2020-05-27| Trials & Approvals

Lynparza Greenlighted by FDA for HRR-Mutated, Metastatic Prostate Cancer

by Rajaneesh K. Gopinath
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By Rajaneesh K. Gopinath, Ph.D.

Within days of Clovis Oncology’s regulatory win for Rubraca, Lynparza bagged FDA authorization for the treatment of metastatic, castration-resistant prostate cancer (mCRPC), becoming only the second PARP inhibitor to be approved for this indication.

On May 20th, M.S.D., and AstraZeneca announced that their PARP inhibitor, Lynparza (olaparib), received the USFDA approval for the treatment of adult patients with mCRPC harboring deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene mutations.


Metastatic Castration-Resistant Prostate Cancer

Prostate cancer is the second most common type of cancer in men. It is often driven by the male sex hormone (androgens), including testosterone. Since the androgen receptor aids in the survival of many prostate cancer cells, it is a common anti-cancer target. mCRPC is a condition where cancer metastasizes to other parts of the body despite androgen-deprivation therapy. Lynparza induces cancer cell death by blocking the D.N.A. damage response (D.D.R.) in tumors that harbor an HRR mutation, resulting in unrepaired, D.N.A. single-strand, and double-strand breaks.

“Prostate cancer has lagged behind other solid tumors in the era of precision medicine. I am thrilled by the approval of Lynparza which now brings a molecularly targeted treatment to men with HRR gene-mutated metastatic castration-resistant prostate cancer in the U.S. The PROfound trial was an international effort. I want to thank the patients, their families, the investigators, and their teams involved in making it possible” said Maha Hussain, Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University who is also one of the principal investigators of the PROfound trial.


PROfound Trial (NCT02987543)

The F.D.A. approval is based on the successful Phase 3 PROfound trial, which is a multi-center, randomized, open-label clinical trial where patients either received a 300 mg olaparib twice daily or received the physician recommended choice of enzalutamide or abiraterone controls (160 mg enzalutamide once daily or one dose of 1000 mg abiraterone + two doses of 5 mg prednisone).

Patients were divided into two cohorts based on their HRR gene mutation status. While patients who have an apparent HRR biomarker mutation (BRCA1 / 2 or A.T.M.) constituted cohort A, the ones with HRR-related gene mutations (BARD1, BRIP1, CDK12, CHEK1 / 2, FANCL, PALB2, PPP2R2A, RAD51B / C / D or RAD54L) were put under cohort B. Radiographic progression-free survival (rPFS) in patients belonging to cohort A was the primary endpoint of the trial. rPFS in the overall population was the key secondary endpoint.

Trial results showed that Lynparza achieved its primary endpoint by significantly reducing the risk of disease progression or death by 66.6% as compared to the control arm (H.R., 0.34; 95% CI, 0.25-0.47; P <0.0001). The median rPFS was 7.4 months for Lynparza and 3.6 months for enzalutamide or abiraterone. Additional results demonstrated that there was a statistically significant improvement in overall survival (51%), too, with a median of 5.8 months for Lynparza and 3.5 months for the control (H.R., 0.49; 95% CI, 0.38 to 0.63; P<0.001). Besides, the PARP inhibitor registered benefits in additional secondary endpoints. The objective response rate (O.R.R.) was 33.3% in the Lynparza arm vs. the control’s 2.3%. It also reduced the risk of pain progression by 56%.

“Today marks the first approval for Lynparza in prostate cancer. In the PROfound trial, Lynparza more than doubled the median radiographic progression-free survival and is the only PARP inhibitor to improve overall survival, versus enzalutamide or abiraterone for men with BRCA or A.T.M. mutations. These results further establish that genomic testing for HRR mutations should be a critical step for the diagnosis and determination of treatment options for men with advanced prostate cancer,” said Dave Fredrickson, Executive V.P., Oncology Business Unit of AstraZeneca.


Companion Diagnostics

Two companion diagnostics were FDA-approved for Lynparza in prostate cancer, one to identify BRCA mutations and the other for HRR-gene alterations. Myriad Genetics’ germline test, BRACAnalysis, was approved to identify BRCA1 and BRCA2 mutations. The comprehensive genomic profiling test of Foundation Medicine Inc. (F.M.I.) was approved to identify HRR-gene alterations in the prostate tumor tissue.

Speaking exclusively to GeneOnline, Brian Alexander, M.D., M.P.H. C.M.O. of F.M.I. said, “It is an exciting approval that gives patients with mCRPC a more targeted treatment option that leverages a weakness within the cancer cell. This also provides a new way of looking at precision medicine. The deficiency in HRR could be assessed by identifying mutations in any of the 14 HRR pathway genes. This approval validates our ability to do that with our FoundationOne CDx’s 324 gene panel”.

Related Article: Lynparza Meets Primary Endpoint in Phase III PROfound Trial



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