Finally: An Active Prostate Cancer Drug That Doesn’t Target Androgen

Most of the recent developments in prostate cancer treatment have addressed the timing and duration of androgen deprivation, who should receive radiation treatments, and the timing of the few available chemotherapy options. But this month’s big news is a welcome change: metastatic castration-resistant prostate cancers (mCRPCs) that harbor mutations in BRCA2 or one of a few other genes have a remarkable response to olaparib (Lynparza), a drug that inhibits the enzyme PARP1.

mCRPC patients with BRCA2 mutations tend to have aggressive disease with a higher Gleason score, higher prostate-specific antigen (PSA) levels, and shorter life expectancy. Nevertheless, in a clinical trial, only this group of patients had a meaningful response to olaparib.

Why test olaparib in prostate cancer? Olaparib was recently approved in the U.S. for treatment of ovarian cancers with BRCA1/2 mutations. Mutations in these and several other genes (ATM, PALB2, CHECK2, FANCA, and HDAC2) are involved in the development of many cancers. They also make cells unable to repair DNA damage, for which the products of these genes are needed. Cells with mutations in these genes—known as DNA damage responsive (DDR) genes—have a specific vulnerability, because unrepaired DNA damage is a general death signal.

PARP1, the target of olaparib, is a key enzyme in fixing DNA damage—the first responder, of sorts. Inhibition of PARP1 in cancer cells that are already barely coping with the burden of routine unrepaired DNA damage puts these cells on the path to death. This is the logic behind exploring PARP1 inhibitors in cancers with specific mutations in DDR genes.

In the recently reported trial TOPARP-A, 49 patients with mCRPC were treated with olaparib. Fresh tumor biopsies were subjected to next generation sequencing (NGS)—in this case, analysis of all protein-coding regions in the DNA—along with DNA from normal cells (in saliva) collected from the patients.

Analysis of the results showed an almost perfect association between clinical responses to olaparib and deficiencies in DDR genes in tumor biopsies. Sixteen of the 49 patients responded to olaparib, and 14 of these had aberrations in DDR genes. This means that though the overall response rate was about 33%, the response of cancers with mutations in DDR genes was 88%.

The duration of response was 40 weeks, and progression-free survival was 9.8 months in the DDR gene-deficient group, versus 2.7 months in the normal DDR gene group. Another important conclusion of the study is that mutations in DDR genes are not as rare as was previously thought; in this trial, they were detected in 30% of the patients.

This study was unprecedented in its depth, in that both normal and tumor tissues were subjected to NGS, and cancer progression was measured not only by routine tests and scans, but also by monitoring levels of cancer cells in the patients’ blood. An important conclusion is that a fairly large sequencing effort may be needed to identify all mCRPC patients who may respond to olaparib. Alternatively, a customized sequencing test for defects in DDR genes could be developed to accompany the use of PARP1 inhibitors. The list of cancers associated with BRCA2 alone now includes not only breast, ovarian, and prostate, but also pancreatic and uterine cancers.

As with almost all targeted drugs, responses to olaparib tend to be transient; that is, they prolong the time during which patients do not experience disease progression, but they don’t prolong overall survival. It is also worth mentioning that the UK’s drugs watchdog—the National Institute for Health and Care Excellence—has already rejected olaparib for treatment of ovarian cancer on the grounds of its cost (£4,000/ month). Add to this the cost of sequencing analysis to identify patients most likely to benefit (albeit transiently) from the drug, and the picture becomes grim in terms of cost effectiveness. (This prompted a bit of black humor from one science blogger.)

Considering that olaparib benefits about one-third of patients with incurable prostate cancer, its use in clinic should hopefully be approved soon. Development of a relevant companion diagnostic test should be a high priority.