Controversies Involving the Systemic Treatment for Metastatic Prostatic Cancer

In the United States, 1987 estimates of cancer incidence by site indicate that prostatic cancer is equal to lung cancer as the first in incidence in adult males. Over 90,000 new cases are diagnosed and between 25-30,000 patients die of this disease each year. While early prostatic cancer is a surgically curable disease, the majority of patients present with widely metastatic cancer, where the main objective of treatment is palliation

Antiandrogen withdrawal in castrate-refractory prostate cancer

BACKGROUND. Antiandrogen withdrawal is a potential therapeutic maneuver for patients with progressive prostate cancer. This study was designed to examine antiandrogen withdrawal effects within the context of a large multi-institutional prospective trial. METHODS. Eligibility criteria included progressive prostate adenocarcinoma despite combined androgen blockade. Eligible patients received prior initial treatment with an antiandrogen plus orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist. Patients were stratified according to type of antiandrogen, type of progression (prostate-specific antigen [PSA] or radiographic), presence or absence of metastatic disease, and prior LHRH agonist versus surgical castration. RESULTS. A total of 210 eligible and evaluable patients had a median follow-up of 5.0 years; 64% of patients previously received flutamide, 32% bicalutamide, and 3% nilutamide. Of the 210 patients, 21% of patients had confirmed PSA decreases of ≥50% (95% CI, 16% to 27%). No radiographic responses were recorded. Median progression-free survival (PFS) was 3 months (95% CI, 2 months to 4 months); however, 19% had 12-month or greater progression-free intervals. Median overall survival (OS) after antiandrogen withdrawal was 22 months (20 and 40 months for those with and without radiographic evidence of metastatic disease, respectively). Multivariate analyses indicated that longer duration of antiandrogen use, lower PSA at baseline, and PSA-only progression at study entry were associated with both longer PFS and OS. Longer antiandrogen use was the only significant predictor of PSA response. CONCLUSIONS. These data indicate a relatively modest rate of PSA response in patients who were undergoing antiandrogen withdrawal; however, PFS can be relatively prolonged (≥1 year) in approximately 19% of patients. Cancer 2008. © 2008 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58635/1/23473_ftp.pd

Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer

Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. Experimental Design: In ARMOR1, 49 patients received increasing doses (650–2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700–3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition

Test-retest repeatability of organ uptake on PSMA‐targeted 18F‐DCFPyL PET/CT in patients with prostate cancer

Objectives We evaluated 18F-DCFPyL test–retest repeatability of uptake in normal organs. Methods Twenty-two prostate cancer (PC) patients underwent two 18F-DCFPyL PET scans within 7 days within a prospective clinical trial (NCT03793543). In both PET scans, uptake in normal organs (kidneys, spleen, liver, and salivary and lacrimal glands) was quantified. Repeatability was determined by using within-subject coefficient of variation (wCOV), with lower values indicating improved repeatability. Results For SUVmean, repeatability was high for kidneys, spleen, liver, and parotid glands (wCOV, range: 9.0%–14.3%) and lower for lacrimal (23.9%) and submandibular glands (12.4%). For SUVmax, however, the lacrimal (14.4%) and submandibular glands (6.9%) achieved higher repeatability, while for large organs (kidneys, liver, spleen, and parotid glands), repeatability was low (range: 14.1%–45.2%). Conclusion We found acceptable repeatability of uptake on 18F-DCFPyL PET for normal organs, in particular for SUVmean in the liver or parotid glands. This may have implications for both PSMA-targeted imaging and treatment, as patient selection for radioligand therapy and standardized frameworks for scan interpretation (PROMISE, E-PSMA) rely on uptake in those reference organs

Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/mm2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P \u3c .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned

Lack of repeatability of radiomic features derived from PET scans: results from a 18F‐DCFPyL test–retest cohort

Objectives PET-based radiomic metrics are increasingly utilized as predictive image biomarkers. However, the repeatability of radiomic features on PET has not been assessed in a test–retest setting. The prostate-specific membrane antigen-targeted compound 18F-DCFPyL is a high-affinity, high-contrast PET agent that we utilized in a test-retest cohort of men with metastatic prostate cancer (PC). Methods Data of 21 patients enrolled in a prospective clinical trial with histologically proven PC underwent two 18F-DCFPyL PET scans within 7 days, using identical acquisition and reconstruction parameters. Sites of disease were segmented and a set of 29 different radiomic parameters were assessed on both scans. We determined repeatability of quantification by using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland–Altman analysis. Results In total, 230 lesions (177 bone, 38 lymph nodes, 15 others) were assessed on both scans. For all investigated radiomic features, a broad range of inter-scan correlation was found (r, 0.07–0.95), with acceptable reproducibility for entropy and homogeneity (wCOV, 16.0% and 12.7%, respectively). On Bland–Altman analysis, no systematic increase or decrease between the scans was observed for either parameter (±1.96 SD: 1.07/−1.30, 0.23/−0.18, respectively). The remaining 27 tested radiomic metrics, however, achieved unacceptable high wCOV (≥21.7%). Conclusion Many common radiomic features derived from a test–retest PET study had poor repeatability. Only Entropy and homogeneity achieved good repeatability, supporting the notion that those image biomarkers may be incorporated in future clinical trials. Those radiomic features based on high frequency aspects of images appear to lack the repeatability on PET to justify further study

Comparative Survival of Asian and White Metastatic Castration-Resistant Prostate Cancer Men Treated With Docetaxel

There are few data regarding disparities in overall survival (OS) between Asian and white men with metastatic castration-resistant prostate cancer (mCRPC). We compared OS of Asian and white mCRPC men treated in phase III clinical trials with docetaxel and prednisone (DP) or a DP-containing regimen. Individual participant data from 8820 men with mCRPC randomly assigned on nine phase III trials to receive DP or a DP-containing regimen were combined. Men enrolled in these trials had a diagnosis of prostate adenocarcinoma. The median overall survival was 18.8 months (95% confidence interval [CI] = 17.4 to 22.1 months) and 21.2 months (95% CI = 20.8 to 21.7 months) for Asian and white men, respectively. The pooled hazard ratio for death for Asian men compared with white men, adjusted for baseline prognostic factors, was 0.95 (95% CI = 0.84 to 1.09), indicating that Asian men were not at increased risk of death. This large analysis showed that Asian men did not have shorter OS duration than white men treated with docetaxel

High SUVs have more robust repeatability in patients with metastatic prostate cancer: results from a prospective test-retest cohort imaged with 18F-DCFPyL

OBJECTIVES: In patients with prostate cancer (PC) receiving prostate-specific membrane antigen- (PSMA-) targeted radioligand therapy (RLT), higher baseline standardized uptake values (SUVs) are linked to improved outcome. Thus, readers deciding on RLT must have certainty on the repeatability of PSMA uptake metrics. As such, we aimed to evaluate the test-retest repeatability of lesion uptake in a large cohort of patients imaged with (18)F-DCFPyL. METHODS: In this prospective, IRB-approved trial (NCT03793543), 21 patients with history of histologically proven PC underwent two (18)F-DCFPyL PET/CTs within 7 days (mean 3.7, range 1 to 7 days). Lesions in the bone, lymph nodes (LN), and other organs were manually segmented on both scans, and uptake parameters were assessed (maximum (SUV(max)) and mean (SUV(mean)) SUVs), PSMA-tumor volume (PSMA-TV), and total lesion PSMA (TL-PSMA, defined as PSMA − TV × SUV(mean))). Repeatability was determined using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis. RESULTS: In total, 230 pairs of lesions (177 bone, 38 LN, and 15 other) were delineated, demonstrating a wide range of SUV(max) (1.5–80.5) and SUV(mean) (1.4–24.8). Including all sites of suspected disease, SUVs had a strong interscan correlation (R(2) ≥ 0.99), with high repeatability for SUV(mean) and SUV(max) (wCOV, 7.3% and 12.1%, respectively). High SUVs showed significantly improved wCOV relative to lower SUVs (P < 0.0001), indicating that high SUVs are more repeatable, relative to the magnitude of the underlying SUV. Repeatability for PSMA-TV and TL-PSMA, however, was low (wCOV ≥ 23.5%). Across all metrics for LN and bone lesions, interscan correlation was again strong (R(2) ≥ 0.98). Moreover, LN-based SUV(mean) also achieved the best wCOV (3.8%), which was significantly reduced when compared to osseous lesions (7.8%, P < 0.0001). This was also noted for SUV(max) (wCOV, LN 8.8% vs. bone 12.0%, P < 0.03). On a compartment-based level, wCOVs for volumetric features were ≥22.8%, demonstrating no significant differences between LN and bone lesions (PSMA-TV, P =0.63; TL-PSMA, P =0.9). Findings on an entire tumor burden level were also corroborated in a hottest lesion analysis investigating the SUV(max) of the most intense lesion per patient (R(2), 0.99; wCOV, 11.2%). CONCLUSION: In this prospective test-retest setting, SUV parameters demonstrated high repeatability, in particular in LNs, while volumetric parameters demonstrated low repeatability. Further, the large number of lesions and wide distribution of SUVs included in this analysis allowed for the demonstration of a dependence of repeatability on SUV, with higher SUVs having more robust repeatability