- Response to treatment with the PARP inhibitor olaparib was observed in 12 of 19 patients with tumors carrying a BRCA1 or BRCA2 mutation, but no responses were observed in patients with tumors carrying wild-type genes. If supported by subsequent phase II and III trials, PARP inhibitors may be effective and safe for patients with breast, ovarian, or prostate cancer carrying BRCA mutations.
- These findings suggest that molecular markers may have the potential to determine which patients will respond to selected agents.
PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.
The design of future clinical trials will need to consider the molecular defect of the tumor rather than just the origin of the primary tumor when selecting patients for the investigation of molecularly targeted agents. The enzyme poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) type 1 (PARP1) functions in the repair of single-stranded DNA breaks. Inhibitors of PARP1 are being evaluated for the treatment of tumors with certain types of DNA-repair defects, including those associated with BRCA mutations. Tumor cells carrying the BRCA1 and BRCA2 mutations are unable to perform homologous-recombination DNA repair because of loss of the wild-type allele. Inhibition of PARP1 in BRCA1- and BRCA2-associated tumor cells, but not in untransformed BRCA+/- or normal cells, leads to the accumulation of unrepaired single-stranded DNA breaks, which are converted to double-stranded breaks during DNA replication.1
A phase I trial was conducted to assess the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of olaparib (AZD2281), an investigational oral PARP inhibitor.2 Dosing was initiated at 10 mg daily for 2 of every 3 weeks and was increased to â¥60 mg BID in continuous 4-week cycles. Pharmacokinetic evaluation of olaparib was determined from plasma samples, and pharmacodynamic profiles were determined from samples of peripheral-blood mononuclear cells, plucked eyebrow-hair follicles, and tumor samples. Antitumor activity was evaluated from radiologic assessments (computed tomography or magnetic resonance imaging) every two cycles and was graded according to the Response Evaluation Criteria in Solid Tumors. Additional evaluations were carried out using serum tumor markers where relevant and using the appropriate criteria for response.
Sixty adults with advanced solid tumors refractory to the standard of care were enrolled, including 22 confirmed carriers of a BRCA1 or BRCA2 mutation and one with a family history of BRCA mutation who refused mutational testing but was considered likely to be a carrier. Of these 60 patients, half had ovarian (n = 21) or breast (n = 9) cancer.
Olaparib was quickly absorbed, with peak plasma concentration occurring 1 to 3 hours after oral administration. The terminal-elimination half-life was 5 to 7 hours. Dose-related increases in peak plasma concentration and AUC10 were seen for doses up to 100 mg BID. Steady state was achieved after 14 days.
Inhibition of >90% of PARP1 activity was observed in mononuclear cells following attainment of steady state in patients administered olaparib â¥60 mg BID. PARP inhibition was also shown by loss of signal from a biomarker for PARP activity in tumor-biopsy specimens after 8 days of treatment and by formation of Î³H2AX foci, a marker of double-stranded DNA breaks, in plucked eyebrow-hair follicles.
The maximum administered dose of olaparib was 600 mg BID, and the maximum tolerated dose was 400 mg BID. These doses were determined after three patients experienced dose-limiting toxicities: grade 3 mood alteration and fatigue on day 1 in a patient with advanced ovarian cancer receiving 400 mg BID, grade 4 thrombocytopenia during the first month in a patient with mesothelioma receiving 600 mg BID, and grade 3 somnolence on day 8 in a patient with metastatic breast cancer receiving 600 mg BID.
Most adverse events deemed possibly related to treatment were grade 1 or 2, including nausea in 19 patients (32%), fatigue in 18 (30%), vomiting in 12 (20%), dysgeusia in eight (13%), and anorexia in seven (12%). The incidence of myelosuppressive events was low and included anemia (grade 1â2 in two patients and grade 3â4 in one) and thrombocytopenia (grade 4 in two patients). The incidence of adverse events in patients with and without BRCA mutations was similar.
The two fatalities occurring during the study were considered unlikely to be related to olaparib therapy. One patient with advanced nonâsmall-cell lung cancer and a history of lower respiratory tract infections died from respiratory failure after 4 months of study treatment. A patient with ovarian cancer died of gram-negative septicemia in the absence of neutropenia after 1 month of treatment; this patient had a history of inguinal disease with cutaneous involvement and bacterial colonization.
Clinical evaluation findings are summarized in Figures 1 and 2. No evidence of durable objective antitumor activity was observed in the 35 patients who were not carriers of a BRCA mutation. Among the 22 carriers and 1 suspected carrier, 2 had an insufficient duration of dosing for clinical evaluation, and 2 had tumor types not associated with BRCA mutations (small-cell lung cancer, vaginal adenocarcinoma). Of the remaining 19 patients, 12 (63%) had a clinical response (ie, radiologic or tumor marker response or disease stabilization); these included 9 patients with ovarian cancer, 2 with breast cancer, and 1 with prostate cancer. The longest duration of disease response was >76 weeks. Most of the patients with clinical response were receiving 200 mg or 400 mg BID olaparib (Figure 2).2,3
Figure 1. Summary of Clinical Evaluation of Patients with Advanced Solid Tumors Receiving Olaparib2
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aPatients did not receive olaparib long enough for clinical evaluation.
bClinical evaluation based on radiologic assessment or tumor-marker.
cSome patients had more than one type of response and are counted in more than one category.
Figure 2. Number of Clinical Responders According to Olaparib Dose3
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Note: Unless stated otherwise, patients received olaparib BID continuously.
In summary, these results suggest that olaparib therapy may have an acceptable adverse-event profile and activity against some tumors carrying BRCA mutations. More data are needed to confirm these findings. It will also be necessary to clarify the molecular characteristics of nonresponding and responding tumors in the clinical setting, particularly with respect to homologous recombination. Other mutations that impair homologous recombination, such as the RecA homologue RAD51, impart sensitivity to PARP1 inhibition. Secondary BRCA2 mutations can restore BRCA function and confer resistance to the toxic effects of PARP1 inhibition. Furthermore, the demonstration of response to PARP1 inhibition in breast, ovarian, and prostate cancer also shows the importance of a clinical drug development strategy that focuses on molecular defects rather than strictly on the origin of the primary tumor.
1. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006;66:8109-8115.
2. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.
3. Supplementary appendix. In: Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.