【2022 ASCO-GU】Going a step further│The era of PARPi combined with abiraterone for the first-line treatment of mCRPC is coming?

*For medical professionals only for reference Metastatic castration-resistant prostate cancer (mCRPC) is the terminal stage of prostate cancer, and its treatment progress has always attracted the attention of clinical experts
.

The results of clinical trials tell us that the median survival time of mCRPC patients receiving novel endocrine therapy is about 3 years[1-2]
.

However, in the real world, although 83.
9% of mCRPC patients can receive novel endocrine therapy (NHT) in the first line, the average treatment time is less than 6 months, and the median overall survival time is less than 2 years [3]
.

This has to make us think, in a more complex real-world population, in addition to diagnosing mCRPC earlier and giving effective treatment in a timely manner, how can we further improve the effectiveness of patient treatment: it is to stratify patients and make treatment more effective.
Precise? Or is it first-line multidrug combination therapy? HRR-related gene mutations are a common prognostic factor for mCRPC, and previous studies have also demonstrated the effectiveness of PARP inhibitors (PARPi) in the later-line treatment of mCRPC [4], so whether the first-line use of PARPi + NHT combination therapy for mCRPC has a greater effect on patients Benefit? In 2022, ASCO-GU announced two blockbuster Phase III studies of PARPi combined with abiraterone in the first-line treatment of mCRPC - the MAGNITUDE and PROpel studies.
This article invited Professor He Zhisong from Peking University First Hospital to review the first analysis results of the two studies.
and in-depth analysis
.

 1.
The MAGNITUDE study: Niraparib (NIRA) combined with abiraterone acetate and prednisone (AAP) as first-line therapy for metastatic castration resistance with and without homologous recombination repair (HRR) gene variants Phase III study in patients with prostate cancer (mCRPC) [5] MAGNITUDE (NCT03748641) is a randomized, double-blind, placebo-controlled Phase III clinical study to evaluate the efficacy of HRR-related gene mutations in mCRPC patients with or without mutations.
Whether combined use of NIRA on the basis of AAP can improve patient outcomes
.

The study allowed the inclusion of patients in the mCRPC stage who had previously received AAP therapy for ≤4 months
.

Patients with HRR BM+ (ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2), and those without specific genetic alterations (HRR BM-) were randomized 1:1 to receive NIRA 200 mg QD+AAP or placebo (PBO) + AAP treatment
.

The primary endpoint was imaging progression-free survival (rPFS) as assessed by a blinded independent central review committee (BICR)
.

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

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

(Figure 1) Figure 1.
MAGNITUDE Study Design 423 HRR BM+ patients were randomly assigned to NIRA+AAP (n=212) or PBO+AAP (n=211)
.

The median age was 69 years, 23% had prior AAP therapy, 21% had visceral metastases, and 53% had BRCA1/2 mutations (Figure 2)
.

The median follow-up time was 18.
6 months
.

Figure 2.
Baseline Characteristics of HRR BM+ Patients in the MAGNITUDE Study In the BRCA1/2+ subgroup and all HRR BM+ patients, NIRA+AAP significantly improved BICR-assessed rPFS compared with PBO+AAP, with separate risk of radiographic progression or death The reductions were 47% (16.
6 vs 10.
9 months) and 27% (16.
5 vs 13.
7 months), and investigator-assessed rPFS was consistent with BICR (Figure 3)
.

Consistent rPFS benefit was also shown in a subgroup analysis of all HRR BM+ patients (Fig.
4)
.

Figure 3.
rPFS analysis of BRCA1/2 subgroup and all HRR BM+ patients in MAGNITUDE study Figure 4.
rPFS subgroup analysis of all HRR BM+ patients in MAGNITUDE study In the BRCA1/2+ subgroup and all HRR BM+ patients, NIRA+ AAP also Improved other endpoints, delayed time to cytotoxic chemotherapy start (TTCC), time to symptom progression (TTSP) and time to PSA progression (TTPP), and improved ORR
.

The first interim analysis of OS is immature
.

In HRR BM+ patients, grade 3/4 AEs occurred in 67% and 46.
4% of patients in the NIRA+AAP and PBO+AAP groups, respectively, and 10.
8% and 4.
7% of patients discontinued treatment, with no new safety signals observed ( Figure 5)
.

There were no clinically significant differences in overall quality of life (FACT-P) (Figure 6)
.

Figure 5.
Incidence of AEs in NIRA+AAP and PBO+AAP groups in all HRR BM+ patients in MAGNITUDE study Figure 6.
MAGNITUDE study all HRR BM+ patients in the NIRA+AAP group to maintain quality of life A planned futility analysis showed no benefit of NIRA+AAP therapy on the prespecified composite endpoint (first occurrence of PSA progression or rPFS; HR, 1.
09; 95% CI, 0.
75-1.
57)
.

MAGNITUDE prospectively detects HRR-related gene mutations in tissue and blood to explore the benefit of NIRA+AAP combination therapy in mCRPC patients with and without HRR-related gene alterations
.

In HRR BM- patients, no benefit was observed with NIRA+AAP treatment
.

In HRR BM+ patients, NIRA+AAP significantly improved the primary clinical outcome
.

No new safety events occurred in the NIRA+AAP group, AEs were manageable, and quality of life was maintained
.

The MAGNITUDE study underscores the importance of HRR gene mutation testing in mCRPC patients to identify those patients who can maximize the benefit of NIRA+AAP therapy
.

The findings support NIRA+AAP as a new first-line treatment option for HRR-mutated mCRPC patients
.

 2.
PROpel study: Phase III trial of olaparib (OLA) combined with abiraterone (ABI) versus placebo (PBO) combined with ABI first-line (1L) in patients with metastatic castration-resistant prostate cancer (mCRPC)[6] ]PROpel is a randomized, double-blind, placebo-controlled Phase III trial to evaluate the efficacy and safety of OLA + ABI in first-line treatment of mCRPC
.

Participants were mCRPC patients treated with 1L after failure of primary androgen deprivation therapy, and enrollment was independent of HRR status
.

Patients were randomized 1:1 to receive OLA (300 mg bid) or PBO in combination with ABI (1000 mg QD) plus prednisone or prednisolone (5 mg bid)
.

The primary endpoint was investigator-assessed rPFS, with multiple secondary endpoints including overall survival (OS) (Figure 7)
.

Baseline characteristics of patients in the two groups were matched consistently (Figure 8)
.

Figure 7.
PROpel study design Figure 8.
Interim analysis of patient baseline characteristics in PROpel study showed that OLA+ABI compared with PBO+ABI significantly prolonged rPFS in mCRPC patients regardless of HRR status (24.
8 vs 16.
6 months) , reduced the risk of radiographic progression or death by 34%, and the rPFS sensitivity analysis by BICR was consistent with the primary analysis (Figure 9)
.

Figure 9.
Subgroup analysis of rPFS analysis, the primary endpoint of the PROpel study, showed improvement in rPFS in all subgroups, including patients with HRR mutations detected by circulating tumor DNA (HR 0.
50, 95% CI, 0.
34–0.
73) and those without Patients with HRR mutations (HR 0.
76, 95% CI, 0.
60–0.
97) (Figure 10)
.

Figure 10.
Subgroup analysis of rPFS, the primary endpoint of the PROpel study, OLA+ABI also significantly improved time to first subsequent treatment, time to second progression-free survival or death, and ORR
.

OS is currently immature, with 228 deaths (28.
6%)
.

In the OLA+ABI and PBO+ABI groups, the incidence of grade ≥3 AEs was 47.
2% and 38.
4%, respectively, and 13.
8 and 7.
8% of patients discontinued OLA and PBO due to AEs, respectively.
The incidence of ABI discontinuations due to AEs was similar.
(8.
5% vs 8.
8%) (Figure 11)
.

The most frequently reported grade ≥3 adverse event (AE) in the OLA+ABI and PBO+ABI groups was anemia (15.
1 vs 3.
3%) (Figure 11)
.

Quality of life (FACT-P) was comparable between the two groups (Fig.
12)
.

Figure 11.
Incidence of AEs and common AEs in the PROpel study Figure 12.
Quality of life analysis in the PROpel study The results of the interim analysis of the PROpel study showed that OLA+ABI first-line treatment of mCRPC significantly improved rPFS compared with PBO+ABI, regardless of HRR status
.

The safety and tolerability profile of OLA+ABI was consistent with the known safety profile of the individual drugs
.

These results suggest that OLA+ABI can benefit without HRR stratification in the treatment of 1L mCRPC
.

Expert comments: The MAGNITUDE study and the PROpel study both explored the efficacy and safety of PARPi combined with abiraterone in the first-line treatment of mCRPC.
The primary endpoint was rPFS, and the secondary endpoint was OS.
Two similar studies have reached different conclusions
.

MAGNITUDE results showed that, relative to PBO+AAP, no benefit was observed with NIRA+AAP treatment in HRR BM- patients, while in HRR BM+ or BRCA1/2+ patients, NIRA+AAP significantly improved rPFS, delayed Time to cytotoxic chemotherapy, time to symptom progression, and time to PSA progression
.

The MAGNITUDE study highlights the importance of HRR gene mutation testing in mCRPC patients, who can maximize the benefit of NIRA+AAP therapy in HRR BM+ patients
.

The results of the PROpel study showed that, regardless of whether the HRR gene was mutated or not, OLA+ABI in the first-line treatment of mCRPC patients could bring clinical benefits compared with PBO+ABI, such as rPFS and PFS2
.

How to treat similar studies with different conclusions? First of all, from the perspective of the study design, the MAGNITUDE study conducted HRR gene testing before enrollment, and patients with HRR BM+ and HRR BM- entered different cohorts; the PROpel study did not conduct HRR gene testing before enrollment, and after treatment Retrospective genetic testing and subgroup analysis showed that 28% and 29% of the OLA+ABI group and PBO+ABI group were HRR BM+, respectively, and the genetic testing results at this time were not representative of the baseline situation
.

From the perspective of the included population, the MAGNITUDE study included patients in the mCRPC stage who received ABI therapy for less than 4 months, and patients in the mHSPC and NM-CRPC stages who received chemotherapy or ARi therapy, which is more in line with real-world population characteristics; PROpel study included For mCRPC patients without ABI treatment, if they are treated with other new endocrine drugs (NHT), they should be discontinued for more than 12 months before enrollment, and chemotherapy in the mHSPC stage is allowed
.

With the increasing use of NHT in the treatment of advanced prostate cancer, a large proportion of mCRPC patients may not currently be eligible for the PROpel study inclusion criteria
.

In addition, the evaluation methods of the primary endpoint rPFS are also different.
The MAGNITUDE study is evaluated by BICR, while the PROpel is evaluated by the investigator.
The former can avoid bias to a greater extent
.

Looking specifically at the value of rPFS, in MAGNITUDE, in the BRCA1/2+ subgroup and all HRR BM+ patients, the median rPFS in the PBO+AAP group was 10.
9 and 13.
7 months, respectively; in the PROpel study, mCRPC without HRR status was considered Among patients, the median rPFS in the PBO+ABI group was 16.
6 months, which was close to the median rPFS in the AAP group in the COU-AA-302 study (16.
5 months) [7]
.

This may be due to the fact that patients with BRCA1/2 mutations or HRR BM+ have a higher degree of malignancy, and the proportion of patients with HRR BM+ in the two studies is inconsistent.
We also look forward to the announcement of the proportion of patients with BRCA1/2 mutations in the PROpel study
.

What are the implications of these two studies for clinical practice? At present, the OS data of the two studies are immature, and it is necessary to wait for the final OS data, hoping to break the curse of mCRPC patients' survival time of less than 3 years
.

In clinical practice, it is also necessary to consider the safety and economy of combined medication, reduce the disease burden of patients, and live long and well
.

In general, new endocrine therapy represented by abiraterone can significantly improve the survival of mCRPC patients.
For patients with obvious adverse prognostic factors in clinical evaluation, it is necessary to conduct genetic testing before treatment, so that targeted Combination therapy with PARPi inhibitors maximizes patient benefit
.

Expert Profile Professor He Zhisong Director and Chief Physician of Urology Department of Peking University First Hospital Deputy Director of Peking University Urology Institute Deputy Director of Chinese Society of Clinical Oncology (CSCO) Council Member of Chinese Society of Clinical Oncology Urothelial Cancer Committee Vice Chairman of the Prostate Cancer Committee of the Society Member of the Renal Cancer Professional Committee of the Chinese Society of Clinical Oncology Member of the Standing Committee of the Urology and Male Genital Tumor Professional Committee of the Chinese Anti-Cancer Association Member of the Oncology Group of the Urology Branch of the Chinese Medical Association ) Vice President, Chinese Medical Doctor Association, Integrative Medicine Physician Branch, Integrative Urology Professional Committee :[1].
Ryan CJ, et al.
Lancet Oncol.
2015;16(2):152-160.
[2].
Beer TM, et al.
N Engl J Med.
2014;371(5):424-433 .
[3].
Shore ND et al.
Adv Ther 2021; 38:4520‒40.
[4].
de Bono J, et al.
N Engl J Med.
2020;382(22):2091-2102.
[5] .
2022 ASCO GU, Kim N.
Chi, Oral Abstract Session[6].
2022 ASCO GU, Fred Saad, Oral Abstract Session[7].
Ryan CJ, et al.
N Engl J Med.
2013 Feb 7;368(6) :584.
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform