Lynparza (Olaparib) Achieves Primary Endpoint in Phase 3 PROfound Trial for Metastatic Castration-Resistant Prostate Cancer with HRR Mutations

Recently, MSD and AstraZeneca announced that Lynparza (olaparib) achieved positive results in the Phase 3 PROfound clinical trial for the treatment of male patients with metastatic castration-resistant prostate cancer (mCRPC). These patients carried homologous recombination repair gene mutations (HRRm) and had experienced disease progression following prior novel hormonal anticancer therapies (such as enzalutamide and abiraterone). To date, this is the only Phase 3 trial of a PARP inhibitor in metastatic castration-resistant prostate cancer to have yielded positive results. The PROfound trial also demonstrated the potential value of genetic testing in this high-risk patient population.

Prostate cancer is the second most common cancer in men worldwide. In 2018, it was estimated that there were 1.2 million new cases, with approximately 360,000 deaths attributed to the disease. Prostate cancer ranks as the fifth leading cause of cancer-related mortality in men. Castration-resistant prostate cancer (CRPC) represents an advanced stage of the disease; specifically, in patients with metastatic castration-resistant prostate cancer (mCRPC), the disease continues to progress despite androgen deprivation therapy. For these patients, standard androgen receptor (AR)-targeted therapies demonstrate limited efficacy, resulting in a poor prognosis.

PROfound is a prospective, multicenter, randomized, open-label Phase 3 trial designed to evaluate the efficacy and safety of Lynparza compared with enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after prior treatment with a novel hormonal anticancer therapy and harbor mutations in one of 15 genes associated with the homologous recombination repair (HRR) pathway, including BRCA1/2, ATM, and CDK12. The trial results demonstrated that, among male patients with mCRPC harboring BRCA1/2 or ATM gene mutations (the HRR gene mutation subgroup), Lynparza resulted in a statistically significant and clinically meaningful improvement in the primary endpoint of radiographic progression-free survival (rPFS) compared with enzalutamide or abiraterone. Approximately 25% of men diagnosed with mCRPC have HRR gene mutations, with BRCA1/2 and ATM mutations accounting for the majority. The safety and tolerability profile of Lynparza was largely consistent with that observed in previous trials.

AstraZeneca and MSD plan to present the full data from the trial at upcoming medical conferences and communicate the results to regulatory authorities worldwide. Meanwhile, the two companies are also exploring other therapies for prostate cancer, including the ongoing Phase 3 PROpel trial, which is evaluating the efficacy of Lynparza in combination with abiraterone as a first-line treatment for mCRPC.

Lynparza is a “first-in-class” PARP inhibitor that was first approved by the FDA in December 2014 for the treatment of patients with advanced ovarian cancer harboring germline BRCA mutations, becoming the first PARP inhibitor approved globally. It has since received FDA approval for the treatment of ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer. In August 2018, Lynparza (brand name: Lipuzhuo) was approved for marketing in China, marking the first targeted novel drug for ovarian cancer to be launched in the country.

In July 2017, AstraZeneca and MSD entered into a global research and development collaboration to jointly develop and commercialize Lynparza. The two companies are not only co-developing Lynparza monotherapy for various cancer types but also exploring the efficacy of combining Lynparza with Imfinzi and Keytruda. Since the establishment of this partnership, Lynparza has demonstrated superior efficacy in multiple clinical trials. In addition to its applications in ovarian and breast cancers, results presented at the 2019 ASCO Annual Meeting indicated that Lynparza doubled progression-free survival in patients with germline BRCA-mutated pancreatic cancer. According to MSD’s estimates, this PARP inhibitor holds promise for the treatment of prostate cancer, lung cancer, and other cancer types harboring BRCA mutations.

References:

[1] LYNPARZA^® (olaparib) Phase 3 PROfound Trial in HRR Mutation-Selected Metastatic Castration-Resistant Prostate Cancer Met Primary Endpoint. Retrieved 2019-08-07, from https://www.mrknewsroom.com/news-release/oncology/lynparza-olaparib-phase-3-profound-trial-hrr-mutation-selected-metastatic-cast

▽Follow [WuXi AppTecDe】WeChat Official Account