Olaparib Reported as the First Gene-Targeted Therapy to Benefit Patients With mCRPC

A significant proportion of patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations responded well to treatment with olaparib (Lynparza) in a phase II TOPARP-B trial (NCT01682772), making olaparib the first gene-targeted therapy to show benefit in this patient population, the Institute of Cancer Research reported in a press release.

"This study and another phase III trial place olaparib on the verge of becoming the first genetically targeted treatment in prostate cancer. I'm excited by these findings, and keen to see further research assessing how we can combine olaparib with other treatments to extend patients' lives even more dramatically, said Paul Workman, chief executive director, The Institute of Cancer Research, in the press release.

The phase II data, which were recently published inThe Lancet Oncology,showed confirmed composite responses in 25 of the evaluable patients who were treated with 400mg of olaparib (54.3%; 95% CI 39.0—69.1) and 18 of the 46 patients who received 300mg of olaparib (39.1%; 25.1–54.6). Additionally, radiographic progression-free survival (rPFS) activity was observed in 8 patients in the 400mg cohort and 6 in the 300mg cohort. Prostate-specific antigen declines of 50% (PSA50) were also observed in 17 of the patients treated with the higher dose of olaparib and 13 of those who received the lower dose. Patients in both cohorts also achieved circulating tumor cell (CTC) count conversion, 17 of whom were recipients of olaparib 400mg and 18 of whom received olaparib 300mg.

In addition to the overall study population, antitumor activity was observed across multiple subgroups of patients with gene aberrations. In the patients withBRCA ½mutations, 25 out of 30 achieved a composite OS, 11 experienced an objective response, 23 achieved a PSA50 response and 24 had a RECIST 1.1 or PSA50 response. Seventeen out of 22 patients withBRCA ½also had a CTC conversion.

Composite OS was observed in 7/19 patients with ATM mutations. Participants with ATM mutations also 1 objective response, 1 PSA50 response and 2 RECIST 1.1 or PSA50 responses. Five of the patients in this subgroup had CTC conversion.

In theCDK12subgroup, fewer responses were seen. Five patients out of 20 achieved a composite OR and 5 patients also had a CTC conversion. No additional responses were observed in this group of patients.

The subgroup analysis of individuals withPALB2mutations showed more responses than what was observed in theCDK12group. Composite ORs were seen in 4/7 patients and 4 ORs, 4 PSA50 responses and 4 RECIST 1.1 or PSA50 responses were detected. There were no CTC conversions in this subgroup.

Among patients with other gene alterations associated with sensitivity to DDR or PARP inhibitors, 4 composite OR were seen as wells as 2 PSA50 responses, 2 RECIST 1.1 or PSA50 responses, and 2 CTC conversions. The study investigators report that two of the mutations assessed in this subgroup wereFANCAandCHEK2.

The authors of the published research wrote, “The TOPARP-B trial has confirmed the antitumor activity of olaparib against metastatic castration-resistant prostate cancer with specific DDR gene aberrations. The number of composite responses observed in the cohort of patients who received 400 mg tablets of olaparib twice daily met the predefined criteria for success, validating the DDR biomarker identified in TOPARP-A as being predictive of response.”

One hundred and seven adverse events (AEs) were reported overall. However, the toxicity profile observed in this study was considered to be consistent with previously reported data on olaparib and other PARP inhibitors. In both cohorts, the most common grade ¾ AE was anemia, which occurred in 31% ( n = 15) of participants given 300mg of olaparib and 37% (n = 18) of those treated with a 400mg dose. Other common AEs in the study participant overall were fatigue (n = 53), nausea (n = 32), platelet count decreased (n = 27), and decreased appetite (n = 25). There was a higher occurrence of AEs in the 400mg cohort than the 300mg cohort.

Permanent discontinuation of treatment occurred in 18 (19%) of study patients overall.

The study included 148 participants with advanced castration-resistant prostate cancer. The patients were treated with single-agent olaparib either 400mg or 300mg twice daily over a 28-day cycle. Patients in both cohorts continued treatments until disease progression, unacceptable toxicity, or a decision to withdrawal for any reason. The primary endpoint of the study was the response rate to olaparib, which was defined by the objective response, PSA50, and CTC conversion.

The study also evaluated key secondary endpoints, which were, rPFS, PFS, time to PSA50 progression, duration of PSA response, and overall survival.

Patients aged 18 years or older with histologically confirmed mCRPC with Eastern Cooperative Oncology Group performance statuses of 0, 1, or 2, and a life expectancy of 12 weeks or more were eligible to enroll in the study. Patients were also required to have documented prostate cancer progression and be surgically or medically castrated with testosterone levels of < 50 ng/dL (< 2.0 nM).

Individuals were ineligible to enroll if they had surgery or local prostatic intervention within 28 days of the first treatment cycle, had prior treatment with a PATP inhibitor or had uncontrolled illnesses, acute toxicities due to prior chemotherapy, or other conditions that may interfere with olaparib treatment.

The TOPARP-B study is no longer recruiting patients, but it remains active with a target completion date of February 2020. After witnessed promising activity in patients with mCRPC, the Institute for Cancer Research now plans to explore olaparib combinations.

"The next step is to work out how to combine olaparib with other drugs to keep cancer at bay for much longer. That's the kind of research we will be carrying out in our new Centre for Cancer Drug Discovery, which aims to create innovative new treatments designed to overcome cancer evolution and drug resistance,&rdquo; Workman mentioned in a statement.

References

1. Olaparib becomes first gene-targeted medicine to show benefits in prostate cancer [press release]. London, United Kingdom: Institute for Cancer Research; December 2, 2019. https://bit.ly/2PddwzM. Accessed December 3, 2019.
2. Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. DOI:10.1016/S1470-2045(19)30684-9.