2021 ASCO GU | Inventory of major research in the field of prostate cancer treatment

On February 11-13, 2021, local time in the United States, the American Society of Clinical Oncology Annual Meeting of Urogenital Tumors (ASCO GU) was held online.

During the conference, in the oral report session and the abstract express session, let’s take a look at the major researches in the field of prostate cancer treatment! 01 Oral report dedicated to these molecular factors may help nmCRPC patients benefit! Background: The SPARTAN study (NCT01946204) is a placebo-controlled phase III study in patients with non-metastatic castration-resistant prostate cancer (nmCRPC).

The results of the study showed that compared with placebo + androgen deprivation therapy (ADT), apatamide + ADT can significantly improve the metastasis-free survival (MFS) of patients.

This exploratory analysis assessed the potential biological characteristics of patients with long-term responses to apatamide and placebo.

Methods: According to the time to metastasis, the investigator described the biomarker cohort of the SPARTAN study as long-term response (LTR) or early progression (EP), and further based on the quartile of the apatamide group and the placebo group Divide.

Patients who progressed in the first quartile with the shortest time to metastasis (apatamide group, 21; placebo group, 17) were classified as EP, and in the last quartile (apatamide group, 17) Patients who progressed in group, 39; placebo group, 20) were classified as LTR.

Gene expression profiles were obtained from 233 cases of primary prostate tumors.

A two-sample t test was used to compare the genetic characteristics predicted by cancer biology between LTR and EP patients in the apatamide group and the placebo group.

The significance level between LTR and EP was set at p<0.
05.Results: The median time to metastasis of LTR patients in the apatamide group and placebo group were 40.
5 months and 22 months, respectively, and the median time to metastasis of EP patients in the two groups were 7.
3 months and 3.
6 months, respectively .

Among the three types of conventional mechanisms (immunomodulation, proliferation, and hormone dependence), factors significantly related to LTR in the apatamide group include: T cell activation (p=0.
0045), stimulation (p=0.
0642), and cytokine response (P=0.
0489), interferon production (γ response, p=0.
0227), decreased T cell rejection (p=0.
0652), low proliferation capacity (p=0.
0435) and hormone-dependent increase (p=0.
0485).

Factors related to the early progression of placebo treatment include: high risk (DECIPHER, p=0.
0406; potential metastasis risk, p=0.
0077), hormone ineffectiveness (Basal type, p=0.
0115; low androgen receptor activity, p=0.
0437) And neuroendocrine differentiation (p=0.
0125).

Conclusion: These molecular determinants can help nmCRPC patients choose apatamide or other androgen signaling inhibitors, so that patients can get more benefits, but a larger sample size study is still needed.

The final results of the ACIS study update the background: Because metastatic castration-resistant prostate cancer (mCRPC) is driven by activated androgen receptors and elevated intratumoral androgens, androgen reduction may require dual suppression.

Apataamide and abiraterone acetate have been approved for the treatment of prostate cancer, and they have unique receptor and ligand inhibitory effects, respectively.

The ACIS study compared the imaging progression-free survival (rPFS) of mCRPC patients treated with apatamide or placebo + abiraterone acetate + prednisone without chemotherapy.

Methods: In addition to receiving continuous ADT, mCRPC patients who have not used other prolonged survival treatments since diagnosis were randomly assigned to receive apatamide (240 mg, orally, once a day) + abirate acetate at a ratio of 1:1 Dragon (1000 mg orally, once a day) + prednisone (5 mg orally, twice a day) or placebo + abiraterone acetate + prednisone.

Stratified according to the presence of visceral metastasis, the Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, and geographic area.

The primary endpoint is rPFS (researcher assessment; defined as the time from randomization to imaging progression or death), and secondary/other endpoints include prostate-specific antigen (PSA) remission rate, overall survival (OS), safety, Time to PSA progression, time to long-term use of opioids, time to use of cytotoxic chemotherapy, and pain progression (NCT02257736).

Results: From December 2014 to August 2016, a total of 982 patients were included in the study.

In the final analysis of rPFS, compared with the abiraterone acetate and prednisone groups, the median rPFS of patients who used apatamide combined with abiraterone acetate and prednisone was prolonged by 6 months (22.
6 months vs.
prednisone).
At 16.
6 months, the HR was 0.
69 [95%CI 0.
58-0.
83]; p <0.
0001), which was consistent with the results of the first interim analysis of OS (median follow-up time 25.
7 months).

The final analysis showed that compared with the abiraterone acetate and prednisone groups, the use of apatamide combined with abiraterone acetate and prednisone to treat PSA decreased by ≥50% was significantly higher.

In addition, although not statistically significant, the median OS of apatamide combined with abiraterone acetate and prednisone was longer.

Time to PSA progression, time to opioid use, time to start of cytotoxic chemotherapy, and pain progression were not statistically different between the two groups.

The security of this report is consistent with previous research, and there are no new security incidents.

The proportion of adverse events (TEAE) that occurred during grade 3/4 treatment in the apatamide combined with abiraterone acetate and prednisone group was 63.
3% (310/490), while in the abiraterone acetate and prednisone group it was 56.
2% (275/489). Among them, the incidence of grade 3 TEAE was higher in the apatamide combined with abiraterone acetate and prednisone group (56.
1%[275/490] vs.
45.
6%[223/489]), but the incidence of grade 4 TEAE was higher Low (7.
1%[35/490] vs.
10.
6%[52/489]).

Table study results conclusion: The final analysis of the ACIS study reached the primary endpoint.
The study confirmed that compared with the treatment of abiraterone acetate and prednisone, the imaging of apatamide combined with abiraterone acetate and prednisone in the treatment of mCRPC patients without chemotherapy The risk of academic progress or death was reduced by 31%.

Biomarker analysis: Randomized Phase II study of olaparib±cediranib in the treatment of mCRPC patients.
Background: Previous reports have shown that compared with olaparib alone, cediranib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor) (Drug) combined with olaparib (a poly-ADP ribose polymerase inhibitor) can prolong rPFS in patients with metastatic castration-resistant prostate cancer (mCRPC).

At this meeting, the researchers reported the latest clinical data on the total population and the subgroups of homologous recombination (HR) gene status.

Methods: mCRPC patients who have received at least first-line systemic treatment in the past were randomly assigned to receive olaparib (200 mg, orally, twice a day) + cediranib (30 mg, orally, once a day) or olaparib at a ratio of 1:1 Parril (200mg, orally, twice a day).

The patient is required to undergo a baseline transfer biopsy.

Use BROCA-HR analysis to perform second-generation sequencing on available samples.

Homologous recombination defects (HRD) are defined as homozygous deletions or deleterious mutations in HR genes (including BRCA1, BRCA2, ATM, etc.
).

The primary end point is rPFS, and the secondary end point is OS (NCT02893917).

Results: A total of 84 patients were analyzed, of which 26 (31.
0%) were HRD mCRPC. The most common HR genetic changes include BRCA2 (n = 17, 20%), CDK12 (n = 9, 11%) and ATM (n = 7, 8%).

Consistent with previous reports, in the general population, treatment with olaparib + cediranib significantly improved the rPFS of patients compared with olaparib alone.

Among HRD mCRPC patients, rPFS has the most obvious benefit.

However, there was no significant difference in rPFS among patients with effective homologous recombination mechanism (HRP).

Compared with HRP mCRPC patients, the rPFS and OS of HRD mCRPC patients are numerically longer, regardless of the treatment group (rPFS: 8.
8 months vs.
4.
3 months, p=0.
14; OS: 18.
6 months vs.
12.
3 months , P=0.
24).

Table rPFS and OS results conclusion: Compared with olaparib alone, olaparib+cediranib improves the rPFS of mCPRC patients.

Biomarker analysis showed that the rPFS benefit of olaparib+cediranib in HRD mCRPC patients was better than that of olaparib alone.

The data of this study confirms that patients with HRD mCRPC can receive olaparib+cediranib treatment and support further research.

02 Abstract Express Special TITAN Study Final Analysis Results Background: The TITAN study evaluated the efficacy and safety of apatamide versus placebo for metastatic castration-sensitive prostate cancer (mCSPC).

At the first interim analysis, the median follow-up time was 22.
7 months.
Compared with placebo, apatamide significantly improved the overall survival (OS) (HR=0.
67) and imaging progression-free survival of mCSPC patients (RPFS) (HR=0.
48).

At this meeting, TITAN research announced the final efficacy and safety results.

Methods: The study included 1052 patients who were randomly assigned to receive apatamide or placebo + androgen deprivation therapy (ADT) at a 1:1 ratio.

Results: Results: At a median follow-up of 44 months, 208 (39.
5%) patients in the placebo group crossed over to the apatamide group.

The median duration of treatment in the apatamide group and placebo group were 39.
3 months and 20.
2 months, respectively, and the median duration of treatment in the placebo→apatamide group was 15.
4 months.

Despite the crossover, the OS of the main apatamide group was better than that of the placebo group (table).

Table curative effect analysis The 2-year survival rates of apatamide and placebo groups were 65% and 52%, respectively.

The safety results are consistent with previous studies.

Conclusion: The follow-up results of the past 4 years show that apatamide+ADT can significantly improve the OS of patients with mCSPC.
The combined treatment reduces the risk of death by 35%; after adjusting for cross-treatment factors, the risk of death is reduced by 48%.

In addition, the combination treatment regimen also achieved consistent benefits in other endpoints and has acceptable safety.

Clinical trial information: NCT02489318.

KEYNOTE-365 study B cohort analysis background: systemic treatments (for example, docetaxel and cabazitaxel) can improve the survival rate of patients with metastatic castration-resistant prostate cancer (mCRPC), but more effective treatments are still needed .

KEYNOTE-365 is a phase Ib/II study designed to evaluate the efficacy and safety of pembrolizumab in combination with 4 different drugs (groups A, B, C, and D) for mCRPC patients.

The previous data of cohort B (at a median follow-up of 20 months) showed that pembrolizumab + docetaxel + prednisone showed good results in mCRPC patients who were previously treated with abiraterone or enzalutamide.
Tolerance and anti-tumor activity.

The meeting announced the latest efficacy data and safety data after an additional 1 year of follow-up.

Methods: Cohort B enrolled mCRPC patients who did not respond to or did not tolerate chemotherapy (abiraterone or enzalutamide [≥4 weeks]) and progressed within 6 months after screening (PSA progress or radioactive bone/soft tissue progress) .

The enrolled patients received pembrolizumab (Q3W, 200 mg, intravenous injection) + docetaxel (75 mg/m2 IV Q3W intravenous injection) + prednisone (5 mg, oral, twice a day).

The primary endpoints are safety, PSA remission rate (PSA remission rate is >50% lower than baseline), and objective remission rate (ORR) assessed by the Independent Blind Center (BICR).

Results: The median age of 104 patients was 68 years, 23.
1% of patients were PD-L1 positive (PD-L1 CPS≥1), 25% of patients had visceral metastases, and 50% of patients had measurable lesions.

At a median follow-up of 32.
4 months, the ORR of cohort B was 23.
1%, the DCR was 76%, the median DOR was 8 months, and the median time to PSA progression was 29.
3 months.

The most common (≥30%) treatment-related adverse events in the analysis of efficacy are diarrhea (41.
3%), fatigue (41.
3%) and hair loss (40.
4%).

The incidence of treatment-related adverse events of grade 3~5 was 44.
2%.

Conclusion: The results of an additional 1 year follow-up showed that pembrolizumab+docetaxel+nipredone showed better ORR and PSA remission rates compared with patients in the database who received abiraterone or enzalutamide.

The safety is consistent with that of a single drug.
Phase III KEYNOTE-921 will further verify the efficacy.

Clinical trial information: NCT02861573CheckMate 9KD study B cohort final results update Background: CheckMate 9KD is a phase II study to evaluate the efficacy and safety of nivolumab + rucaparib + docetaxel or enzalutamide in mCRPC patients Sex.

Nivolumab shows limited anti-tumor activity in mCRPC patients.
Docetaxel is a standard chemotherapy regimen in mCRPC patients.
It can enhance the anti-tumor immune response of immune checkpoint inhibitors.
Therefore, docetaxel + sodium Wuliyuumab can be used in combination.

In this meeting, the researchers announced the final results of CheckMate 9KD study B cohort (nivolumab + docetaxel).

Methods: Cohort B enrolled mCRPC patients who had not undergone chemotherapy, were undergoing androgen deprivation treatment, and had previously received at most 2 new anti-androgen therapies (such as abiraterone, enzalutamide).

The enrolled patients received nivolumab (360mg) + docetaxel (75 mg/m2 Q3W) + prednisone (5mg, BID) for up to 10 cycles, followed by nivolumab (480 mg) Q4W) until the disease progresses or unacceptable toxicity (up to 2 years).

The primary endpoints were ORR and PSA remission rate (PSA reduction ≥50%).

Secondary endpoints include rPFS, overall survival (OS), and safety.

Results: The median age of 84 patients was 71 years, 27% had visceral metastases, 54% had measurable lesions, the median number of cycles of docetaxel treatment was 8, and the median dose of nivolumab The number was 11.
At a median follow-up of 15.
2 months, the ORRs of patients who received or did not receive new anti-androgen therapy were the same.
The ORRs were 38.
7% and 42.
9%, respectively.
The median rPFS was 8.
7 months and 12 months, respectively.
The bit OS was 16.
2 months and not reached, respectively.

Among the 45 patients with measurable lesions, 1 patient (2.
2%) achieved complete remission, and 17 (37.
8%) patients achieved partial remission.

The most common treatment-related adverse events in the analysis of the efficacy of the table were fatigue (39.
3%), diarrhea (35.
7%) and hair loss (34.
5%).

47.
6% of patients had grade 3 to 4 treatment-related adverse events, the most common being neutropenia (16.
7%).

Treatment-related adverse events led to discontinuation of the drug in 29.
8% of patients.

The most common immune-related adverse events were related to the gastrointestinal tract (35.
7%) or skin (26.
2%).

Conclusion: Regardless of whether you have received new anti-androgen therapy in the past, nivolumab + docetaxel shows encouraging anti-tumor activity in mCRPC patients without chemotherapy, and the safety is consistent with each single agent.

The results of the study support the further phase III CheckMate 7DX, which aims to explore the effectiveness and safety of nivolumab + docetaxel versus placebo + docetaxel for mCRPC.

Clinical trial information: NCT03338790.

References: 1.
Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Abstract 82.
Final results from ACIS, a randomized, placebo (PBO)-controlled double-blind phase 3 study of apalutamide (APA) and abiraterone acetate plus prednisone (AAP) versus AAP in patients (pts) with chemo-naive metastatic castration-resistant prostate cancer (mCRPC).
Abstract 93.
Biomarker analysis from a randomized phase II study of olaparib with or without cediranib in men with metastatic castration-resistant prostate cancer (mCRPC).
Abstract 74.
Final analysis results from TITAN: A phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT).
Abstract 115.
KEYNOTE-365 cohort B: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)--pretreated patients with metastatic castration-resistant prostate cancer (mCRPC)—New data after an additional 1 year of follow-up.
Abstract 106.
CheckMate 9KD Arm B final analysis: Efficacy and safety of nivolumab plus docetaxel for chemotherapy-naïve metastatic castration-resistant prostate cancer.
Abstract 12.
Rapid abstract sessionEfficacy and safety of nivolumab plus docetaxel for chemotherapy-naïve metastatic castration-resistant prostate cancer.
Abstract 12.
Rapid abstract sessionEfficacy and safety of nivolumab plus docetaxel for chemotherapy-naïve metastatic castration-resistant prostate cancer.
Abstract 12.
Rapid abstract session