【2022 ASCO-GU】 New exploration of endocrine therapy for mHSPC in the future

*For medical professionals to read for reference only.
Since the survival benefit of traditional CAB regimen compared with ADT alone in the treatment of metastatic prostate cancer is extremely limited, after weighing the efficacy and safety, major international guidelines no longer recommend traditional CAB as a long-term treatment for metastasis For the treatment of sex hormone-sensitive prostate cancer (mHSPC), novel endocrine therapy (NHT) represented by apalutamide is recommended as the first-line regimen
.

In China, traditional CAB treatment still has a place, and NHT represented by apalutamide is gradually widely used
.

Let's take a look at the RCTs and real-world research results on traditional CAB and NHT treatment of mHSPC reported in this ASCO-GU to see how it can guide clinical practice
.

 1.
A randomized controlled trial of GnRH antagonist monotherapy versus GnRH agonist combined with bicalutamide (CAB) in patients with mHSPC (KYUCOG-1401) Previous studies have found that traditional CAB is more effective than ADT alone in advanced prostate cancer patients.
The 5-year survival rate increased by only 2.
9% [1]
.

And bicalutamide + ADT has no significant OS benefit compared with ADT alone in the treatment of metastatic prostate cancer [2]
.

The purpose of this study was to observe whether there was a difference in clinical response between CAB and ADT
.

A total of 200 mHSPC patients were included in the study and randomly assigned to the ADT group (GnRH antagonist single agent) and the CAB group (GnRH agonist + bicalutamide), of which the ADT group would delay the addition of bicalutamide after PSA progression.

.

The results showed that the PSA progression-free time in the CAB group was significantly better than that in the ADT group (13.
8m vs 18.
6m, HR 1.
40, P=0.
041), and the PSA progression time was prolonged by 4.
8 months (Figure 1)
.

The proportion of patients who achieved or maintained castration levels was slightly higher in the ADT group (significant difference at 60 weeks, p = 0.
046) (Figure 2), but endpoints such as time to CAB failure, rPFS, and OS were not observed between the groups Statistically significant difference (Figure 1)
.

Figure 1 Comparison of endpoints between the two groups, where A is the ADT group and B is the CAB group.
Figure 2 The number of patients with testosterone not reaching castration levels between the 2 groups 2.
Receiving intensive androgen deprivation therapy and not achieving optimal PSA remission ( Survival outcomes and characteristics of patients with metastatic castration-sensitive prostate cancer (mCSPC) with PSA≤0.
2 ng/mL.
A previous large phase 3 clinical study showed that in patients with mCSPC receiving intensive ADT therapy (ADT combined therapy), the Compared with patients whose PSA never dropped below 0.
2 ng/mL, patients with PSA≤0.
2 ng/mL had significantly longer progression-free survival (rPFS)[3] and overall survival (OS)[4]
.

This retrospective study validated this association in the real world
.

All 134 patients enrolled in this study started receiving intensive ADT therapy in combination with novel hormone therapy (NHT) or docetaxel within 3 months after the diagnosis of mHSPC (the article does not mention the use of NHT and docetaxel.
specific number of people)
.

Among them, 104 patients achieved optimal PSA response (OR, ie, PSA minimum value ≤0.
2 ng/mL), and 30 patients did not
.

Statistical analysis found that the median PSA value at the start of treatment was 18.
1 vs 74.
5 ng/mL in the OR and non-OR groups
.

Compared with the non-OR group, the OR group significantly reduced the risk of disease progression by 72% (60.
6m vs 13.
2m, HR 0.
28, P < 0.
001) and significantly reduced the risk of death by 79% (94.
9m vs 35.
2m, HR 0.
21, P < 0.
001) ) (Figure 3)
.

Figure 3 Comparison of PFS and OS between the OR group (the lowest PSA value ≤ 0.
2 ng/mL) and the non-OR group (the lowest PSA value > 0.
2 ng/mL) Tumor genomic characterization, it was found that the most common mutations in subjects were TP53 (49%), TMPRSS2 (36%), and PTEN (28%), however no mutations in either gene were observed in the OR and non-OR groups the incidence of differences (Figure 4)
.

Figure 4 Comparison of genomic profiles of OR group (PSA nadir ≤ 0.
2 ng/mL) and non-OR group (PSA nadir > 0.
2 ng/mL) This study shows that most mCSPC patients can achieve optimal PSA remission with intensive ADT therapy
.

PSA nadir ≤0.
2 ng/mL was associated with longer OS and PFS
.

 3.
Evaluation of drug interactions in routine treatment of patients with metastatic prostate cancer Prostate cancer usually occurs in the elderly population.
Because of the common comorbidities, patients often need to take multiple drugs, so drug-drug interactions (DDI) occur.
risk
.

This study aimed to quantify and characterize the presence of DDI in prostate cancer treatment
.

A total of 91 patients with metastatic prostate cancer were enrolled in the study, and each patient used a median of 6 concomitant medications
.

The DDI status of each patient was assessed from 2 perspectives: the "true DDI" between each patient's actual prescribed anticancer drugs and their concomitant medications in this study; "Modeled DDI"
.

In addition to electronic tools, the "real DDI" also sets up pharmacists to participate in the analysis manually
.

Statistically, no true DDI was found for apalutamide in this study
.

In the modeled DDI, enzalutamide and apalutamide were the two drugs with greater risk (Figure 5).

.

The results showed that DDIs were common if queried by instrument, however not all DDIs found were clinically meaningful according to the Hatoum scale
.

Only the advice of a pharmacist and a doctor should be necessary to determine whether a DDI has clinical effects
.

Figure 5 Real DDI/Modeled DDI ratio of different prostate cancer drugs according to 3/2 analysis methods One of several main treatments for metastatic prostate cancer
.

However, studies have found that there is almost no difference in survival benefit between CAB regimen and ADT alone, and better treatment methods are urgently needed
.

With the popularization of second-generation AR inhibitors represented by apalutamide, many international guidelines such as NCCN, EAU, and AUA no longer recommend CAB as a long-term treatment for mHSPC; and domestic CSCO and CUA guidelines are only partially In this case, CAB is recommended for the treatment of mHSPC, and the level of evidence is 2 or 3
.

However, at present, bicalutamide is still widely used in China, and it will take time for the full popularization of NHT
.

The first study mentioned above once again confirmed that CAB has no long-term benefits such as rPFS and OS compared with ADT
.

In terms of reducing PSA, the time from ADT group to PSA progression in this study was 13.
8 months, which was close to the data of previous studies [5].
Although there was a statistically significant difference in the time to PSA progression between the two groups in this study, it was only 18.
6 months in the CAB group.
months
.

We know that mHSPC patients usually enter the mCRPC stage soon after PSA progression, and mCRPC is the terminal stage of prostate cancer disease development with a significantly increased risk of disease progression and death [6]
.

Therefore, delaying disease progression has become an important therapeutic goal in mHPSC stage.

.

The TITAN study (a large phase 3 clinical study of apalutamide in mHSPC) showed that in the case of PSA progression at a median of 12.
9 months in the placebo group, the apalutamide group remained at a median follow-up of 44 months.
Failure to achieve PSA progression significantly reduces the risk of PSA progression by 73% [5]
.

With the widespread application of second-generation anti-androgen drugs represented by apalutamide, the disease progression of mHSPC patients has been significantly delayed, and the survival period has also been significantly prolonged
.

In addition, another feature of this conference report is that the ADT regimen uses LHRH antagonists.
Compared with more traditional LHRH agonists, LHRH antagonists have no ignition effect, which may reduce the risk of sudden exacerbation of symptoms in patients [ 7], but it is worth noting that LHRH antagonists as ADTs cannot be used alone according to the guidelines, and must be used in combination with NHT
.

The MAB regimen of second-generation anti-androgens combined with ADT has become a better treatment option for mHSPC patients
.

It is true that rPFS and OS are "hard indicators" for evaluating the effect of drug treatment, but due to their large time span, they are not easily observed in clinical practice, so some short-term predictive indicators are needed
.

In clinical practice, PSA is a convenient, fast, and easy-to-monitor indicator, and it is also the easiest indicator for patients to understand disease progression.
Studies have found that early, rapid and deep PSA decline in prostate cancer patients has long-term benefits.
predicted value
.

A post hoc analysis of the TITAN study found that patients with a PSA of 0.
2 ng/mL had an 81% lower risk of rPFS (HR 0.
19, P < 0.
0001) and an 83% lower risk of death (HR 0.
17, P < 0.
0001).
0.
0001)[4]
.

In this study, patients with PSA≤0.
2 ng/mL significantly delayed disease progression by nearly 4 years, and overall survival was significantly prolonged by nearly 5 years, which once again confirmed the association of deep PSA reduction and better long-term endpoints
.

The combination regimen of apalutamide + ADT can bring rapid, deep and durable PSA decline to patients, PSA90 and PSA≤0.
2ng/ml can be achieved at 1.
9 months, and the proportion of PSA reaching the target within the initial 12 months It has always maintained an upward trend, and finally 72% of patients reached PSA90, and 67% of patients achieved PSA≤0.
2ng/ml[3]
.

Recent real-world studies have also shown that compared with enzalutamide and abiraterone, apalutamide can reach PSA90 and PSA<0.
2ng/ml the fastest and highest ratio [8], and compared with enzalutamide and abiraterone amine, this advantage of apalutamide continued until the end of the 12-month study [9]
.

Long-term observation has indeed confirmed that apalutamide can significantly reduce the risk of imaging progression or death in mHSPC patients by 52%, and significantly reduce the risk of death by 48% [5]
.

With apalutamide, patients can get a better early PSA response, which predicts better long-term benefits, and patients can also be inspired to build confidence in fighting the disease
.

In applying NHT, clinicians may encounter drug-drug interaction concerns
.

We know that because drug metabolism involves many liver enzymes and transporters, in theory, each drug may be involved in drug interactions as a substrate, inducer, or inhibitor, affecting other drugs or being affected by other drugs
.

But theoretical drug interactions do not necessarily lead to changes in clinical efficacy
.

Taking apalutamide as an example, although there are theoretically many "modeled DDIs", including a variety of anticoagulants, post-hoc analysis of large phase 3 clinical trials found that the apalutamide group in combination with anticoagulants There was no increase in thrombotic and embolic events in patients compared with controls
.

It suggested that the clinical efficacy of these anticoagulants was not affected by apalutamide [10]
.

In fact, a really serious DDI will have an eye-catching black box warning in the instructions.
If you encounter such DDI in clinical work, you need to pay special attention and use it with caution
.

Overall, in the treatment of mHSPC, novel AR inhibitors + ADT have good performance in delaying PSA progression, delaying imaging progression, delaying progression to CRPC, prolonging overall survival, and safety
.

As a better new AR inhibitor, apalutamide can quickly, deeply and lastingly reduce PSA, and bring long-term benefits such as rPFS and OS.
Longer survival, better quality of life, and more hope for the patient's family
.

Expert Profile Professor Zhang Shudong Deputy Director, Chief Physician, Doctoral Supervisor, Department of Urology, Peking University Third Hospital, Postdoctoral Fellow of Medical University of Vienna, Clinical Fellow of the University of Hong Kong Queen Mary Hospital, Mayo Clinic, Cleveland, John Hopkins, MD Anderson Cancer Center, UCSF, USC, Guy's UK, Visiting scholar at Royal Marsden and many other hospitals
.

Member of the Minimally Invasive Group of the Urology Branch of the Chinese Medical Association (CUA), member of the International Exchange Committee, Deputy Head of the Oncology Group of the Youth Committee of the Urological Branch of the Chinese Medical Association Member of the editorial board of "Chinese Journal of Urology", "BJUI" Chinese version and other journals, "Journal of Peking University (Medical Edition)" and other international and domestic journal reviewers, presided over the National Natural Science Foundation of China, Beijing Natural Science Foundation, More than 10 projects including key projects of the National Health Commission, Peking University and hospitals
.

Published more than 60 papers by the first or corresponding author, and more than 10 papers in SCI, with a total IF: more than 80 points, and a single IF: 30.
849
.

Won the "Rising Star Award" of the World Chinese Urological Association, the Best Poster Award of the European Urology Annual Conference, the Third Prize of Chinese Medical Science and Technology, the Second Prize of Science and Technology Progress of the Ministry of Education, the Young Post Expert of Peking University School of Medicine, and the Top 10 Prostate Tumor Top 100 Chinese Famous Doctors etc.

_
Participated in the editing and translation of more than 10 monographs, and co-edited 1 book
.

Authored and participated in the compilation of 5 guides and consensuses
.

He is good at robot-assisted laparoscopic surgery for difficult tumors, and has been invited to perform surgery many times in CUA, CACA-GU national annual conferences and academic annual conferences in various provinces and cities
.

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Klotz L, et al.
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[3].
Kim Chi.
ASCO 2020, poster P5541[4].
Kim Chi.
AUA 2021, Abs PD34-11[5].
Chi KN , Chowdhury S, Bjartell A, et al.
Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study.
J Clin Oncol.
2021;39(20):2294- 2303.
doi:10.
1200/JCO.
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03488[6].
Scher HI et al.
PLoS One 2015;10:e0139440[7].
Klotz L, Boccon-Gibod L, Shore ND, et al.
The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer.
BJU Int.
2008;102(11):1531-1538.
doi:10.
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x[8].
Pilon D, et at.
Presented at AMCP Nexus; October 18-21, 2021[9].
2022, ASCO-GU poster B9[10].
Potdar R, Gartrell BA, Given R, et al.
Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies.
Am J Cancer Res.
2022;12(1):445-450.
Published 2022 Jan 15*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform