[From study08 to PROpel] Olapali mCRPC's road to the front line of the whole crowd

*For reference only for medical professionalsForeword There is an unmet clinical need for the first-line treatment of metastatic castration-resistant prostate cancer (mCRPC), and better treatment options are urgently needed
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Mechanistically, the combination of olaparib and abiraterone has a synergistic anti-tumor effect; the Phase II clinical study Study08 safety cohort PK study did not find two-drug interactions and drug dose-limiting toxicity, and full doses of olaparib and abiraterone are recommended into follow-up research
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Study08 showed that the combination therapy brought significant clinical benefit to mCRPC patients (regardless of HRR mutation status), and the overall safety was good
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The combination therapy then entered the confirmation road of the Phase III PROpel study
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In September 2021, it was reported that the PROpel study achieved positive results in the first-line whole population of mCRPC, and the data will be announced at the ASCO-GU conference next week on February 18 (China time)
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On this occasion, Professor Dong Baijun from the Department of Urology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine was specially invited to review the research and development of the combination therapy of olaparib and abiraterone for us
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There is an unmet need for the first-line treatment of mCRPC.
Globally, prostate cancer has become the second most common malignant tumor in men and the fifth most lethal [1]
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In China, according to data from the National Cancer Center in 2019, prostate cancer already ranks sixth in the incidence of male malignant tumors, and the incidence continues to increase in both urban and rural areas [2]
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mCRPC is the terminal stage of prostate cancer, with high degree of malignancy and high lethality.
The 5-year survival rate is less than 30%.
Although the median overall survival of patients in clinical studies has been close to 3 years, in the real world, the median survival rate of patients Still less than 2 years [3]
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According to real-world data, after the first-line treatment of mCPRC progresses in clinical practice, less than half of the patients can receive second-line treatment, which may be the key to the survival of patients in the real world [4]
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Therefore, further improving the clinical benefit of the first-line treatment of mCRPC is an urgent problem to be solved in the treatment of mCRPC patients
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Novel endocrine therapy (NHA) represented by abiraterone has confirmed the definite efficacy in the mCRPC population.
Olaparib has also become the standard therapy for mCRPC patients with HRR mutation who have progressed after NHA treatment through the PROfound study, and it is currently the only treatment in China.
Approved PARP inhibitor for prostate cancer indication
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Whether the combination of the two can bring better clinical benefits to mCRPC patients in the first-line treatment has been highly anticipated
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[Preclinical] Olaparib and abiraterone have synergistic anti-tumor effects Preclinical studies suggest that olaparib and abiraterone have synergistic anti-tumor effects
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On the one hand, cell-level studies have shown that PARP-1 promotes the transcriptional activity of androgen receptor (AR) after entry into the nucleus, and PARP inhibition can assist NHA to block the AR pathway [6,7]; on the other hand, AR pathway inhibitors downregulate DDR Gene transcription [7,8], increases DNA damage, and induces tumor cell sensitivity to PARP inhibitors
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In preclinical animal model studies, it has also been confirmed that the combination of olaparib and abiraterone has a synergistic effect of 1+1>2, enhancing the anti-tumor efficacy
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The synergistic effect of PARPi and AR pathway inhibitors [PK study] The Study08 safety cohort study showed that there is no drug interaction between olaparib and abiraterone, and the full dose can be used Study08 is a double-blind, randomized controlled, phase II study, The results were published in Lancet Oncology [9]
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The study first conducted a safety cohort PK study to determine the appropriate drug dose.
The results showed that there was no drug interaction between olaparib and abiraterone, and no drug dose-limiting toxicity was found.
The full dose of olaparib can be 300mg BID In combination with Abiraterone 1000mg QD
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The PK results of olaparib and abiraterone combination therapy versus abiraterone monotherapy 【Phase II study】Study08 proves that olaparib and abiraterone combination can benefit the entire population of mCRPC patients.
Sitaxel-treated mCRPC patients were randomized 1:1 to receive olaparib + abiraterone or placebo + abiraterone to evaluate the efficacy and safety of olaparib combined with abiraterone in the treatment of patients with mCRPC
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The results of the Study 08 study design showed that the clinical efficacy of olaparib combined with abiraterone in the treatment of mCRPC was better than that of abiraterone monotherapy in the intention-to-treat (ITT) population, rPFS: 13.
8 vs 8.
2 months (HR 0.
65, 95% CI).
0.
44-0.
97, p=0.
034), suggesting that olaparib combined with abiraterone can bring clinical benefit to mCRPC in the whole population
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ITT population rPFS Kaplan-Meier curve This study exploratively analyzed the improvement of rPFS by combination therapy and monotherapy under different HRR mutations
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The results showed that whether it was HRRm-positive group, HRRm-negative group or HRR mutation status partially confirmed group, the combination therapy could prolong the rPFS of patients to a certain extent compared with the monotherapy group
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Subgroup analysis: rPFS Kaplan-Meier curve in different HRR mutation populations The safety of combined treatment with olaparib and abiraterone is good.
For cancer patients, treatment-related adverse reactions have always been a special concern for doctors
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The results of the safety analysis of the study showed that the overall incidence of adverse events in the combination therapy group and the single-agent group was 93% vs 80%, and the incidence of grade 3 and above adverse events was 54% vs 28%, respectively
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Although the incidence of adverse events was higher in the combination arm than in the monotherapy arm, there was no significant difference in health-related quality of life between the two groups (85% vs 80% worsening), which was based on a combination of clinical efficacy and tolerability rating
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In addition, the safety profile of combination therapy was consistent with known reports of each drug by cross-sectional comparison of combination therapy with monotherapy, and combination therapy did not add new types of adverse events
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【Phase 3 study】PROpel study will be announced at ASCO-GU soon, olaparib combination therapy is expected to become a new first-line treatment regimen for mCRPC in the whole population Phase III study of efficacy and safety of first-line therapy in selected mCRPC patients without genetic testing
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The study included 796 patients with mCRPC who were not previously treated with chemotherapy and NHA, and were randomly assigned to olaparib (full dose, 300 mg BID) + abiraterone treatment group or placebo + abiraterone treatment group.
The primary endpoint was Image progression-free survival time for all subjects, secondary endpoints will look at overall survival, time to first follow-up treatment and time to second progression
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In September 2021, the PROpel study announced good news that it had reached the primary endpoint of rPFS and was the first phase III registration clinical study to announce positive results in the first-line population of mCRPC
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The final data of the study will be released by ASCO-GU on February 18 this year, let us look forward to it together
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Expert Profile Dr.
Dong Baijun Deputy Chief Physician, Ph.
D.
, Master Supervisor, Department of Urology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine Member of the Prostate Cancer Group of the Chinese Anti-Cancer Association Urinary and Male Genital Oncology Committee The correspondent editorial board is mainly engaged in the clinical diagnosis, treatment and research of urinary tract tumors, especially prostate cancer.
He is good at precise, painless, targeted puncture of the prostate, robotic-assisted/laparoscopic function-preserving radical surgery for prostate cancer, and cryoablation/high-energy focused ultrasound for prostate cancer.
/ Nanoknife and other ultra-minimally invasive surgery, molecular diagnosis and precise diagnosis and treatment of prostate cancer, individualized treatment of castration-resistant prostate cancer, comprehensive diagnosis and treatment of neuroendocrine differentiated prostate cancer,
etc.

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Siegel, RL et al.
CA: a cancer journal for clinicians, 71(1), 7–33.
[2].
2019 National Cancer Center Data.
[3].
IARC.
Cancer Today – Estimated number of new cases in 2020.
[4].
George DJ, et al.
Clin Genitourin Cancer.
2020;18:284–294[5].
Mateo J et al.
N Engl J Med 2015; 373: 1697–708.
[6].
Polkinghorn WR et al.
Cancer discov, 2013; 3(11); 1245–53.
[7].
Schiewer MJ et al.
Cancer Discov 2012; 2: 1134–49.
[8].
Asim M et al .
Nat Commun 2017; 8: 374[9].
Noel Clarke et al.
Lancet Oncol 2018; 19: 975–86