Coming: Prostate Cancer Treatment Guided by Biomarkers

Megan Brooks

October 28, 2015

In a phase 2 study, men with metastatic castration-resistant prostate cancer whose tumors harbored certain DNA-repair defects were much more likely to respond to the oral PARP (poly [ADP-ribose] polymerase) inhibitor olaparib (Lynparza, AstraZeneca Pharmaceuticals LP) than their peers whose tumors did not have these mutations.

"Biomarker-guided therapy is coming for 20% to 30% of the most aggressive prostate cancers," Johann S. de Bono, MD, told Medscape Medical News.

"PARP inhibition, an oral tablet–based therapy without the toxicity of chemotherapy, is highly active against this disease," said Dr de Bono, who specializes in developing new molecularly targeted therapies for prostate cancer and leads the prostate cancer team at the Institute of Cancer Research, in London, United Kingdom.

Prostate cancer is a molecularly heterogeneous disease. Yet, unlike several other malignancies, current treatments for prostate cancer are not based on molecular stratification.

PARP inhibition has been shown to have durable antitumor activity in men with advanced prostate cancer and germline BRCA2 mutations, which led Dr de Bono and colleagues to test the antitumor activity of the PARP inhibitor olaparib in sporadic cases of metastatic, castration-resistant prostate cancer with DNA-repair defects. Their findings were published online October 28 in the New England Journal of Medicine.

Earlier and slightly different data from the study were first presented in April at the annual meeting of the American Association for Cancer Research (AACR), as reported by Medscape Medical News.

Olaparib is a PARP inhibitor approved for use in the United States for the treatment of ovarian cancer, but only in women with BRCA mutations.

High Response Rate in Patients With Mutations

The 50 men in the TOPARP-A trial were treated with 400-mg olaparib twice daily for varying periods. All 50 patients had been previously treated with docetaxel (multiple brands); 49 had also received abiraterone (Zytiga, Janssen Pharmaceuticals Inc) or enzalutamide (Xtandi, Astellas Pharma, Inc); and 29 had received cabazitaxel (Jevtana, sanofi-aventis).

Overall, 16 of 49 evaluable patients had a response to olaparib (33%; 95% confidence interval [CI], 20 - 48).

Genomic testing of fresh tumor tissue samples revealed mutations in various DNA-repair genes, including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2, in 16 patients (33%). Overall, in both unadjusted and adjusted analyses, patients who harbored DNA-repair gene defects had a significantly higher response rate (P < .001 in a multivariable logistic- regression model for response).

Fourteen of the 16 (88%) "biomarker-positive" men had a response to olaparib, compared with only 2 of 33 (6%) biomarker-negative patients. The specificity of biomarker positivity was 94%.

These findings suggest that a "common subset of metastatic prostate cancers can be molecularly stratified for treatment," the investigators write.

At the AACR meeting, another olaparib researcher provided some context for the frequency of the various prostate cancer–related mutations. BRCA2 is present in about 12% of prostate cancers, and ATM is present in about 7%. These are the most common of the various genetic mutations associated with prostate cancer, said Joaquin Mateo, MD, a fellow at the Institute of Cancer Research in London and a colleague of Dr de Bono.

"We welcome this paper," Chandan Guha, MD, PhD, vice chair, Department of Radiation Oncology, Montefiore Einstein Center for Cancer Care, New York City, who was not involved in the study, noted in an interview with Medscape Medical News.

"What's interesting," he noted, "is if you take all comers, only 33% responded, but that became 88% if you 'cherry-picked' " the patients with DNA-repair defects. "We definitely expect that PARP inhibitors with radiation might have a role in prostate cancer."

If you take all comers, only 33% responded, but that became 88% if you 'cherry-picked.' Dr Chandan Guha

"Essentially, for every cancer, there is a move to targeted therapy," and prostate cancer is no exception, Dr Guha said. "Therapy is only going to be successful if you are treating the right patient. Everybody's disease is different, and as more and more sequencing data are available, we know that this cancer comes in various forms," he added.

The primary endpoint of the TOPARP-A trial was response rate, defined as either an objective response, determined in accordance with Response Evaluation Criteria for Solid Tumors, or a reduction of at least 50% in prostate-specific antigen (PSA) level or a reduction in circulating tumor cell count from 5 or more cells per 7.5 ml of blood to less than that.

The median duration of treatment for the 16 patients who responded to therapy was 40 weeks. Of those, 12 patients received olaparib for more than 6 months, and four received the drug for longer than 1 year.

Overall, 11 of the 49 patients (22%) experienced a reduction of at least 50% in PSA level with the drug. The median circulating tumor cell count at baseline was 37 cells per 7.5 ml of blood; 14 of the 49 men (29%) experienced a confirmed reduction to <5 cells per 7.5 ml.

Median radiologic progression-free survival was 9.8 months in the biomarker-positive group vs 2.7 months in the biomarker-negative group (P < .001). Overall survival was also longer in the biomarker-positive group (median, 13.8 months vs 7.5 months; P = .05), "even though established prognostic factors were balanced between the two groups," the investigators note.

Anemia (20%) and fatigue (12%) were the most common grade 3 or 4 adverse events seen with olaparib, consistent with prior studies of the PARP inhibitor.

A second study of olaparib, known as TOPARP-B, is currently enrolling only patients who screen positive for the DNA-repair mutations linked to response in TOPARP-A.

The study was supported by funds from the Cancer Research UK Clinical Trials Awards and Advisory Committee, SU2C, PCF, the Experimental Cancer Medicine Center, and the UK National Institute for Health Research Biomedical Research Center. Dr de Bono reports financial ties to AstraZeneca.

N Engl J Med. 2015;373:1697-1708.


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