2022 ASCO-GU MAGNITUDE opens a new era of PARPi and NHT

ASCO-GU announced the results of the MAGNITUDE trial on the morning of February 18, 2022, Beijing time.
Niraparib combined with abiraterone can significantly improve the clinical outcomes of first-line mCRPC patients with HRR mutations.
1 Foreword Worldwide, as of 2022 , Prostate cancer has become the malignant tumor with the first incidence and the second fatality rate in men [1]
.

In China, prostate cancer ranks sixth in the incidence of male malignant tumors [2], and the incidence continues to increase in both urban and rural areas
.

mCRPC is the terminal stage of prostate cancer, with high degree of malignancy, high lethality, and a 5-year survival rate of less than 30%; although the median overall survival of patients in clinical studies has been close to 3 years, the median survival of patients in the real world is still insufficient 2 years[3]
.

According to real-world data, less than half of the patients with mCPRC can receive second-line treatment after the first-line treatment progresses, which may be the key to the survival of patients [4]
.

In order to improve the overall outcome of Chinese prostate cancer patients, further expanding the clinical benefit of first-line mCRPC therapy in China is an urgent problem to be solved in mCRPC treatment
.

Compared with homologous recombination repair (HRR)-negative patients, patients with HRR-related gene alterations may have a worse prognosis
.

Previous studies have shown that HRR-related genes, including BRCA1/2, are mutated at a frequency of 20%-30% in mCRPC, and respond to PARP inhibitors (PARPi) such as niraparib (NIRA)
.

Combining PARPi with androgen receptor pathway-targeted therapy (ARi) may also benefit unselected mCRPC
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The MAGNITUDE trial evaluated whether NIRA combined with abiraterone plus prednisone (AAP) versus AAP could improve outcomes in patients with mCRPC, regardless of the presence or absence of HRR-related gene alterations
.

2 Study Overview Methods The MAGNITUDE study is a prospective, international, multicenter, randomized, double-blind phase 3 trial to evaluate the antitumor efficacy of niraparib in combination with abiraterone versus abiraterone in first-line mCRPC.
In eligible mCRPC patients, patients were allowed to receive ≤4 months of prior AAP therapy
.

The enrolled patients were divided into HRR marker positive (HRR BM+, including nine genes of ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and no specific gene changes ( In the HRR BM-) group, patients were randomized 1:1 to receive NIRA 200 mg or placebo (PBO) QD in combination with AAP
.

Stratification factors included prior taxane-based chemotherapy in mHSPC stage and ARi treatment with abiraterone in mHSPC stage and NM-CRPC stage
.

The primary endpoint was imaging progression-free survival (rPFS) assessed by blinded independent central review (BICR) in patients with BRCA1/2 mutations in the BM+ arm, and rPFS in all HRR BM+ patients
.

Secondary endpoints were time to cytotoxic chemotherapy start (TTCC), time to symptom progression (TTSP) and overall survival (OS)
.

Other endpoints included time to PSA progression (TTPP) and objective response rate (ORR)
.

Figure 1 Results of the MAGNITUDE trial design: 423 HRR BM+ patients were randomized to NIRA+AAP (n=212) or PBO+AAP (n=211)
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The median age of enrolled patients was 69 years, 23% had prior AAP therapy, 21% had visceral metastases, and 53% had BRCA1/2 mutations
.

Figure 2.
Baseline of HRR BM+ patients in the MAGNITUDE trial.
There were slightly more patients with visceral metastases in the experimental group than in the control group.
The median follow-up time was 18.
6 months
.

BICR assessment: NIRA+AAP significantly improved rPFS in BRCA1/2 subgroups and HRR BM+ patients, reducing the risk of disease progression or death by 47% (16.
6 vs 10.
9 months) and 27% (16.
5 vs 13.
7 months), respectively months)
.

Investigator-assessed rPFS was consistent with BICR
.

NIRA+AAP delayed TTCC, TTSP and TTPP and improved ORR in HRR BM+ patients
.

OS is currently immature
.

Figure 3 Niraparib + abiraterone combination therapy significantly improved rPFS in patients with BRCA1/2 mutationsFigure 4 Niraparib + abiraterone combination therapy significantly improved rPFS in patients with HRR mutations New safety signal
.

Among HRR BM+ patients, grade 3/4 AEs occurred in 67% and 46.
4% of patients in the NIRA+AAP group and PBO+AAP group, respectively, and 9% and 3.
8% of patients discontinued treatment, respectively
.

There were no clinically significant differences in overall quality of life (FACT-P) between the two groups
.

 Conclusions: NIRA+AAP significantly improved rPFS and other clinical outcomes in first-line treatment of mCRPC patients with HRR gene
.

3 Experts' Comments A series of major breakthroughs have been made in the treatment mode of advanced and metastatic prostate cancer in recent years, bringing more treatment options to patients
.

Novel endocrine therapy represented by abiraterone has confirmed the exact efficacy in mCRPC population
.

How to further improve the patient's treatment benefits, the MAGNITUDE trial provides a new idea
.

HRR mutations may be associated with poor outcomes in prostate cancer patients
.

Taking mHSPC as an example, our single-center retrospective analysis showed that newly diagnosed mHSPC patients with HRR mutations had significantly shorter time to CRPC (TTCR) than wild-type patients (HR 2.
37; p < .
001), and those with BRCA mutations The patient's TTCR was even worse (HR 3.
73, p<.
001) [5]
.

PARP inhibitors can cause synthetic lethality in tumor cells with HRR mutations, resulting in tumor cell death; in addition, previous experiments also suggested that abiraterone may have a synergistic effect with PARP inhibitors to enhance the efficacy of PARP inhibitors
.

Therefore, for patients with HRR mutations, whether the combination of PARP inhibitors and abiraterone for the first-line treatment of mCRPC can further expand the treatment benefits of patients has become one of the focuses of clinicians in recent years
.

In the previous 302 trial of abiraterone, the median rPFS of first-line patients with mCRPC without chemotherapy was 16.
5 months [6], and in the interim analysis of this MAGNITUDE trial, mCRPC patients with HRR mutations were The median rPFS of abiraterone treatment in the control group was 13.
7 months, and the rPFS of patients with BRCA1/2 mutation was only 10.
9 months, suggesting that there is a greater urgency for treatment in first-line patients with HRR mutation-positive mCRPC
.

Niraparib combined with abiraterone can significantly prolong rPFS in first-line mCRPC patients with HRR mutation, and significantly delay imaging disease progression.
For mCRPC patients with BRCA1/2 mutation, the combination therapy can even significantly prolong rPFS for more than half a year
.

Reduced rPFS risk by 50% (rPFS benefit assessed by investigators in the BRCA1/2 subgroup), and no new safety signals were identified
.

This trial confirms that PARP inhibitor and novel endocrine combination therapy can bring greater therapeutic benefit to patients with HRR mutation, and MAGNITUDE is also the first to clearly demonstrate the combination of PARP inhibitor and abiraterone in patients with BRCA1/2 mutation Clinical trials of benefit in mCRPC1 line
.

Niraparib is also conducting another AMPLITUDE (NCT04497844) trial in combination with abiraterone in the mHSPC phase in China.
It is expected that the indications of niraparib and abiraterone will be approved in China to benefit Chinese patients.
Looking forward to seeing the success of the AMPLITUDE trial as soon as possible
.

Expert Profile Professor Ye Dingwei, Vice President of Fudan University Affiliated Cancer Hospital, Chief Expert of MDT in Urological Oncology Director of Shanghai Institute of Urological Oncology Director of Prostate Tumor Institute of Fudan University ) Chairman of the Chinese Society of Clinical Oncology (CSCO) Chairman of the Prostate Cancer Expert Committee Vice Chairman of the Renal Cancer Expert Committee of the Chinese Society of Oncology (CSCO) Vice Chairman of the Immunotherapy Expert Committee of the Chinese Society of Clinical Oncology (CSCO) Chairman of the Urological Oncology Collaborative Group (UCOG) of the China Cancer Hospital Executive Director of the China Anti-Cancer Association and Executive Director of the Chinese Society of Clinical Oncology Director of the Chinese Anti-Cancer Association Genitourinary Oncology Committee (CACA-GU) Prostate Cancer Group Leader NCCN Kidney Cancer Diagnosis and Treatment Guidelines Chinese Edition Deputy Leader NCCN Prostate Cancer, Kidney Cancer, Bladder Cancer Asian Diagnosis and Treatment Consensus Expert Committee Member of Advanced Prostate Cancer Asia Pacific Consensus Expert Committee Member Vice President of Urology Branch of Shanghai Medical Association Former President of Shanghai Anti-Cancer Association et al Reference[1] Siegel, RL, Miller, KD, Fuchs, HE, Jemal, A.
Cancer statistics, 2022.
CA Cancer J Clin.
2022.
[2] 2019 National Cancer Center data [3] Shore ND, Laliberté F .
, Ionescu-Ittu R.
et al.
Real-World Treatment Patterns and Overall Survival of Patients with Metastatic Castration-Resistant Prostate Cancer in the US Prior to PARP Inhibitors.
Adv Ther 38, 4520–4540 (2021).
[4] George DJ, Sartor O, Miller K, et al.
Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States.
Clin Genitourin Cancer.
2020;18(4):284-294.
[5] Wei Y, Wu J, Gu W, et al.
Prognostic Value of Germline DNA Repair Gene Mutations in De Novo Metastatic and Castration-Sensitive Prostate Cancer.
Oncologist.
2020;25(7):e1042-e1050.
doi:10.
1634/theoncologist.
2019-0495[6] Ryan CJ, Smith MR, de Bono JS, et al; Abiraterone in metastatic prostate cancer without previous chemotherapy.
N Engl J Med.
2013;368(2):138-148.
Prognostic Value of Germline DNA Repair Gene Mutations in De Novo Metastatic and Castration-Sensitive Prostate Cancer.
Oncologist.
2020;25(7):e1042-e1050.
doi:10.
1634/theoncologist.
2019-0495[6] Ryan CJ, Smith MR, de Bono JS, et al; Abiraterone in metastatic prostate cancer without previous chemotherapy.
N Engl J Med.
2013;368(2):138-148.
Prognostic Value of Germline DNA Repair Gene Mutations in De Novo Metastatic and Castration-Sensitive Prostate Cancer.
Oncologist.
2020;25(7):e1042-e1050.
doi:10.
1634/theoncologist.
2019-0495[6] Ryan CJ, Smith MR, de Bono JS, et al; Abiraterone in metastatic prostate cancer without previous chemotherapy.
N Engl J Med.
2013;368(2):138-148.