Olaparib may be effective in some men with biochemically recurrent prostate cancer without hormone therapy

The cancer drug olaparib may be effective in treating biochemically recurrent prostate cancer without concomitant hormone therapy in men with mutations in genes such as BRCA2, according to a Phase II clinical trial involving 51 patients conducted at the Johns Hopkins Kimmel Cancer Center and three other sites.

The study was conducted in men who had signs of cancer recurrence, measured by high levels of the protein prostate-specific antigen (PSA), after surgical removal of the prostate. After treatment with olaparib, PSA levels fell by at least 50% in 13 participants, including all 11 with BRCA2 mutations – a sign that their cancer was in remission.

A report on the work was published on 22 August in JAMA OncologyThe other participating centers were the University of Nebraska Medical Center in Omaha, the Allegheny Health Network Cancer Institute in Pittsburgh and the Thomas Jefferson University Hospital in Philadelphia.

While most men with localized prostate cancer are cured with surgery or primary radiation therapy, up to 40% of men experience relapse, as measured by rising PSA levels, explains lead study author Cathy Handy Marshall, MD, MPH, assistant professor of oncology at Johns Hopkins University.

The study was co-led by Dr. Emmanuel Antonarakis, a former Kimmel Cancer Center prostate cancer expert who is now associate director of translational research at the University of Minnesota Masonic Cancer Center and an associate professor at Johns Hopkins University.

A common treatment approach for recurrent prostate cancer is androgen deprivation therapy – drugs that stop testosterone production. But many men are reluctant to take the drug because the lack of testosterone can lead to side effects such as hot flashes, fatigue or weight gain, Marshall says.

“We have conducted a number of studies to find therapies for prostate cancer that do not involve hormone suppression to avoid these side effects,” she says.

Olaparib is a precision oncology drug that blocks the ability of the protein PARP to repair damaged DNA. It is approved by the U.S. Food and Drug Administration to treat metastatic prostate cancer in combination with hormone therapy. However, it is not known whether the drug would work without the accompanying hormone suppression, Marshall says.

The researchers enrolled 51 patients in the study from May 2017 to November 2022. Each participant suffered from biochemically recurrent prostate cancer after radical prostatectomy (surgery to remove the prostate, seminal vesicles, and nearby lymph nodes).

Twenty-seven (53%) of the participants were classified as biomarker-positive, meaning they had mutations in some genes that made their cancers more likely to be sensitive to olaparib. The patients had an average age of about 64 years and a mean baseline PSA level of 2.8 nanograms per milliliter.

Most participants had a Gleason grade of 3 or higher, meaning they had high-grade cancer. About 86% of participants had received radiotherapy after surgery. In patients with positive biomarkers, alterations in BRCA2 were most common (11 patients), followed by alterations in the ATM and CHEK2 genes (six patients each).

Participants received 300 milligrams of olaparib orally twice daily (without hormonal suppression) until their PSA doubled, their cancer worsened as determined by imaging or other signs or symptoms, or until they had unacceptable side effects/toxicity from the drug. The duration of therapy varied – in some cases it was more than two years, Marshall says.

About half (13 of 27 patients) of the biomarker-positive group had a PSA decline of 50% or more, including all 11 patients with BRCA2 mutations. The median duration of response was 25 months. The other two PSA responses were seen in participants with a CHEK2 mutation and an ATM mutation.

No PSA responses were observed in the 24 men in the biomarker-negative group, leading the study authors to conclude that therapy should not be considered for these patients in the future.

Median PSA progression-free survival (the time until PSA levels worsened) was 19.3 months overall and 22.1 months in the biomarker-positive subgroup, compared with 12.8 months in the biomarker-negative subgroup. Median metastasis-free survival (time from treatment to detection of metastases) was 32.9 months overall and 41.9 months in the biomarker-positive subgroup, compared with 16.9 months in the biomarker-negative subgroup.

In addition, the median time to next cancer therapy was 15.4 months overall and 22.7 months in the biomarker-positive subgroup, compared to only 2.4 months in the biomarker-negative subgroup.

The most common side effects with olaparib were fatigue, nausea and leukopenia (less than normal number of infection-fighting white blood cells).

“This study is a breakthrough because it shows for the first time that a non-hormonal drug can induce durable complete remissions in patients with recurrent prostate cancer and BRCA2 mutations – one of the most aggressive subtypes of this disease,” says Antonarakis.

“This is a real paradigm shift because we can now offer these patients a non-hormonal precision therapy that is safe and effective while avoiding the side effects caused by hormone withdrawal.”