Development of a preliminary nomogram to predict progression of bone scan for castration-resistant prostate cancer

179 Background: Bone Scan Lesion Area (BSLA) is a biomarker that can be computed semi-automatically from whole-body scintigraphic imaging as a measure of overall bone tumor burden. Initial development and validation, including correlation with outcomes, was performed in trial cohorts from a single drug treatment with controls in subjects with metastatic castrate-resistant prostate cancer (CRPC). A 30% increase/decrease in BSLA was defined as progression/response on bone scan. We hypothesize that, when applied to an independent treatment trial cohort with a different mechanism of drug action, baseline BSLA and Week 12 change post-treatment are predictive of a subject's overall survival. Methods: From an anonymized imaging research database a cohort of 198 CRPC subjects was identified who enrolled in a treatment trial (127 treated, 71 placebo). This cohort was independent of those used for biomarker development and initial validation, and involved a different mechanism of drug action. Subjects underwent standard of care whole-body bone scintigraphy with 99mTc-Methyl diphosphonate (99mTc-MDP). BSLA was calculated at baseline and response at Week 12. Multivariate Cox regression was used to test whether (1) baseline BSLA, and (2) early changes in BSLA (12 weeks post treatment) were predictive of overall survival. Results: BSLA < 2000 mm2 at baseline was a prognostic factor (HR=0.6; p=0.003) and predictive of longer survival (HR=0.4; p<0.001). Subjects without PD by BSLA at Week 12 had significantly longer survival than subjects with PD: median 170 days vs. 186 days in the placebo group and 260 days vs. 392 days in the treatment group. The overall survival rates between non-PD and PD subjects were statistically different (HR=0.64, p=0.007). Conclusions: BSLA is calculated semi-automatically from bone scans and provides a quantitative and objective treatment response assessment. Baseline BSLA and early changes post treatment were found to be predictive of overall survival in patients with metastatic castration-resistant prostate cancer. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different drug treatments.

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Automated bone scan index as an imaging biomarker in metastatic castration resistant prostate cancer (mCRPC) patients treated with radium-223.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e16600 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e16600-e16600

Author(s):

Aseem Anand ◽

Stephanie Daignault ◽

Luke T. Nordquist ◽

Jorge Ramos ◽

Rohit K. Jain ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Scan ◽

Imaging Biomarker ◽

Castration Resistant Prostate Cancer ◽

Bone Scan Index ◽

Castration Resistant ◽

Radium 223

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Evaluation of bone metastasis of castration-resistant prostate cancer after enzalutamide and abiraterone using Bone Scan Index on bone scintigraphy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.e596 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. e596-e596

Author(s):

Suguru Kadomoto ◽

Kouji Izumi ◽

Takahiro Nohara ◽

Konaka Hiroyuki ◽

Yoshifumi Kadono ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Bone Metastases ◽

Bone Scintigraphy ◽

Bone Scan ◽

Average Rate ◽

Castration Resistant Prostate Cancer ◽

Bone Scan Index ◽

Castration Resistant ◽

Better Than

e596 Background: It was ambiguous till now to evaluate the change of bone metastasis by various treatments. To quantify the change of bone metastases by enzalutamide, abiraterone, and docetaxel for the castration-resistant prostate cancer (CRPC) with bone metastases (bmCRPC), we employed Bone Scan Index (BSI) on bone scintigraphy. Methods: We retrospectively evaluated the change of PSA and bone metastases of CRPC patients who were treated with enzalutamide (Enz), abiraterone (Abi) and/or docetaxel (DOC) in our hospital. All patients underwent Tc-99m MDP bone scintigraphy. The degree of bone metastases was analyzed using BSI, which was calculated by BONENAVI (FUJIFILM RI Pharma, Japan; EXINIbone, EXINI Diagnostics, Sweden). 19 patients were treated with enzalutamide (8 cases: pre-docetaxel, 11 cases: post-docetaxel). The median PSA of patients treated with Enz was 12.64 ng/ml (1.63-199 ng/ml). And 11 patients were treated with abiraterone (5 cases: pre-docetaxel, 6 cases: post-docetaxel). The median PSA of patients treated with Abi was 26.37 ng/ml (2.29-199 ng/ml). Results: We observed decline of PSA in 18/30 cases (9 cases: pre-DOC, 9 cases: post-DOC). Decline of PSA to 50% or more was observed in 14 cases. In contrast, decline of BSI was observed in 53.3% (16/30) cases and decline of PSA to 25% or more was observed in only 6 cases. BSI decreased in 84.6% (11/13) of pre-DOC setting and in 29.4% (5/17) of post-DOC setting indicating that change of BSI was poor in post-DOC setting. However, DOC had already decreased BSI in 91.7% (11/12) before Abi or Enz treatment. Moreover, the average rate of BSI decline in the patients that BSI decreased by DOC was better than the patients that BSI decreased by Abi/Enz (-48.46% vs -28.56%). Finally, although the rate of BSI change by Enz was weakly correlated with the rate of PSA decline (y = 0.3906x + 25.35, R2 = 0.3423), BSI continued to increase in four cases in spite of PSA decline. Conclusions: BSI using BONENAVI on bone scintigraphy was helpful for evaluating the effectiveness of treatment and following-up of bmCRPC.

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Practice Patterns and Predictors of Followup Imaging after a Negative Bone Scan in Men with Castration Resistant Prostate Cancer: Results from the SEARCH Database

The Journal of Urology ◽

10.1016/j.juro.2014.11.014 ◽

2015 ◽

Vol 193 (4) ◽

pp. 1232-1238 ◽

Cited By ~ 7

Author(s):

Katharine N. Sourbeer ◽

Lauren E. Howard ◽

Daniel M. Moreira ◽

Hiruni S. Amarasekara ◽

Lydia D. Chow ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Scan ◽

Practice Patterns ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study

Journal of Clinical Oncology ◽

10.1200/jco.2013.54.5954 ◽

2014 ◽

Vol 32 (30) ◽

pp. 3391-3399 ◽

Cited By ~ 85

Author(s):

Matthew R. Smith ◽

Christopher J. Sweeney ◽

Paul G. Corn ◽

Dana E. Rathkopf ◽

David C. Smith ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Soft Tissue ◽

Tumor Cells ◽

Phase Ii ◽

Bone Scan ◽

Castration Resistant Prostate Cancer ◽

Bone Biomarkers ◽

Castration Resistant ◽

Analgesic Use

Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

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Results of a phase II trial of abiraterone acetate (AA) combined with dutasteride (DUT) for men with metastatic castration resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.126 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 126-126

Author(s):

Rana R. McKay ◽

Lillian Werner ◽

Katherine A. Zukotynski ◽

Liran Domachevsky ◽

Aymen Elfiky ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Scan ◽

Specific Antigen ◽

Abiraterone Acetate ◽

Type I ◽

Castration Resistant Prostate Cancer ◽

Prior Therapy ◽

Castration Resistant ◽

Psa Nadir ◽

Grade 3

126 Background: Although abiraterone acetate (AA), a CYP17 inhibitor, increases survival in men with metastatic castration resistant prostate cancer (mCRPC), tumors eventually progress on therapy. The primary purpose of this study was to identify mechanisms of resistance to AA via analysis of the androgen receptor signaling pathway in serial tumor biopsies of men receiving AA and dutasteride (DUT), a type I and II 5-α reductase inhibitor. In this analysis, we report secondary endpoints including prostate specific antigen (PSA) response, toxicity, and incidence of flare. Methods: We enrolled 40 men with mCRPC. Patients initially received AA (1,000 mg daily) and prednisone (5 mg daily). After two months (mos), DUT (3.5 mg daily) was added. Therapy was continued until radiographic progression. A flare was recorded on bone scan, CT, or both if there were worsening lesions from baseline to 3 mos, decreasing PSA more than 50% from baseline at 3 mos, and stabilization or reduction of lesions at 6 mos. Results: Median follow-up was 13 mos. At the time of analysis, nine men remain on treatment. Twenty five percent and 18% of men received prior therapy with ketoconazole and/or chemotherapy, respectively. The median PSA at baseline was 28.8 ng/mL. After 2 mos of AA, median PSA declined by 54% to 10.9 ng/mL. Median PSA nadir was 6.3 ng/mL, reached at a median of 3.2 mos from baseline. 34 men (85%) experienced some degree of PSA decline. Twenty four men (60%) had a greater than or equal to 50% PSA decline and 12 (30%) had a greater than or equal to 90% PSA decline, reached at a median of 1.4 and 2.4 mos from baseline, respectively. There were 73% grade 1, 23% grade 2, 4% grade 3, and no grade 4 adverse events (AEs).AEs of interest included fatigue (45%), hypertension (38%, n=2 grade 3), hypokalemia (15%, n=0 grade 3), liver function test increases (15%), and edema (2%, n=0 grade 3). Seventeen men had imaging available for analysis, of whom four (23%) had flare on both 3 mos CT and bone scan and four (23%) had flare on only 3 mos CT scan. Conclusions: Given time of median PSA nadir, DUT may enhance efficacy of AA, though this warrants further investigation. Therapy with AA, prednisone (5 mg daily), and DUT is well tolerated with low rates of severe mineralocorticoid toxicity. Flare is seen on imaging in 47% of patients receiving AA. Biopsy data evaluating mechanisms for resistance to AA are not yet available. Clinical trial information: NCT01393730.

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Identification of a predictive factor of metastatic castration-resistant prostate cancer patients’ response to alternative antiandrogen therapy with flutamide.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.321 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 321-321

Author(s):

Masato Yasui ◽

Shuko Yoneyama ◽

Koichi Uemura ◽

Takashi Kawahara ◽

Yusuke Hattori ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Factors ◽

Hormone Therapy ◽

Predictive Factors ◽

Hormonal Therapy ◽

Bone Scan ◽

Second Line ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

N Stage

321 Background: Recently, new androgen pathway inhibitors, abiraterone and enzalutamide, are demonstrated to improve overall survival for metastatic castration-resistant prostate cancer (mCRPC). In Japan, alternative antiandrogen (AA) as second-line hormonal therapy for mCRPC that relapses after initial hormone therapy have been commonly used before new androgen pathway inhibitors. In this study, we attempted to identify the predictive factors for efficacy of AA as second-line hormone therapy. Methods: We identified consecutive 65 mCRPC patients treated with AA as second-line hormonal therapy. All patients were treated with maximum androgen blockade (MAB) initially and evaluated antiandrogen withdrawal syndrome after relapse. We analyzed the correlations between progression-free survival (PFS) of AA and clinicopathological characteristics, including patients’ age, initial PSA levels, PSA levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease (EOD) classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB. Results: The median duration of prostate cancer sensitivity to MAB was 11.3 months (range: 1.5-53.0 months). In multivariate analysis, four significant risk factors for poor PFS were identified; initial PSA levels ( > 263 ng/mL vs ≤ 263; HR 0.53, p = 0.038), N stage (1 vs 0; HR 3.00, p = 0.001), EOD classifications (3-4 vs 1-2; HR 2.50, p = 0.007), and the previous duration of prostate cancer sensitivity to MAB ( < 12 months vs ≥ 12; HR 2.16, p = 0.026). We stratified the patients into two cohorts with low risk (0-2 risk factor present) and high risk (3-4 risk factors present). We found a significant difference in PFS among risk groups (median PFS 7.3 months vs 1.5, p < 0.000). Conclusions: Initial PSA, N stage, EOD classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB were the significant predictive factors for efficacy of AA as second-line hormone therapy in patients with mCRPC. These findings might support that decision-making of when to start the new AR pathway inhibitors.

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