NEW YORK – Researchers are planning larger follow-up studies of AstraZeneca's Lynparza (olaparib) in biomarker-selected subgroups after a Phase II trial showed the PARP inhibitor was effective in treating patients with recurrent prostate cancer without accompanying hormone therapy.
After initial surgery and radiotherapy treatment of localized prostate cancer, up to 40 percent of patients can experience recurrence as indicated by rising prostate specific antigen (PSA) levels. The standard treatment for recurrent disease is androgen deprivation therapy. However, because these drugs suppress testosterone production, side effects can be life-changing. Patients on androgen deprivation therapy may experience low libido, erectile dysfunction, weight gain, decreased muscle mass, hot flashes, and development of breast tissue.
Cathy Handy Marshall, an assistant professor in the department of oncology at Johns Hopkins University, is exploring alternative therapies for recurrent prostate cancer that are not hormone-suppressing. In a clinical trial published in JAMA Oncology last month, Handy Marshall and colleagues evaluated Lynparza's activity in 51 patients with recurrent prostate cancer following radical prostatectomy.
Lynparza is already approved in the US for treating patients with homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer after they have progressed on prior anti-androgen therapy with Pfizer and Astellas Pharma's Xtandi (enzalutamide) or Janssen's Zytiga (abiraterone). Lynparza is also approved in combination with Zytiga and prednisone or prednisolone for patients with BRCA1/2-mutated metastatic castration-resistant prostate cancer.
Most interventional clinical trials in this setting test new therapies in combination with standard-of-care androgen deprivation therapy. Handy Marshall and her collaborators did not know in advance whether treatment with Lynparza would be effective without hormonal suppression.
Handy Marshall said the study published in JAMA Oncology was inspired by the desire among patients to avoid hormone deprivation therapy and its side effects. At the same time, other studies were revealing a high prevalence of DNA repair mutations among men with prostate cancers. "We knew that these mutations exist, and [Lynparza] may be an option even in the absence of hormonal therapy," Handy Marshall said.
To be eligible for the trial, patients' PSA levels must have doubled within six months, their absolute PSA value had to be at least 1.0 ng/mL, and they had to have a testosterone level of 150 ng/dL or more. Patients received 300 mg of Lynparza twice daily until their baseline PSA levels doubled, they experienced radiographic progression, or they had unacceptable side effects.
The researchers tracked PSA response as the primary outcome measure of the trial, and they explored outcomes in relation to homologous recombination repair gene mutation status including alterations in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCE, PALB2, RAD51B, RAD51C, and RAD51D.
Among 51 patients, including 27 with mutations in HRR genes and 24 without, 13 patients responded to Lynparza, all of them with HRR mutations. The responder group included all 11 patients with BRCA2 alterations. The other two confirmed responses occurred in a patient with a CHEK2 mutation and one with an ATM mutation. There were no responses among the HRR-negative patients.
The median progression-free survival as determined by PSA response was 19.3 months in the overall population — 22.1 months in the biomarker-positive group and 12.8 months in biomarker-negative patients. Among all patients, median metastasis-free survival was 32.9 months, while those in the biomarker-positive group lived a median of 41.9 months without metastasis, and the biomarker-negative patients lived a median of 16.9 months without metastasis.
The study authors noted that the 100 percent response rate to Lynparza among patients with BRCA2-altered prostate cancer is higher than the 50 percent to 60 percent response rates on Lynparza with hormonal suppression seen in this patient group in other studies. "Treating patients with BRCA2-altered prostate cancer earlier in the disease course, prior to the development of greater tumor heterogeneity induced by [androgen deprivation therapy] and other systemic therapies, may be contributing to these higher response rates," they wrote, adding that it is unclear how combining androgen deprivation therapy with Lynparza in those other studies could impact Lynparza sensitivity.
Study author Emmanuel Antonarakis, a genitourinary medical oncologist at the University of Minnesota's Masonic Cancer Center, noted in a statement that the JAMA Oncology study is the first to show that recurrent prostate cancer patients with BRCA2 mutations, one of the most aggressive subtypes of prostate cancer, can have complete remissions to a non-hormonal drug.
The main takeaway from the study for Handy Marshall is that all prostate cancer patients need not be treated with hormone therapy. "As we learn more about the disease, we can start thinking about how these targets can be used even in the absence of androgen deprivation therapy," she said, adding that the study also clearly shows that Lynparza "does not seem to … benefit people who do not have any of the HRR mutations."
Handy Marshall and her collaborators are already contemplating follow-up studies to confirm these findings and explore the mechanisms underlying therapy response in patients with HRR deficiency. "This was a biomarker unselected study, and now where we are is that these studies of PARP inhibitors should not be biomarker unselected, and there really needs to be more [study of which patients] who have biomarkers are more likely to respond," she said.