#ESMO20: AZ, Merck’s PARP Inhibitor Surpasses Standard of Care in Prostate Cancer Trial
By Ruchi Jhonsa, Ph.D.
When prostate cancer is first detected, it is treated using therapies that reduce the levels of androgens fuelling the growth of cancer. However, if cancer spreads despite the treatment, it becomes castration-resistant prostate cancer (mCRPC), which physicians usually treat with androgen inhibitors like J&J’s Zytiga (enzalutamide) or Astellas’ and Pfizer’s Xtandi (abiraterone). While the therapy provides benefits, it is limited in its effect on improving overall survival.
CRPC is a challenging disease to treat, and with limited therapies in the market, it is projected that the number of CRPC cases would go up rapidly. An estimated 10-20% of men with prostate cancer would develop CRPC within five years of follow-up. This demands for novel therapies that can suppress the growth of cancer using pathways other than androgen receptor signaling.
Most of the prostate cancers have a mutation in DNA repair genes like BRCA1 or BRCA2, which belong to the class of homologous recombinational repair (HRR) proteins. In the absence of BRCA proteins, the cells rely heavily on other DNA repair proteins for survival. Due to which these cancer cells are highly sensitive to inhibitors of repair proteins that mend single-stranded breaks such as PARP.
Lynparza Shines in PROfound Study
On 20th September, AstraZeneca and Merck reported the final results from the PROfound study that showed clinically meaningful improvement in overall survival of mCRPC patients with Lynparza (Olaparib) treatment over androgen inhibitor drugs enzalutamide and abiraterone. “Lynparza is the only PARP inhibitor to demonstrate overall survival versus enzalutamide or abiraterone for men with BRCA or ATM mutations,” said Jose Baselga, Executive Vice President, Oncology, R&D.
The drug had gained the USFDA approval when it hit the primary endpoint of progression-free survival in May this year. It is now being recommended by the European Medicines Agency for marketing authorization in the European Union for patients with mCRPC harboring BRCA1/2 mutations who have previously undergone therapy with the hormone agent.
In 2017, AstraZeneca and Merck announced a global collaboration to develop the world’s first PARP inhibitor, Lynparza. The drug received the USFDA approval in May 2020 based on the results from the PROfound Phase III trial that showed that the drug could cut the risk of disease progression by 66% in men with BRCA1/2 or ATM genes mutation and by 51% in the patient population that harbored all HRR mutations including, BRCA1, BRCA2, ATM, and 12 other genes.
Final results from the trial, however, were announced in the Presidential Symposium at the 2020 European Society of Medical Oncology virtual congress. Lynparza could reduce the risk of death by 31% in comparison to enzalutamide or abiraterone. Men with BRCA1, BRCA2, or ATM-mutated cancers lived 19.1 months on Lynparza treatment versus 14.7 months on enzalutamide or abiraterone-despite 66% of men crossing over from the control arm to the treatment following the disease progression.
The improvement in overall survival, however, was restricted to men with BRCA1/2 and ATM mutations. All other patients with mutations in BRCA1/2, ATM, and 12 other genes had a “non-statistically significant improvement in overall survival” with a 21% reduction in risk of death.
With this remarkable OS data, AstraZeneca and Merck are exploring additional trials in metastatic prostate cancer, including the ongoing PROpel Phase III trial testing Lynparza as a 1st-line medicine for patients with mCRPC in combination with abiraterone. Data from this trial is expected in 2021.
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “The PROfound trial is the first positive Phase III trial using molecular biomarker testing to help identify treatment options for certain men with metastatic castration-resistant prostate cancer. These results further underpin the importance of genomic testing for HRR gene mutations to identify this at-risk patient population and help physicians make treatment decisions. These results demonstrate the potential of Lynparza for metastatic castration-resistant prostate cancer patients with certain HRR mutations.”
Editor: Rajaneesh K. Gopinath, Ph.D.
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