Study Patients

Table 1. Table 1. Baseline Characteristics of the 50 Study Patients.

From July 2012 through September 2014, a total of 50 patients (30 in stage 1 and 20 in stage 2 of the study) were enrolled at seven centers. All patients received at least one dose of olaparib. One patient was lost to follow-up after the first week; the data monitoring committee decided that this patient could not be evaluated for a response (Fig. S2 in the Supplementary Appendix). At the time of data cutoff, 35 of the 50 patients (70%) had died, with 4 patients remaining in the study after at least 40 weeks of therapy. The median overall survival was 10.1 months (interquartile range, 5.1 to 15.6), with a median follow-up of 14.4 months (range, 1.4 to 21.9). Table 1 summarizes the baseline characteristics of the patients.

Antitumor Activity

Table 2. Table 2. Changes in PSA Levels and CTC Counts, Best Radiologic Response, Duration of Treatment, and Biomarker Status for the 16 Patients with a Treatment Response.

Sixteen of the 49 patients who could be evaluated had a response to olaparib on the basis of the composite definition of response specified in the study protocol (response rate, 33%; 95% confidence interval, 20 to 48). The median duration of treatment for the 16 patients who had a response was 40 weeks, with 12 patients receiving olaparib for more than 6 months and 4 patients receiving it for more than 12 months. Overall, 11 of the 49 patients (22%) had reductions in the PSA level of 50% or more. The median circulating tumor-cell count at baseline was 37 cells per 7.5 ml of blood (interquartile range, 14 to 110); 14 of the 49 patients (29%) had a confirmed reduction in the circulating tumor-cell count to less than 5 cells per 7.5 ml. Of the 49 patients who could be evaluated, 32 (65%) had measurable disease at baseline according to RECIST, version 1.1; 6 of these patients (19%) had a confirmed radiologic partial response (Table 2).

Defects in DNA Damage-Repair Genes

Paired samples from tumor biopsies performed before treatment and during treatment were available for all patients participating in the study; 28 patients underwent bone marrow biopsies, and 22 underwent imaging-guided biopsies of nodal or visceral metastases. Of the 49 patients who could be evaluated for a response, 43 had tumor-biopsy material that was suitable for next-generation sequencing. For the other 6 patients, archival tumor samples obtained at diagnosis were analyzed.

Figure 1. Figure 1. Genomic Aberrations in DNA Repair in Patients with Metastatic, Castration-Resistant Prostate Cancer. Data are shown for the 49 patients who could be evaluated for a response. Mutations and deletions in DNA-repair genes were identified through next-generation sequencing studies. Green shading indicates patients who were classified as having a response to olaparib in the clinical trial. Patients were considered to be biomarker-positive if homozygous deletions, deleterious mutations, or both were detected in DNA-repair genes (but not single copy deletions without events detected in the second allele). A star indicates that a particular genomic event was detected in germline DNA. Archival tumor samples were used for the sequencing studies in Patients 13, 18, 21, 40, 41, and 49 because the biopsy samples obtained during the trial were negative for tumor content.

Overall, 16 patients (33%) had tumor aberrations in DNA-repair genes (Figure 1). BRCA2 aberrations were detected in 7 patients: 2 had somatic homozygous deletions, 2 had a combination of somatic mutations and loss of heterozygosity, and 3 had a previously unidentified germline pathogenic mutation with somatic loss of the second allele. Five other patients had tumors with ATM aberrations. Three of these patients had germline mutations predicted to cause truncation of the ATM protein, and 2 of the 3 also had aberrant alleles in somatic DNA (1 with loss of heterozygosity and 1 with a missense mutation in the kinase domain–coding region of ATM). The other 2 patients had ATM mutations with no germline events: 1 had a frameshift mutation (p.V2288fs*1) predicted to cause truncation before the C-terminal phosphoinositide 3-kinase (PI3K) catalytic domain (normally formed by amino acid residues 2712 through 2962), as well as ATM domains required for p53 activation and the response to DNA damage,25,26 and 1 had a missense mutation (p.N2875H) within the PI3K catalytic domain of ATM.27 Homozygous somatic deletions of BRCA1 or CHEK2 occurred with FANCA deletion in 3 patients. A somatic frameshift mutation in PALB2 (partner and localizer of BRCA2) was also detected in a patient with a heterozygous PALB2 deletion. Finally, biallelic somatic aberrations in histone deacetylase 2 (HDAC2), which has a role in ATM function and the response to DNA damage,28-30 were identified in 1 patient.

Figure 2. Figure 2. Antitumor Activity of Olaparib and Association with Defects in DNA-Repair Genes, According to Biomarker Status. Panels A and B show radiologic progression–free survival and overall survival curves, respectively, for patients with genomic defects in DNA-repair genes (biomarker-positive group) and patients without such defects (biomarker-negative group). The hazard ratio for radiologic progression in the biomarker-positive group as compared with the biomarker-negative group was 0.24 (95% confidence interval [CI], 0.11 to 0.50), and the hazard ratio for death was 0.47 (95% CI, 0.22 to 1.02). Panels C and D show mean percentage changes in prostate-specific antigen (PSA) levels and circulating tumor-cell (CTC) counts, respectively, over the course of treatment in the biomarker-positive and biomarker-negative groups.

Overall, patients with aberrations in DNA-repair genes had a significantly higher response rate in unadjusted and adjusted analyses (P<0.001 in a multivariable logistic-regression model for response) (Tables S2 through S5 in the Supplementary Appendix); 14 of 16 biomarker-positive patients (88%) had a response to olaparib. Conversely, only 2 of 33 biomarker-negative patients (6%) were classified as having a response (sensitivity, 88%; specificity, 94%). Radiologic progression–free survival was significantly longer in the biomarker-positive group than in the biomarker-negative group (median, 9.8 vs. 2.7 months; P<0.001 by the log-rank test) (Figure 2). Overall survival was also prolonged in the biomarker-positive group (median, 13.8 months, vs. 7.5 months in the biomarker-negative group; P=0.05 by the log-rank test), even though established prognostic factors were balanced between the two groups (Table S6 in the Supplementary Appendix).

Figure 3. Figure 3. Radiologic Evidence of Tumor Responses to Olaparib at Week 12. Panel A shows CT scans of the chest, obtained in the lung and soft-tissue window settings, from a 61-year-old man with metastatic, castration-resistant prostate cancer (Patient 39) who had a response to olaparib; there was shrinkage of the lung and nodal (arrows) metastatic deposits after 12 weeks of therapy (right), as compared with baseline (left). Whole-exome sequencing showed a somatic homozygous deletion of BRCA2. Panel B shows CT scans with coronal reconstruction in a 70-year-old man with a somatic BRCA2 frameshift insertion (p.Y2154fs*21) and somatic deletion of the second allele (Patient 20). The scans show the response in the mediastinal and abdominal lymph nodes (arrows). The patient received treatment for a total of 48 weeks. Panel C shows multiparametric whole-body MRI scans, including diffusion-weighted imaging, with coronal three-dimensional reconstruction and selected axial images in a 79-year-old man (Patient 1) who had a response to olaparib, with an 85% reduction in the PSA level. The patient received treatment for a total of 73 weeks. The images show reduction in the water content within the skeletal metastasis, which in conjunction with other findings on imaging would be consistent with tumor regression during therapy (right), as compared with baseline (left). Next-generation sequencing of the baseline bone marrow–biopsy specimen revealed a somatic missense mutation within the ATM phosphoinositide 3-kinase catalytic domain (p.N2875S), with no evidence of genomic loss of the second allele and with maintenance of ATM expression on immunohistochemical assessment.

All seven patients with BRCA2 loss had PSA levels that fell by 50% or more from baseline; of these seven patients, all five with measurable disease also had a radiologic partial response (Figure 3). Four of the five patients with deleterious ATM mutations had a response to olaparib, including all three patients with DNA mutations predicted to cause loss of the kinase catalytic domain of ATM but with no defects in the second ATM allele.

An additional three patients who were classified as biomarker-positive had a response to olaparib. Patient 26, who had a somatic homozygous deletion of both BRCA1 and FANCA, had a response, with a reduction in the circulating tumor-cell count from 12 to 0 cells per 7.5 ml; olaparib was discontinued prematurely after 19 weeks because of myelosuppression with radiologic stable disease (Table 2). Patient 48, whose tumor had biallelic PALB2 aberrations, had a durable response that lasted for 39 weeks. The third patient with a response (Patient 8), who had biallelic somatic aberrations in HDAC2, received the study treatment for 62 weeks. His transcriptome revealed low HDAC1 and HDAC2 messenger RNA expression (Fig. S4 in the Supplementary Appendix). Conversely, a patient with defective mismatch DNA repair due to biallelic MLH3 loss with somatic homozygous deletion of FANCA and CHEK2 did not have a response to therapy, nor did the fifth patient with mutant ATM, who had radiologic progression of the liver metastases and an increase in the PSA level at the first response assessment.

Finally, in two other patients categorized as having a response according to trial criteria, tumor-exome sequencing identified no genomic defects fulfilling the study definition of defective DNA repair. However, one of the two patients (Patient 11) had little evidence of a true response, with a drop in circulating tumor-cell counts from 6 cells to 1 cell per 7.5 ml and radiologic progression at 12 weeks. The other patient (Patient 16) had a clear radiologic response according to RECIST, as well as an 86% reduction in the PSA level. This patient’s tumor had monoallelic deletions of both BRCA2 and PALB2, with no detectable loss of the other allele evident on whole-exome sequencing.

Safety

The median duration of olaparib treatment was 12 weeks (interquartile range, 11 to 24). The average delivered-dose intensity was 87%. The most commonly reported adverse events that developed during treatment are summarized in Table S7 in the Supplementary Appendix. Grade 3 or 4 drug-related events were primarily anemia (in 10 of the 50 patients [20%]), fatigue (in 6 patients [12%]), leukopenia (in 3 patients [6%]), thrombocytopenia (in 2 patients [4%]), and neutropenia (in 2 patients [4%]). Overall, 13 patients (26%) required a reduction in the dose of olaparib to 300 mg twice a day; anemia was the most common indication for the dose reduction (in 7 patients). These episodes of anemia were considered to be largely drug-related, although most of the patients with anemia had extensive bony disease involvement; the median baseline hemoglobin level was 11.2 g per deciliter. Three of the 13 patients required a second dose reduction, to 200 mg of olaparib twice a day. Olaparib was permanently discontinued in 3 patients (6%) because of adverse events.