Lynparza Particularly Effective in Prostate Cancer Patients Carrying BRCA Mutations, Phase 2 Study Shows

Lynparza (olaparib), a breast and ovarian cancer treatment, is also showing promising results in men with metastatic castration-resistant prostate cancer (mCRPC) who carry mutations in DNA repair genes, particularly the BRCA1 and BRCA2 genes, according to data from a Phase 2 study.

The study’s final data, “Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, Phase 2 trial,” was published in the journal The Lancet Oncology.

Lynparza is an oral treatment developed by AstraZeneca and Merck (known as MSD outside the U.S. and Canada), which has been approved to treat advanced forms of ovarian and breast cancer.

As a PARP inhibitor, Lynparza works by blocking the activity of the PARP enzyme — a DNA damage sensor — leading to the accumulation of DNA damage and ultimately the death of cancer cells.

This therapy is particularly effective in cancer cells that rely on PARP to survive and grow due to defects in other DNA repair pathways — such as those with mutations in homologous recombination (HR) genes, including the BRCA genes.

This association is also present in prostate cancer, according to data from the first part of the TOPARP Phase 2 clinical trial (NCT01682772) called TOPARP-A, which was designed to identify biomarkers of response to PARP inhibitors in 49 previously treated mCRPC.

The study’s second part, called TOPARP-B, sought to validate this association in 98 men with mCRPC and mutations in HR genes. The men were recruited at 17 U.K. hospitals. This was the first prospective clinical trial in a genetically pre-defined patient population with mCRPC.

Participants were randomly assigned to receive 300 mg or 400 mg of Lynparza (49 men for each dose) twice a day, in four-week cycles, until evidence of cancer progression or unacceptable toxicity.

The study’s primary goal was assessing whether Lynparza could lead to treatment responses in at least 43% of patients in each group. Secondary goals included the evaluation of overall survival, progression-free survival (the time a patient lived without signs of disease progression), and Lynparza’s safety profile.

Patients were from 61 to 73 years old, and carried mutations in several HR genes, including BRCA1/2 (the most common), ATM, CDK12, PALB2, and others. They were followed for a median of 24.8 months.

The study met its primary goal for the higher dose of Lynparza, with 54.3% responding to treatment, while 39.1% on the lower dose responded to the treatment — possibly due to a higher proportion of hard-to-treat patients, the researchers said.

Lynparza was particularly effective in men with BRCA mutations, with more than 80% of them responding to treatment, 40% living without disease progression for more than a year, and a median overall survival of 17.7 months.

Treatment responses were also observed in more than half of patients carrying PALB2 mutations (who lived for a median of 16.6 months), in 37% of those with ATM mutations (who lived for a median of 13.9 months), and in 20% of those with other mutations.

Anemia was the most common severe or life-threatening adverse event in both groups. One man receiving 300 mg of Lynparza died from a heart attack, which was considered to be likely associated with treatment.

“Our trial has shown that men with prostate cancer who were selected for faults in DNA repair genes responded very well to the targeted drug [Lynparza], especially where they had BRCA mutations in their tumours,” Johann de Bono, PhD, professor at the Institute of Cancer Research (ICR), in London, and the trial’s chief investigator, said in a press release.

Paul Workman, the institute’s chief executive, said that “the next step is to work out how to combine [Lynparza] with other drugs to keep cancer at bay for much longer.”

“That’s the kind of research we will be carrying out in our new Centre for Cancer Drug Discovery, which aims to create innovative new treatments designed to overcome cancer evolution and drug resistance,” he added.

TOPARP data led to the design and launch of several registered trials of Lynparza and other PARP inhibitors (NCT02987543, NCT02975934, and NCT03148795) in this patient population.

One such study, the PROfound Phase 3 trial, has shown that Lynparza outperforms standard treatment with Xtandi (enzalutamide) or Zytiga (abiraterone) in mCRPC patients with mutations in BRCA1, BRCA2, or ATM, the most common among HR gene mutations.

“This study and [PROfound] place [Lynparza] on the verge of becoming the first genetically targeted treatment in prostate cancer,” said de Bono, who is also a consultant medical oncologist at The Royal Marsden NHS Foundation Trust, which sponsored the trial along with ICR.

The researchers also noted that these findings support the implementation of routine tumor genetic testing of men with mCRPC to identify those who may significantly benefit from PARP inhibitors, such as Lynparza.