A new standard for first-line treatment of prostate cancer (mCRPC)! PARP inhibitor + new hormone therapy combination regimen Lynparza + Zyetiga is about to be approved in Europe and the United States!

Nov.
16, 2022 /Biovalley BIOON/ -- AstraZeneca and Merck & Co have announced that the European Medicines Agency (EMA) Committee on Medicinal Products for Human Use (CHMP) has issued a positive review recommending the approval of the PARP inhibitor-like anticancer drug Lynparza (Chinese brand name: Lipzo, generic name: olaparib, Olaparib): a combination of abiraterone and prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) who are not clinically amenable to chemotherapy
.

Prostate cancer is the most common cancer in men in Europe, with an estimated 473,000 cases and 108,000 deaths
in 2020.
It is estimated that about 10-20% of patients with advanced prostate cancer will develop castration-tolerant prostate cancer (CRPC) within 5 years, and at least 84% of these men will develop metastases
when CRPC is diagnosed.
The prognosis for patients with advanced prostate cancer is particularly poor, and the 5-year survival rate is still very low
.

The European Commission (EC) is expected to make a final review decision
within the next 2 months.
If approved, it would represent the first combination
of an EU PARP inhibitor with a novel hormone drug.
Currently, Lynparza's application for these indications is also under priority review by the US FDA, which expects to make a review decision
in the fourth quarter of 2022.

Positive review of CHMP based on the results of
the Phase 3 PROpel trial (NCT03732820).
The data were published in the New England Journal of Medicine (NEJM) in June this year, see: Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer
.

PROpel is a randomized, double-blind, multicenter Phase 3 trial comparing the efficacy, safety, and tolerability
of current standard care therapies Zytiga (abiraterone acetate) and Lynparza + Zyetiga combination therapy in a first-line setting in patients with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy or novel hormonal drugs (NHA) and carry or do not carry a mutation in the Homologous Recombinant Repair (HRR) gene.
Patients in both treatment groups also received prednisone or prednisolone twice a day
.

The primary endpoint results showed that first-line treatment with Lynparza + Zytiga showed statistically significant and clinically significant improvements
in radiological progression-free survival (rPFS) compared with Zytiga.
Whether the HRR gene is mutated or not, patients receive clinically meaningful therapeutic benefits
.

PROpel test results (click on the picture for a larger image, image source: NEJM)

Specifically, in a predetermined interim analysis, the primary endpoint showed that first-line treatment with Lynparza + Zyetiga reduced the risk of disease progression or death by 34% compared with Zytiga across the study population (HR = 0.
66; 95% CI: 0.
54 to 0.
81; p<0.
0001).

The median rPFS was 24.
8 months in the Lynparza+Zyetiga group compared to 16.
6 months
in the Zytiga group.
Through blinded independent central review (BICR) analysis, Lynparza+Zytiga extended median rPFS by almost one year (27.
6 versus 16.
4 months)
compared to Zytiga.

The results also showed that Lynparza + Zytiga showed a favorable trend towards improved overall survival (OS) compared to Zytiga, but the difference was not statistically significant at data cut-off (analysis at 28.
6% data maturity) (HR=0.
86; 95%CI: 0.
66-1.
12; p=0.
29).

。 Data from additional secondary efficacy endpoints, such as time to first follow-up treatment (TFST; HR=0.
74; 95%CI: 0.
61-0.
90), second progression-free survival (PFS2: HR=0.
69; 95%CI: 0.
51-0.
94), exploratory endpoints including objective response rate (ORR: odds ratio OR=1.
60; 95%CI: 1.
02-2.
53), prostate-specific antigen level, and determination of PSA progression time (HR=0.
55; 95%CI: 0.
45-0.
68), This further supports the therapeutic benefits
of the Lynparza+Zyetiga regimen compared to Zytiga alone in the trial population as a whole.

The safety and tolerability of Lynparza in combination with Zytiga is consistent
with the results observed in previous clinical trials and the known characteristics of each drug.
There was no increase in the rate of discontinuation of Zytiga in patients treated with the combination of Lynparza and Zytiga compared to patients treated with Zytiga alone, and there was no adverse effect on health-related quality of life (as assessed by the FACT-P [Assessment of Therapeutic Function in Prostate Cancer] questionnaire).

Prostate cancer is the second most common cancer in men, causing about 375,000 deaths
in 2020.
In a clinical trial setting, the overall survival of patients with mCRPC is about 3 years, while in the real-world setting, this time is even shorter
.
About half of patients with mCRPC may receive only one effective treatment, with the benefits of subsequent treatments diminishing
.
About 20-30% of patients with mCRPC develop HRR gene mutations
.

For prostate cancer, Lynparza has been approved in the United States for the treatment of patients with mCRPC who have progressed to the disease after prior treatment with enzalutamide or abiraterone and carry HRR gene mutations (BRCA coating and other HRR gene mutations
).
In the European Union, China, and Japan, Lynparza is approved for use in patients
with mCRPC who have progressed to the disease after prior to novel hormone therapy (NHA) and carry BRCA mutations.

The results of the PROpel trial are impressive because this active controlled trial sets a higher standard of care
.
In this trial, the first-line treatment of mCRPC with the Lynparza+Zyetiga regimen showed significant clinical improvement compared with the standard-of-care therapy Zytiga, regardless of whether the tumor carried the HRR gene mutation
.
If approved, the Lynparza+Zyetiga combination will provide a much-needed new treatment option
for first-line patients.

Lynparza, a first-of-its-kind oral polyADP ribose polymerase (PARP) inhibitor that preferentially kills cancer cells using defects in the tumor DNA damage repair (DDR) pathway, gives Lynparza the potential to
treat a wide range of types of tumors with DNA damage repair defects.

Lynparza is the world's first PARP inhibitor to be marketed, first approved by the U.
S.
FDA in December 2014
.
AstraZeneca and Merck entered into a global strategic collaboration in oncology in July 2017 to jointly develop and commercialize Lynparza and another MEK inhibitor, selumetinib, for the treatment of multiple types of tumors
.
In the PARP inhibitor category, Lynparza has the most extensive and advanced clinical trial development program
.
AstraZeneca and Merck are collaborating to investigate the therapeutic potential
of Lynparza as monotherapy as well as combination therapy for a wide range of tumor types.
(Biovalley Bioon.
com)

Lynparza in combination with abiraterone recommended for approval in the EU by CHMP as 1st-line treatment for patients with metastatic castration-resistant prostate cancer