Philippine Long Vision - 2022 ESMO Perspective: Peer Phase "Benefit", Exploring the New Development of ADT Combination Treatment and Predictive Biomarkers for Prostate Cancer

The sky is high and refreshing, and Dan Feng welcomes autumn
.
The 2022 European Society for Medical Oncology (ESMO) Annual Meeting came to a successful conclusion
on September 13.
At this year's ESMO conference, there were 80 prostate cancer abstracts, accounting for 44%
of urinary tumor abstracts.
In the past decade, the treatment pattern of prostate cancer has undergone tremendous changes, and clinical practice is changing clinical practice
based on androgen deprivation therapy (ADT) combined with radiotherapy and new endocrine therapy.
At the same time, the study of biomarkers continues to deepen, which can further improve the existing risk prediction model
.
The PROSTATE CANCER session at this ESMO conference answers both questions
.
The editor hereby sorts it out for the benefit of the readers
.

A growing number of studies are looking to explore the efficacy
of radical prostatectomy (RP) and radiotherapy, as well as the combination of other treatments such as ADT, on prostate cancer.
At present, there is sufficient evidence that ADT combined with radiotherapy is one of the
effective ways to treat early-stage prostate cancer.
At this ESMO conference, Professor Chris C.
Parker presented the preliminary results
of the RADIICS-HD trial.
Studies have shown that ADT therapy for 6 months and 24 months on top of RP postoperative radiotherapy has been shown to improve patients with metastatic-free survival (MFS)¹
.
In another DADSPORT meta-analysis, the effects
of hormone therapy (HT) on patients with localized prostate cancer who underwent radiation therapy after RP surgery were evaluated.
The findings showed no significant improvement in overall survival (OS) in the HT group compared with no HT, but MFS²
in patients with localized prostate cancer after 6 months of HT treatment.

Table 1 Comparison of HT and HT-free OS results

AAP (abiraterone acetate + prednisone) or enzalumide (ENZ) combined with ADT has been reported to improve prognosis in patients with metastatic hormone-sensitive prostate cancer (mHSPC
).
The latest report from the STAMPEDE study also states that AAP in combination with ADT therapy can improve OS in mHSPC patients up to 7 ^years3
.

Figure 1 STAMPEDE study design

In another study on mHSPC, mHSPC patients with lymph node +/- bone metastases were assigned to the ADT+/-docetaxel (DOC) group by 2:1 and mHSPC patients with only bone metastases were assigned to the ADT+/-AAP group
by 1:1.
Studies have shown significant OS benefit from ADT in combination with AAP or DOC in both the lymph node +/- bone metastasis group and the bone ^{metastasis-only group4}
.

Dual therapy has brought new hope to patients, so can the triple therapy that is continuously optimized on this basis bring greater survival benefits to patients? The high-profile ARASENS study published data on patient quality of life and related endpoints
.
The darotamine (DARO) + ADT + DOC group (n=652) had fewer all-cause deaths (35.
1% vs 46.
8%) and prostate-cancer-related deaths (26.
1% vs 36.
0%) compared with placebo+ADT+DOC (n=650)⁵
.

Table 2 Comparison of results in the DARO group and the placebo group

The PEACE-1, ARASENS, and ENZAMET studies explored the triple therapy of mHSPC, but there is still a lack of head-to-head comparison between the triplet regimen and novel hormonal drugs (NHA)+ADT, and little
is known about which combinations of drugs provide real therapeutic benefits 。 Based on these questions, the I.
B.
Riaz team presented a systematic review of mHSPC combination therapy at this year's ESMO conference, which noted that the application of triple therapy still needs to be cautious, and that the efficacy of triple therapy in patients with high tumor load appears to be reliable, and that dual therapy may be the first choice for patients with low tumor ^load6
.

Figure 2 Comparison of triple therapy and dual therapy

Judging from this ESMO conference, ADT is still throughout the treatment of prostate cancer patients
.
Commonly used ADT drugs in clinical practice
include gonadotropin-releasing hormone agonists (GnRHa) and GnRH antagonists.
At present, there is a large amount of evidence-based medical evidence to confirm the efficacy and safety
of GnRHa, represented by tripreline, in controlling testosterone levels in the treatment of prostate cancer.
After several weeks of GnRHa treatment, patients may have GnRH receptorization, downregulation and desensitization, thereby inhibiting the release of luteinizing hormone and follicle-stimulating hormone, promoting testosterone to fall to castration levels, achieving the same effect as surgical castration; And drug castration can avoid the psychological problems related to surgical castration, and has the advantage of flexible ^adjustment7
.

The ESMO conference presented the results of a post-mortem analysis of the PEACE-1 Phase III study, which evaluated the association
between 8-month PSA and imaging progression-free survival (rPFS) and OS in patients treated with abiraterone.
The study analysis concluded that in PEACE-1, 8 months of PSA values are effective in predicting rPFS and OS in mHSPC patients, and clinicians need early intervention in patients with 8 months of PSA ^substandard8
.

Table 3 PEACE-1 Post-mortem Analysis Results

The post-opportunistic analysis of the VISION study reported at this conference was designed to assess the association
between PSA decline and clinical outcomes.
The results of the study were that rPFS and OS prolongation were associated
with a decrease in PSA from baseline.
Compared with no decline, PSA decreased > 50% but ≤ 90% and >90%, the risk of imaging progress was reduced by 80% and 96%, and the risk of death was reduced by 58% and 90%,
respectively.
Suggests that PSA predicts clinical outcomes during treatment with ¹⁷⁷Lu-PSMA-6179
.

Figure 3 ^Thetotal FACT-P PSA score for group 177 Lu-PSMA-617 drops to 12 weeks, Kaplan-Meier graph

The lower the PSA threshold, the deeper the PSA drop, the longer the OS and progression-free survival of the patient, and the better
the survival prognosis.
Therefore, it is especially important
to choose a more desirable ADT drug to control PSA levels.
Previous studies have shown that the duration of treatment with triptoreline in the 3-month dosage form until 26 weeks has maintained the median PSA level of 4 ng/ml at¹⁰
.

In addition to PSA, testosterone levels are also important for disease prognosis
.
At present, urological surgeons pay attention to changes in PSA during disease changes, but do not pay enough
attention to testosterone.
Without continuous monitoring of testosterone levels, it is impossible to determine whether the patient is stable at castration levels and it is impossible to accurately determine disease control
.
Therefore, standardized testosterone monitoring has important clinical value
for prostate cancer patients.
Previous studies have shown that 6 months of tripreline therapy maintains testosterone levels < 20 ng/dl in 90% of prostate cancer patients for 12 months or <b14>more11
.
Tripreline has demonstrated the advantages of "deep keto-lowering" and continues to help
testosterone management in prostate cancer patients.

At this year's ESMO conference, a number of new research results on ADT were released, which further confirmed that ADT as the cornerstone combination treatment brings more clinical benefits
to prostate cancer patients.
At the same time, biomarkers also play an important role in diagnosis and treatment decisions, leading to more optimal treatment options for patients and avoiding overtreatment
.
Cutting-edge innovation is an inexhaustible driving force to improve clinical practice, and we look forward to more high-quality research to bring patients the hope of "rebirth"!

References:

1.
Duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) for prostate cancer: First results of the RADICALS-HD trial (ISRCTN40814031).
ESMO 2022.
Abstract LBA9.

2.
Duration of androgen suppression with post-operative radiotherapy (DADSPORT): A collaborative meta-analysis of aggregate data.
ESMO 2022.
Absttact LBA64.

3.
Comparison of abiraterone acetate and prednisolone (AAP) or combination enzalutamide (ENZ) + AAP for metastatic hormone sensitive prostate cancer (mHSPC) starting and rogen deprivation therapy (ADT): Overall survival (OS) results of 2 randomised phase III trials from the STAMPEDE protocol.
ESMO 2022.
Abstract LBA62.

4.
Differential treatment response with nodal metastases in metastatic hormone-sensitive prostate cancer (mHSPC) and evaluation of nodal (N) burden as a prognostic biomarker: Ancillary studies of the docetaxel and abiraterone acetate and prednisolone (AAP) phase III trials from STAMPEDE.
ESMO2022.
Abstract 1359MO.

5.
Quality of life and patient-relevant endpoints with darolutamide in the phase III ARASENS study.
ESMO 2022.
Astract 1360MO.

6.
Mixed treatment comparisons evaluating contemporary therapies in metastatic castration sensitive prostate cancer (mCSPC): A living systematic review.
ESMO 2022.
Astract 1417P.

7.
Bian Xiaojie,Ye Dingwei.
New Ideas for Androgen Deprivation Treatment for Prostate Cancer: Recent Advances in Clinical Research on Maximum Control of Testosterone[J].
China Oncology, 2021, 31 (12): 1209-1214.

8.
8-month PSA strongly predicts outcomes of men with metastatic castration-sensitive prostate cancer in the PEACE-1 phase III trial.
ESMO 2022.
Astract 1361MO.

9.
Association between prostate-specific antigen decline and clinical outcomes in patients with metastatic castrationresistant prostate cancer in the VISION trial.
ESMO 2022.
Astract 1372P.

10.
Lebret T, et al.
Ther Adv Urol.
2015,7(3):125-34.

11.
PLOUSSARD G, MONGIAT-ARTUS P.
Triptorelin in the management of prostate cancer［J］.
Future Oncol, 2013, 9(1): 93-102.

Approval number: DIP-CN-010296 valid until 2024-9-26

Editor: yt

Reviewer: Bingxin

Execution: Wang Mumu

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