Positive Results from Phase III PROfound Trial of Olaparib Demonstrate Improvements in OS

Results from the trial showed a statistically significant and clinically meaningful improvement in overall survival with olaparib versus enzalutamide or abiraterone in men with metastatic castration-resistant prostate cancer selected for BRCA1/2 or ATM gene mutations.

Positive results from the phase III PROfound trial of olaparib (Lynparza) in men with metastatic castration-resistant prostate cancer (mCRPC) who have a homologous repair gene mutation (HRRm) and have progressed on prior treatment with new hormonal agent treatments such as enzalutamide (Xtandi) and abiraterone (Zytiga) were announced by AstraZeneca and MSD, the developers of the agent.1

Results from the trial demonstrated a statistically significant and clinically meaningful improvement in the secondary endpoint of overall survival (OS) with olaparib versus enzalutamide or abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene mutations.

“Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve,” Jose Baselga, executive vice president for Oncology R&D, said in a press release. “We are thrilled by these results for Lynparza and we are working with regulatory authorities to bring this medicine to patients as soon as possible.”

The phase III PROfound trial previously met its primary endpoint in August 2019, demonstrating significantly improved radiographic progression-free survival (PFS) in men with mutations in BRCA1/2 or ATM genes, and had met a key secondary endpoint of radiographic PFS in the overall HRRm population. 

Overall, the study enrolled 387 men with HRRm mCRPC and randomly assigned them in a 2:1 fashion to either treatment with olaparib at 300 mg twice daily, or physician’s choice of enzalutamide or abiraterone acetate plus prednisone (Deltasone). Cohort A included 245 patients with alterations in BRCA1BRCA2, or ATM; cohort B included 142 men with any of 12 other HRR alterations (i.e., BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RA51D, or RAD54L).

The safety and tolerability profile of olaparib in this trial was found to be generally consistent with previous trials of the agent. Moreover, the companies suggested that data from this trial will be presented at an upcoming medical meeting. 

Data from the trial reported at the 2019 ESMO congress indicated that the median radiographic PFS in cohort A was 7.39 months vs 3.5 months in cohort B, representing a 66% reduction in disease progression (P < 0.0001).2 Of all the patients enrolled in the trial, the median PFS was 5.82 months with olaparib vs 3.52 months with the physician’s choice, representing a 51% reduction in the risk for disease progression (P < 0.0001). All secondary endpoints favored olaparib as well, including objective response rate, time to pain progression, and overall survival.

In cohort A, the objective response rate was found to be 33% vs 2.3%, respectively (P < .0001). However, time to pain progression was not reached in patients in cohort A who received olaparib vs 9.92 months for those in the comparator arm (P = .0192). The median overall survival was also not reached in either arm but appeared to trend toward improvement with olaparib at the time of ESMO.

“Lynparza has demonstrated significant clinical benefit across key endpoints in PROfound, including overall survival for patients with BRCA or ATM mutations, and this reinforces its potential to change the treatment standard for patients with metastatic castration-resistant prostate cancer,” Roy Baynes, senior vice president and head of global clinical development, as well as chief medical officer for MSD Research Laboratories, said in a press release. “These data further support MSD and AstraZeneca’s commitment to uncovering the ways in which Lynparza can help patients impacted by cancer.”

Olaparib was granted priority review by the FDA for patients with HRRm mCRPC in January 2020, regulatory reviews ongoing in the EU and other jurisdictions. Further, the companies indicated that they are exploring additional trials in prostate cancer, including the ongoing phase III PROpel trial testing olaparib as a first-line medicine for patients with mCRPC in combination with abiraterone acetate versus abiraterone acetate alone. Data from this trial is first expected in 2021. 


1. Lynparza demonstrated overall survival benefit in phase III PROfound trial for BRCA ½ or ATM-mutated metastatic castration-resistant prostate cancer [news release]. Kenilworth, NJ. Published April 24, 2020. astrazeneca.com/content/astraz/media-centre/press-releases/2020/lynparza-shows-overall-survival-in-prostate-cancer.html. Accessed April 24, 2020. 

2. Hussain M, Mateo J, Fizazi K, et al: PROfound: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations. Ann Oncol. 2019;30(suppl 5):5059. 10.1093/annonc/mdz394