2022 ASCO GU Professor Zeng Hao commented: PROpel-Olapali targets the entire front-line population of mCRPC

*For medical professionals to read for reference, the intensive combination therapy regimen of olaparib combined with abiraterone is very likely to change the treatment pattern and pattern of the entire first-line mCRPC population
.

——Professor Zeng Hao, Department of Urology, West China Hospital The abstract of the 2022 ASCO GU conference was freshly released at 06:00 today.
The PROpel study, as the first phase III clinical study of PARP inhibitor combined with NHA treatment, has been attracting much attention
.

The study was officially announced in September last year to obtain positive results in the full first-line population of metastatic castration-resistant prostate cancer (mCRPC).
Phase III study comparing olaparib plus abiraterone versus placebo plus abiraterone as first-line therapy A synergistic anti-tumor effect can be produced between the pathways
.

A phase II clinical study (NCT01972217, study08) of mCRPC patients previously treated with docetaxel and not selected for homologous recombination repair (HRR) status showed: olaparib combined with abiraterone versus placebo Compared with abiraterone, patients' radiographic progression-free survival (rPFS) was improved
.

The Phase III clinical study PROpel (NCT03732820) will further verify the efficacy and safety of olaparib combined with abiraterone in the first-line treatment of mCRPC
.

Methods: PROpel is a randomized, double-blind, placebo-controlled Phase III study in first-line patients with mCRPC
.

Enrolled patients, regardless of HRR mutation status, were randomized 1:1 to receive olaparib (300 mg twice daily) or placebo in combination with abiraterone (1000 mg once daily) plus prednisone /prednisolone (5 mg twice daily)
.

The primary endpoint was investigator-assessed rPFS, and multiple secondary endpoints including overall survival (OS) were explored
.

Results: 796 patients were randomly assigned to receive olaparib plus abiraterone (n = 399) or placebo plus abiraterone (n = 397)
.

In a preplanned interim analysis, olaparib plus abiraterone as mCRPC1L significantly prolonged patients' rPFS compared with placebo plus abiraterone, regardless of HRR status (median rPFS 24.
8 months vs 16.
6 month; HR 0.
66, 95% CI 0.
54-0.
81; P < 0.
0001)
.

Analysis of pre-defined subgroups showed improved rPFS in all subgroups, including patients with HRR mutations detected by ct-DNA (HR 0.
54, 95% CI 0.
36–0.
79) and patients with no HRR mutations detected (HR 0.
76) , 95%CI 0.
59–0.
97)
.

Results of a sensitivity analysis of rPFS by blinded independent central review showed agreement with the primary analysis (HR 0.
61, 95% CI 0.
49-0.
74; P = 0.
004)
.

OS is currently immature (228 events have occurred, data maturity 28.
6%), and a trend in OS favoring olaparib combined with abiraterone has been observed (HR 0.
86, 95% CI 0.
66-1.
12)
.

In addition, the secondary endpoints of the study showed that olaparib combined with abiraterone was associated with time to first follow-up treatment (HR 0.
74, 95%CI 0.
61-0.
90) and time to second progression-free survival or death (HR 0.
69, 95%).
CI 0.
51-0.
94) showed benefit, suggesting that the combination therapy group can bring long-term benefit
.

In the safety analysis, anemia was the most frequently reported adverse event of grade 3 or higher in both groups (15.
1% vs 3.
3%)
.

Olaparib or placebo was discontinued due to adverse events in 13.
8% vs 7.
8% of patients, respectively
.

The incidence of adverse events leading to discontinuation of abiraterone was similar in the two groups (8.
5% vs 8.
8%)
.

CONCLUSIONS: PROpel's interim analysis met the study's primary endpoint, demonstrating that olaparib plus abiraterone significantly improved rPFS in patients with newly diagnosed mCRPC who had not previously received 1L therapy compared with placebo plus abiraterone, and Regardless of the patient's HRR mutation status
.

The safety and tolerability profile of olaparib in combination with abiraterone was consistent with the known safety profile of the individual drugs
.

These results confirm the benefit of olaparib combined with abiraterone in the first-line treatment of mCRPC without stratification by HRR mutation status
.

Long-term survival follow-up of patients is ongoing for planned OS analysis
.

Comments: From the study abstract, we can find that the PROpel study has locked the entire first-line mCRPC population from the beginning of its design, and does not stratify in advance by gene mutation status.
The confidence in this design comes from the combination of olaparib and abiraterone.
Molecular mechanism study [NC 2017] and subsequent phase II clinical study study08 [Lancet Oncol, 2018]
.

The interim analysis of PROpel found that compared with abiraterone monotherapy, the median rPFS-free time in the combination therapy group exceeded 2 years for the first time, reduced the risk of rPFS by 34%, and prolonged the median rPFS-free survival by 8.
2 months.
The results were statistically significant meaning
.

Subgroup analysis also showed that both CRPC patients with HR mutations and those without HR mutations could benefit from combination therapy, which could reduce the risk of rPFS by 46% and 24%, respectively
.

In terms of safety, the overall incidence of toxic reactions in the combination therapy group was similar to that in the phase II study.
Although the incidence of grade 3-4 adverse events was slightly higher than that in the abiraterone monotherapy group, most patients (86.
2%) could maintain treatment until Progression, and discontinuation rates were similar in the combination and monotherapy groups
.

With the continuous exploration of new drug development and combination therapy combinations for sequential treatment of mCRPC patients, PROpel has become a clinical study that truly achieves a breakthrough in the survival benefit of combination therapy
.

As the first PARP inhibitor for prostate cancer approved in the world or in China, the intensive combination therapy of olaparib combined with abiraterone is very likely to change the treatment mode and pattern of the whole first-line population of mCRPC
.

The PROpel data will be reported in detail in the Oral Abstract Session A: Prostate Cancer on February 18, let us look forward to it together
.

Expert Profile Prof.
Zeng Hao, Department of Urology, West China Hospital, Sichuan University, professor, doctoral supervisor, 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 Youth Committee Member and Deputy Secretary General of the Urological Health Promotion Branch of the China Association for the Promotion of International Exchanges of Health Care Member of the Standing Committee of the Urology Specialized Committee Deputy Head of the Oncology Group of the Urological Specialized Committee of the Sichuan Medical Association Treatment) Deputy Chairman of the Urogenital Oncology Committee of the Society Head of the Advanced Prostate Cancer Group, Urology Branch, Chengdu Medical Association Urology Branch, Advanced Renal Cancer Group Reference: [1] 2022 ASCO GU abstract 11.
PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) placebo (pbo) and abi as first-line (1L) therapy versus patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
[2] Noel C, Pawel W, et al.
Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial.
Lancet Oncol 2018; 19: 975–86.
[3] Asim M, Tarish F,et al.
Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer.
Nat Commun 2017; 8: 374.
*This article is for scientific information only for medical professionals and does not represent the views of this platform