Prof. Zeng Hao's 2022 ASCO GU Prostate Cancer Blockbuster Research Interpretation PROpel Research and MAGNITUDE Research

The introduction of ASCO-GU has come to an end not long ago, and more than 250 abstracts have been published in the field of prostate cancer for clinical reference
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At the 2022 edition of the "CSCO Prostate Cancer Diagnosis and Treatment Guidelines" update kick-off meeting, Professor Zeng Hao of West China Hospital analyzed and interpreted some of the major research progress in the field of prostate cancer in the 2022 ASCO-GU Conference.
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Professor Zeng Hao, Doctoral Supervisor of Urology Department, West China Hospital, Sichuan University, Deputy Director of the Department, Member of the Youth Committee of the Urology Branch of the Chinese Medical Association Member of the International Exchange Committee of the Urological Branch of the Chinese Medical Association Member of the Urothelial Carcinoma Expert Committee of the Society of Oncology The dilemma of first-line treatment of mCRPC A variety of first-line treatment drugs such as docetaxel, abiraterone, enzalutamide, etc.
can improve the survival of castration-resistant prostate cancer (CRPC) patients
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However, resistance to these drugs will eventually develop
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To further improve the overall efficacy of metastatic castration-resistant prostate cancer (mCRPC), two strategies are currently included: sequential therapy and combination therapy
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How to carry out powerful combination of drugs on the basis of existing drugs and mechanisms still needs to be explored
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Exploration of Combination Drugs There are many drugs available in clinical practice, but there are few successful combination regimens
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Exploration of the combination therapy of abiraterone and PARP inhibitor: Abiraterone has been used as one of the clinical drug regimens in the first-line and second-line treatment of mCRPC
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With the manifestation of the clinical efficacy of abiraterone and the advent of PARP inhibitors, the study of the combination of the two as a second-line treatment has gradually been carried out
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In 2018, the results of a small-sample, prospective phase II clinical trial published in Lancet Oncol showed that after the failure of first-line treatment, abiraterone combined with olaparib can make patients achieve very good radiological progression-free survival ( rPFS), but overall survival (OS) was not significantly improved
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Even so, this study is still a good exploration of abiraterone combined with PARP inhibitors
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The theoretical basis of abiraterone combined with PARP inhibitors From 2011 to 2017, a number of basic studies have confirmed that there is a "cross-talk" between the new anti-androgen drug signaling pathway and the PARP inhibitor signaling pathway.
For patients with DDR mutations, The efficacy of anti-androgen drugs can be increased through the synthetic lethal effect of PARP inhibitors; for people without DDR mutations, PARP inhibitors combined with abiraterone can still achieve theoretically better results through the PARP capture mechanism of PARP inhibitors.
good therapeutic effect
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The phase II clinical trial published on Lancet Oncol in 2018 also laid the foundation for the combined treatment of the two
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Interpretation of PROpel Study Results At the ASCO-GU meeting this year, researchers announced the PROpel study, a large phase III prospective clinical trial, which revealed the efficacy of abiraterone combined with olaparib in patients with CRPC
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The trial requires that patients have not used abiraterone before the CRPC stage to be enrolled.
The study randomly divided the patients into two groups, the abiraterone combined with olaparib group and the abiraterone single-agent group
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Baseline status of patients: less than 15% of patients with visceral metastases, and about 30% of patients with HR mutations (in line with HR mutations in the normal CRPC population)
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Figure 1 The evaluation results of the PROpel study design investigators and the independent review committee all believe that abiraterone combined with PARP inhibitors can enable patients to obtain better rPFS and reduce the risk of disease progression or death in patients by 34%-39%
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The results of the rPFS subgroup analysis showed that the visceral metastasis subgroup (less than 15%) could still benefit from the combination therapy of abiraterone and olaparib, but the benefit ratio was lower
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Numerically, patients with visceral metastases had a shorter median (PFS), and PFS obtained from combination therapy was also relatively short, but combination therapy still achieved better outcomes than monotherapy
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Both theory and practice have proved that both HRR-mutated and non-mutated patients can obtain better curative effect from combination therapy, but non-mutated patients have less rPFS benefit from combination therapy
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Due to the insufficient follow-up time, the OS results of the PROpel study are not mature enough, and clinically meaningful OS results have not yet been obtained
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Figure 2 Results of the PROpel study Will first-line treatment of abiraterone combined with olaparib affect the drug selection and efficacy of subsequent treatment? The results showed that the combination therapy could prolong the time for patients to enter second-line and later-line therapy, and even after entering second-line therapy, the PFS2 of patients in the treatment group was longer than that of patients in the control group
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Therefore, the early use of abiraterone combined with olaparib treatment will not affect the benefit of subsequent treatment
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Safety of combination therapy Both olaparib and abiraterone have their own unique set of adverse events
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In the PROFOUND study, the most significant hematologic adverse event rate (grade 3 to 4 anemia) for olaparib was approximately 23%
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In the PROpel study, the combined use of abiraterone resulted in grade 3 to 4 hematologic adverse events in the patient population, particularly anemia in only 15.
1% of patients
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In the COU-AA-302 study using first-line abiraterone monotherapy, the common adverse event of abiraterone was hypertension, and the incidence of grade 3 to 4 hypertension was 5% to 6%
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In the PROpel study, the incidence of hypertension (especially grade 3 to 4 hypertension) was only 3.
5% in the case of drug combination
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Therefore, from the perspective of treatment safety, the combination of the two drugs did not lead to the superposition and accumulation of adverse drug events, and this combination regimen is worthy of recommendation
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The PROpel study suggests that combination therapy may be needed in the first-line treatment of CRPC.
In particular, PARP inhibitors combined with newer anti-androgens seem to bring better efficacy to the first-line treatment of CRPC patients
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But there was also a phase III clinical trial at the ASCO-GU meeting, the MAGNITUDE study, which explored the efficacy of another PARP inhibitor, niraparib, in combination with abiraterone in CRPC patients
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The design of this study is very similar to that of the PROpel study, but the results are different
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Let’s take a look at these two studies together.
Why do similar studies yield different results? Baseline status of patients in PROpel and MAGNITUDE studies: In PROpel study, HRR mutation patients accounted for about 30%; in MAGNITUDE study, HRR mutation accounted for more than 50% of enrolled patients
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In the mutation population, the BRCA2 mutation rate varies greatly.
The BRCA mutation rate in the PROpel study is about 20%; in the MAGNITUDE study, the BRCA2 mutation rate in the enrolled patients is 40%-45%
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In addition, the proportion of patients with visceral metastases in the two studies was different.
In the PROpel study, the proportion of patients with visceral metastases was less than 15%, while in the MAGNITUDE study, the proportion of patients with metastases to liver and lung lesions accounted for about 24%
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Finally, the MAGNITUDE study allowed enrollment of patients with a history of abiraterone therapy of less than 4 months
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Figure 3 MAGNITUDE study design The MAGNITUDE study divided patients into HRR-positive and HRR-negative groups
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The positive group results reached similar conclusions to the PROpel study, but the efficacy of the combination of niraparib and abiraterone was not numerically superior to the efficacy of the combination of olaparib and abiraterone in the PROpel study
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Niraparib combined with abiraterone treatment significantly improved the BRCA1/2 subgroup and HRR-positive group, reducing the risk of disease progression or death by 47% (16.
6 months vs 10.
9 months) and 27% (16.
5 months), respectively vs 13.
7 months)
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Figure 4 The results of the MAGNITUDE study The data show that in the MAGNITUDE study, the positive rate of BRCA1/2 in HRR mutation-positive patients exceeds 50%, while the incidence of BRCA1/2 mutation in the PROpel study is about 20%, and the PROpel study is more in line with the state of normal population distribution
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In 2019, the results of a prospective large clinical trial from Spain showed that patients with BRCA1 and BRCA2 mutations had a worse overall prognosis
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In 2016, a meta-analysis of more than 8,000 patients suggested that patients with visceral metastases also had a poor overall prognosis, and that different metastatic lesions also affected patients' OS and response to therapy
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In addition, the results of the subgroup analysis of the MAGNITUDE study indicated that the proportion of patients who had received abiraterone treatment before enrollment was close to 20%, which was also a risk factor affecting the overall efficacy of clinical trials
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The MAGNITUDE study also analyzed HRR-negative patients, but the results were opposite to those of the PROpel study
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In the HRR-negative subgroup of the MAGNITUDE study, the combination therapy was not more effective than the single-agent group
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However, in the PROpel study, regardless of HRR positive or negative, patients benefited from olaparib combined with abiraterone
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This result may be explained in terms of the mechanism of drug action
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Differences in "synthetic lethality" and "PARP trapping" potency among different PARP inhibitors may be one of the reasons for the difference in efficacy between MAGNITUDE and PROpel
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The above may explain that the PROpel study has similar design ideas to the MAGNITUDE study, but the results are inconsistent
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Conclusion: In the CRPC population with HR mutation, the first-line clinical application of abiraterone combined with olaparib is worth trying by clinicians; for the CRPC population regardless of mutation status, it is necessary to wait for the final OS result of the combination therapy before trying to apply the combination therapy in clinical
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References: 1.
Saad F, et al.
ASCO-GU2022 Abs 11.
2.
Chi KN, et al.
ASCO-GU2022 Abs 12.
Review: XY Typesetting: LR Execution: XY