Not all prostate cancer is alike – especially the aggressive kind. This is very important, because two men with the exact same stage and grade of cancer may have different cancer-related genes. Depending on the genetic makeup of the tumor, one man’s cancer may respond to certain drugs, while another man’s may not. In fact, these drugs may so specifically target the cancer that they are fully effective – even without the addition of androgen deprivation therapy (ADT).

This year, three Hopkins investigators did just that in studies of drugs called PARP inhibitors. In previous studies, PARP inhibitors have shown success in treating patients with faulty DNA repair genes (such as BRCA1/2, CHEK2, ATM, and others) when combined with hormonal therapy. But what if the hormone therapy was omitted? Could a PARP inhibitor stop the cancer on its own, simply by targeting a bad DNA repair gene?

The first trial, recently published in JAMA Oncology, was led by Marshall and Emmanuel Antonarakis, M.D. (now at the University of Minnesota; he remains an Adjunct Professor of Oncology at Hopkins). In this trial, 51 men with a rising PSA after treatment for localized prostate cancer (previous prostatectomy and/or radiation therapy) were treated with the oral PARP inhibitor olaparib (Lynparza®). They did not receive ADT. “Remarkably,” says Marshall, “of the 11 patients with germline (inherited) or somatic (acquired) BRCA2 mutations, all achieved a remission, some of which lasted more than three years!”

However, as the investigators suspected, this treatment is highly specific and only works when there is a mutated DNA repair gene. “None of the men without DNA repair gene mutations benefited from the treatment.”

According to Marshall: “This trial demonstrates that targeted therapy has efficacy in selected patients (those with BRCA2 mutations) with PSA-recurrent prostate cancer, and may provide alternatives to hormonal therapy for some men in this setting.”

The second study was led by Hopkins medical oncologist Mark Markowski, M.D., Ph.D., and Antonarakis, and published in The Oncologist. This trial, called TRIUMPH, went one step further to study 12 patients with metastatic prostate cancer who had an inherited DNA repair gene mutation. Here, patients were treated with a different oral PARP inhibitor, rucaparib (Rubraca®). Patients received no concurrent hormonal therapy or chemotherapy. “Among the seven patients with BRCA1/2 mutations, all but one had significant remissions of their cancer,” says Markowski. The average duration of remission was one year, but some lasted as long as three years. “Patients with other DNA repair gene mutations generally derived less benefit from rucaparib, although one patient with a germline CHEK2 mutation achieved a remission lasting more than two years.”

These results, Markowski continues, are “remarkable and go against the central dogma that hormone therapy is a required component of prostate cancer systemic therapy. We showed that even in the presence of metastatic prostate cancer, some patients can be treated with a non-hormonal therapy that is oral and has minimal side effects compared to ADT.”

Rule Book? What Rule Book?

And this is just the beginning, says Antonarakis: “These two studies represent a paradigm shift in the management of advanced or metastatic prostate cancer, and they break every rule in the rule book. Instead of treating all prostate cancer patients with a one-size-fits-all approach, we are using genetic information to personalize treatment for some patients who may be managed effectively with oral targeted agents and in whom castrating therapies can be avoided or delayed. We are grateful to all the patients who put their trust in us and took a risk to participate in a study that went against the grain of standard practice.”