Lynparza Improves Outcomes in Metastatic Prostate Cancer That Has DNA Repair Defects

A targeted drug that belongs to the family known as PARP inhibitors can extend survival and delay disease progression in some men with advanced prostate cancer that have stopped responding to novel hormonal treatments.

Lynparza (olaparib) is approved by the Food and Drug Administration (FDA) to treat breast, ovarian and pancreatic cancers. In a phase 3 study, whose results were published in the New England Journal of Medicine on April 28, researchers from a variety of institutions reported that the drug is also effective in men with metastatic castration-resistant prostate cancer that has trouble repairing its own DNA. Specifically, Lynparza works in cancers that cannot accomplish a process known as homologous recombination-directed DNA repair due to mutations in genes such as BRCA1, BRCA2 and ATM.

PARP inhibitors work by further impeding DNA repair, causing the cancer cells to die.

Disease that is metastatic and castration-resistant has spread outside the prostate to other parts of the body and progressed despite treatment to eliminate the hormones that drive it. Among patients with this form of the disease, 30% have gene mutations that affect the cancer’s DNA-repair capabilities.

The FDA is reviewing an application for approval of Lynparza to treat this population and expects to make a decision in the second quarter of 2020.

Study Design

According to the researchers, previous studies showed that tumors with BRCA1 or BRCA2 alterations were more sensitive to Lynparza than tumors harboring other homologous recombination repair-related genes. They embarked on their trial to further test that idea.

The randomized phase 3 PROfound trial included men whose disease had progressed while taking either Xtandi (enzalutamide) or Zytiga (abiraterone), novel anti-testosterone drugs. Two-thirds of participants had also previously taken chemotherapy.

All men in the study had an alteration in at least one of 15 genes that play a direct or indirect role in homologous recombination repair: BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L. The 387 men, whose median age was 69, were enrolled between April 2017 and November 2018.

Of all the participants, 256 were given twice-daily Lynparza tablets and 131 were given anti-testosterone pills. This included men in a subgroup given special attention in the study: those with BRCA1, BRCA2 or ATM gene alterations. Among men with those mutations, 162 took Lynparza and 83 took one of the anti-testosterone drugs. For all patients in the trial, treatment continued until disease progressed or side effects became intolerable.

The study’s main goal was to measure the length of time until disease progression in men with BRCA1, BRCA2 or ATM gene mutations, checked via imaging.

Results

Among men in that subgroup, those who took Lynparza went a median 7.4 months before experiencing disease progression compared with 3.6 months in those who took hormonal treatment. The median survival of patients in the Lynparza group was also longer, at 18.5 months versus 15.1 months for those who took hormonal treatment. That finding, based on a preliminary measurement taken with 38% of data available, was not statistically significant, but researchers announced recently that updated results show a statistically significant survival benefit in study participants with BRCA1, BRCA2 and ATM mutations.

Across the whole population of the trial, the time until disease progression was also longer with Lynparza than with hormonal treatment (a median 5.8 months versus 3.5 months, respectively). With 41% of data in, the researchers found that median survival was 17.5 months in all who took Lynparza compared with 14.3 months in all who took hormonal medication.

Safety

Lynparza was associated with a higher incidence of serious, or grade 3, side effects, which researchers said could be attributable to the fact that treatment lasted a median 7.4 months with the PARP inhibitor versus 3.9 months with hormonal treatment.

Anemia and fatigue were side effects common to both treatment groups, and nausea was a commonly reported side effect in those who took Lynparza.

There were 11 cases of pulmonary embolism (lung blockage) among those taking Lynparza compared with one case among men taking hormonal treatment; none were fatal. Three patients reported new cancers, one in the Lynparza group and two in the anti-testosterone group. One death in a Lynparza patient and one death in a patient taking a hormonal drug were considered to be treatment related.

“Exploratory analyses suggest that patients with BRCA1 or BRCA2 alterations derived the most benefit” from Lynparza in the PROfound trial, the researchers concluded. “It is important that (Lynparza) showed activity in patients with alterations in other prespecified genes with a direct or indirect role in homologous recombination repair; detailed analyses are ongoing.”

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