[2021 ASCO-GU] Multi-swords and Combinations | Combination Therapy: A powerful tool for the treatment of prostate cancer?

*Only for medical professionals to read for reference.
From February 11 to 13, 2021, the American Society of Clinical Oncology Symposium on Urogenital Cancer (ASCO-GU 2021) was successfully held on the online platform.

Urinary oncologists and related scientific researchers from all over the world gathered in the "cloud".

Thanks to the in-depth understanding of the pathophysiology of prostate cancer by urology, oncology, and basic medical scientists, we now have more systemic treatments for prostate cancer than in the past, but the disease progression of prostate cancer patients still troubles doctors and patients.
A major treatment problem.

The current treatment of prostate cancer includes local treatment based on surgery and radiotherapy, and systemic treatment based on new endocrine therapy and targeted therapy.

Although these treatment options have achieved certain effects in the treatment of prostate cancer at different stages of the disease, whether the combination of different mechanisms and different types of options can better improve the prognosis, strive for a longer survival time for patients, and maintain a better quality of life at the same time It is a research hotspot in the field of urinary oncology in various countries.
ASCO-GU 2021 has reported numerous studies on combined treatment of prostate cancer.

Salvage radiotherapy + ADT + apatamide + docetaxel Abs 90: STARTAR interim analysis: salvage radiotherapy combined with ADT + apatamide + docetaxel in the treatment of patients with PSA recurrence after radical prostatectomy [1] From March 2018 to February 2020, 39 subjects were enrolled in this study to receive single-arm androgen deprivation therapy (ADT) combined with apatamide therapy, and received standard salvage at week 9 After radiotherapy, he received 6 cycles of docetaxel treatment, and the primary endpoint of the study was prostate-specific antigen (PSA) progression-free survival (see Figure 1 for the study protocol).

Figure 1: STARTAR Study Design This conference first reported the results of the interim analysis of the study.
The median age of the enrolled subjects was 64 years (44-76), and the median PSA level was 0.
58 ng/mL (0.
21-3.
40).
), 46% of patients had Gleason scores of 8-9, and 23% of patients were stage N1 patients.

After a median follow-up of 14 months, all patients have completed the study intervention treatment (ADT + apatamide + radiotherapy + docetaxel), and no patients have experienced PSA progression events.

56% of the enrolled subjects completed 6 cycles of docetaxel chemotherapy.

Common side effects during treatment include hot flashes, rash, fatigue, and bone marrow suppression caused by chemotherapy (see Figure 2 for other safety information).

The mid-term results of this study suggest that for high-risk patients with PSA recurrence after radical surgery, the combination of new endocrine therapy and radiotherapy on the basis of salvage radiotherapy is safe and tolerable, and no serious side effects have occurred.

Figure 2: Safety summary of the interim analysis of the STARTAR study SBRT+AR pathway inhibitor Abs 121: Evaluation of stereotactic radiotherapy (SBRT) combined with AR pathway inhibitors in the treatment of oligometastatic prostate cancer [2] Retrospective analysis of the study for oligometastasis The effectiveness and safety of patients with prostate cancer (metastasis ≤5) who have received AR pathway inhibitors (ARSI) or are receiving ARSI or undergoing ARSI combined with SBRT after progression.

The study divided patients into three groups: 1) ARSI-sensitive (ARSI-s) oligometastatic metastatic hormone-sensitive prostate cancer (mHSPC); 2) ARSI-s oligometastatic castration-resistant prostate cancer (CRPC); 3) ARSI-resistant (ARSI-r) oligometastatic mCRPC.

SBRT radiation dose includes 16-20 Gy/1 Fx, 27-30 Gy/3 Fx and 30-40 Gy/5 Fx radiation dose.

The study analyzed 114 metastatic lesions in 61 patients, with a median follow-up time of 15.
2 months.The results showed that the median progression-free survival (PFS) of the three groups of patients were not reached, 17.
3 months, and 9.
0 months, respectively.
Among them, patients in the ARSI-r oligometastatic CRPC group received complete or partial radiation ablation.
Up to 13 months (see Figure 3).

In addition, in terms of safety, 2 patients had pelvic fractures (Grade 3) and 1 patient had pneumonia (Grade 4).

This study suggests that especially for patients with oligometastatic CRPC with poor ARSI response, the combination of SBRT may improve the treatment benefit of patients.

Figure 3: Evaluation of the effectiveness of SBRT+ARSI: a) PFS of patients in the prognostic group; b) ARSI-r oligometastatic CRPC patients undergoing complete/partial radioablation PFS abiraterone + AKT inhibitor Abs 85: an evaluation of the combination of capivasertib A phase I clinical trial of abiraterone in the treatment of mCRPC patients[3] This is a multicenter phase I clinical trial that explores the appropriate dose of abiraterone combined with the AKT inhibitor capivasertib.
The study divided the enrolled subjects into two groups ( Part A2 exploratory group and Part B2 extended group) single-arm abiraterone 1000 mg QD combined with capivasertib 400 mg BID, stop for 3 days after taking the drug for 4 consecutive days (see Figure 4 for the specific plan), to evaluate the safety of the combined treatment plan and PSA motivation Change the level of study and record the pharmacokinetic data.

Figure 4: Study design and main evaluation indicators From August 2019 to July 2020, a total of 15 subjects from the United States and Spain were enrolled in this trial, with a median age of 67 years (49-82) .

Among them, 12 subjects had received chemotherapy in the past, 10 patients had received enzalutamide and 7 patients had received abiraterone treatment.

The main results of the study showed that no drug dose-dependent toxicity was found in the A2 exploratory group (n=8).

A total of 100 adverse events (AEs) were recorded during 15 subjects enrolled in the intervention treatment (55 cases of grade 1 AEs; 28 cases of grade 2 AEs; 17 cases of ≥ grade 3 AEs, see Figure 5 for specific AEs related to capivasertib) .

In addition, PSA kinetics results showed that the median PSA level at baseline was 47.
3 (0.
4-487.
3) ng/mL.

On the 29th day after treatment, 5 subjects reached a PSA drop of >20%, and 3 subjects showed a continuous decline in PSA within 12 weeks (Figure 6).

The results of this study show that the safety of mCRPC patients receiving abiraterone combined with AKT inhibitors is tolerable, and supports further exploration of the application of abiraterone + AKT inhibitor combination therapy in mCRPC in the future.

Figure 5: All AEs related to capivasertib treatment Figure 6: PSA dynamic changes TPS 178: CAPItello-281 A placebo randomized controlled phase III clinical trial evaluating capivasertib combined with abiraterone in the treatment of mHSPC with PTEN deficiency [4] by PTEN The abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway caused by the deletion may be one of the key mechanisms that promote the progression of prostate cancer.

At present, basic studies have shown that AR pathway and PI3K/AKT pathway have multiple cross-regulation pathways (Figure 7) [5,6].

Based on the results of a phase I clinical trial of abiraterone combined with selective AKT inhibitor capivasertib in the treatment of mCRPC patients, the safety of the combination regimen is tolerable [3], so abiraterone combined with capivasertib may improve the survival benefit of patients with PTEN-deficient mHSPC.

Figure 7: Interaction between AR pathway and PI3K/AKT/mTOR pathway CAPItello-281 is a randomized, double-blind, placebo-controlled international multi-center phase III clinical trial (n≈1000).
The study was based on 1: 1 Divided into the abiraterone + capivasertib or abiraterone + placebo group to assess the primary endpoint imaging progression-free survival (rPFS) and including overall survival (OS), time to follow-up anticancer drug treatment, and bone-related events Multiple secondary endpoints including safety, safety, etc.
(see Figure 8 for the research protocol).

About 30+ countries including China, 350+ research centers participate in this phase III trial.

The study has started the enrollment of subjects in July 2020.
According to Clinicaltrials.
gov, its main study endpoint is expected to be completed in November 2024.
In the future, we can pay more attention to the latest results of this study.

Figure 8: CAPItello-281 study design TPS 179: INNOVATE (NRG-GU008) A project to explore the randomization of salvage radiotherapy + ADT or combined abiraterone + prednisone + apatamide in the treatment of patients with positive lymph nodes after radical prostatectomy Controlled III trial [7] This is a phase III multicenter randomized controlled trial for patients with positive lymph nodes after radical surgery.
It included patients with prostate cancer who had positive lymph nodes after radical surgery and excluded distant sites through imaging evaluation.
After metastasis, 1:1 randomized into group 1: (radiotherapy + ADT for 2 years) and group 2 (radiotherapy + ADT + abiraterone + apatamide for 2 years).
The primary endpoint of the study is metastasis-free survival, and the secondary endpoint For OS, biochemical recurrence-free survival, quality of life (QoL), and safety, it also set exploratory endpoints including Decipher score and PAM50 classification as biomarkers for predicting the prognosis of the disease (see Figure 9 for the specific research plan).

The sample size of the study is estimated to require approximately 586 subjects to be enrolled, and the enrollment of the study was initiated on March 5, 2020.
According to Clinicaltrials.
gov, its main study endpoint is expected to be completed in November 2026.
We Looking forward to the future we can see more reports on the latest research progress of this treatment for patients with biochemical relapse.

Figure 9: INOVATE research design experts comment.
At present, there are many treatments for different disease stages in the field of prostate cancer research.
Among them, we are familiar with classic drugs targeting AR pathways, as well as targeting PI3K/AKT pathways in prostate cancer.
New targeted drugs in the field, but in the face of such a variety of drugs, how should we choose in the future and how to make a good combination? This is also what today's urologists or oncologists have to think about. A new generation of androgen receptor inhibitor apataamide and androgen synthesis inhibitor abiraterone have been recommended by major guidelines at home and abroad for the treatment of prostate cancer at different stages of the disease [8-10], its TITAN and SPARTAN research It was confirmed that for mHSPC and high-risk NM-CRPC patients, apatamide can reduce the risk of death by 35% and 22% compared with placebo (TITAN: NE vs 52.
2 mo, HR 0.
65, 95% CI 0.
53-0.
79; SPARTAN: 73.
9 vs.
59.
9 months, HR 0.
78, 95%CI 0.
64-0.
96) [11,12].

At the same time, the LATITUDE and COU-AA-302 studies reported in the past confirmed that for patients with high-risk mHSPC and mCRPC before chemotherapy, abiraterone can significantly prolong the survival benefit of patients compared with placebo (LATITUDE: 53.
3 vs 36.
5 mo, HR 0.
66, 95% CI 0.
56-0.
78; COU-AA-302: 34.
7 vs 30.
3 mo, HR 0.
81, 95% CI 0.
70-0.
93) [13,14].

So for the current situation of prostate cancer treatment, can we use androgen signaling pathway inhibitors in combination with other various treatment options to achieve the effect of 1+1>2? Just at this year’s ASCO-GU conference, a number of updates about abiraterone combined with apatamide/AKT inhibitors/radiotherapy/chemotherapy for mCRPC, oligometastatic mHSPC, and even biochemical recurrence of prostate cancer after radical surgery were announced.
the study.

It can be seen that the application of new endocrine therapy in different disease stages of prostate cancer is constantly advancing, and the development trend of the pattern of using existing standard treatments androgen synthesis inhibitors in combination with other new targeted therapies in the end-stage mCRPC stage of the disease.

The preliminary results of these studies show that the combination therapy is a promising treatment attempt, so we also look forward to more large-sample research results reported in the future.

At present, a variety of new drugs and combination treatment options are in the process of exploring, whether it is a single drug or a combination of their treatments, the safety or effectiveness of the treatment is still limited.

How to choose the best treatment plan and how to make a reasonable combination is the biggest challenge facing the clinical diagnosis and treatment of prostate cancer.

With the development of non-invasive liquid biopsy and next-generation sequencing technologies, specific biomarkers that help select or exclude specific therapies have become a research hotspot, and are also expected to be the development trend of precision treatment of prostate cancer in the future.

However, the relevant clinical studies currently carried out are mostly carried out on European and American populations, and there are very few Asian populations in this type of research.
This also makes many conclusions that may have racial differences.

The difference between the role and predictive ability of many biomarkers and the western population is still unclear.

In future research, it is also necessary for our Chinese researchers to make further efforts to explore an integrated precision medical model suitable for our Asian prostate cancer patients.

Expert profile Prof.
Jun Xiao, Director of Urology, First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Chief Physician, Doctor of Medicine, Chinese University of Science and Technology Doctoral Supervisor, Postdoctoral Workstation Supervisor, Chinese Medical Doctor Association Urology Branch Member, Chinese Anti-Cancer Association Urology and Male Reproductive Member of the Systemic Oncology Committee Member of the Standing Committee of the Prostate Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO) Deputy Chairman of the Urology Branch of the Anhui Medical Association Deputy Chairman of the Urology Branch of the Anhui Medical Association , Vice-Chairman of the Anhui Andrology Branch, visiting scholar at Universität Tübingen, Germany, is good at various minimally invasive surgery and full management of urogenital and male reproductive system tumors. Presided over a number of subjects such as the National Natural Science Foundation of China, the Provincial Key R&D Program Project, and the Provincial Natural Science Foundation, and published more than 10 SCI papers.
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16(2): p.
152-60.
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20(5): p.
686-700.
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Ryan, CJ, et al.
, Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.
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152-60.