTEUS study, a phase clinical trial, brings good news in the future
.

3.
New endocrine therapy combined with other treatments to treat prostate cancer has always been a research hotspot.
Among them, abiraterone is the leading one.
With the continuous discovery of new targets and new drugs, abiraterone is combined with chemotherapy, PARP inhibitors, and bone resorption inhibition.
Researches on drugs, etc.
are ongoing.
In this report, the autophagy inhibitor used in combination with apatamide has also been found to increase the anti-tumor activity of abiraterone [11], which means that the new endocrine therapy combined with autophagy Inhibitors of phagocytosis may become a new direction in the treatment of prostate cancer in the future, and we look forward to the results of related clinical studies in the future
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 The significant survival benefits of apatamide in the mHSPC and NM-CRPC stages have made it a powerful weapon in the field of prostate cancer.
With the continuous progress of research, we also expect that apatamide can be used in the earlier stage of the disease.
The stage brings benefits to patients
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Finally, I also hope that this powerful weapon can enter the medical insurance as soon as possible and benefit more prostate cancer patients
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 Reference: [1].
2021 EAU Congress.
Abstract P0845[2].
Chi KM, et al.
Final analysis results from TITAN: a phase 3 study of apalutamide vsplacebo in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy.
J Clin Oncol 39, 2021 (suppl 6; abstr 11).
[3].
2021 EAU Congress.
Abstract V41[4].
2021 EAU Congress.
Abstract P0437[5].
Daniel Eberli, et al.
Apalutamide in combination with autophagy inhibitors improves treatment effects in prostate cancer cells, UrologicOncology: Seminars and Original Investigations, Volume 38, Issue 8, 2020, Pages 683.
e19-683.
e26, ISSN1078-1439.
[6].
Clegg, NJ, et al.
, ARN-509: a novel antiandrogen for prostatecancer treatment.
Cancer Res, 2012.
72(6): p.
1494-503.
[7].
2018ESMO 797PD: LATITUDE study: PSA response characteristics and correlation with overall survival (OS) and radiological progression-free survival (rPFS) in patients with metastaticcastration-sensitive prostate cancer (mCSPC) receiving ADT+abiraterone acetate and prednisone (AAP) or placebo (PBO )[8].
EAU-EANM-ESTRO_ESUR_ISUP_SIOG-Guidelines-on-Prostate-Cancer-2021[9].
Kumar, S.
, et al.
Neo-adjuvant and adjuvanthormone therapy for localised and locally advanced prostate cancer.
CochraneDatabase Syst Rev, 2006: CD006019.
[10].
2019 EAU congress.
Abstract PT-136.
[11].
Mortezavi A, Salemi S, Kranzbühler B, Gross O,Sulser T, Simon HU, Eberli D.
Inhibition of autophagy significantly increases the antitumor effect of Abiraterone in prostate cancer.
World J Urol.
2019 Feb; 37(2): 351-358.
doi: 10.
1007/s00345-018-2385-5.
Epub 2018 Jun 27.
PMID: 29951789.
*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform