Rosa Nadal

AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer

BACKGROUND The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. METHODS We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival. RESULTS A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA. CONCLUSIONS Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

IMPORTANCE We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown. OBJECTIVE To investigate whether AR-V7-positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men. DESIGN, SETTING, AND PARTICIPANTS We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men. MAIN OUTCOMES AND MEASURES We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates, PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone). RESULTS Of 37 taxane-treated patients enrolled, 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7-positive and AR-V7-negative men (41% vs 65%; P = .19). Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7-positive and AR-V7-negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7-positive men, whereas outcomes did not differ by treatment type in AR-V7-negative men. In AR-V7-positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003). CONCLUSIONS AND RELEVANCE Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7-positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7-negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell-based AR-V7 detection may serve as a treatment selection biomarker in CRPC.

Small cell carcinoma of the prostate

Pure small-cell carcinoma (SCC) of the prostate is a rare entity and one of the most aggressive malignancies of the prostate. Histologically, prostatic SCCs of the prostate are part of a spectrum of anaplastic tumours of the prostate and are similar to SCCs of the lungs. In most cases, SCC of the prostate is associated with conventional prostatic adenocarcinoma. Both components of these mixed tumours frequently share molecular alterations such as ERG gene rearrangements or AURKA and MYCN amplifications, suggesting a common clonal origin. The clinical behaviour of small-cell prostate carcinomas is characterized by extensive local disease, visceral disease, and low PSA levels despite large metastatic burden. Commonly, the emergence of the SCC occurs in patients with high-grade adenocarcinoma who are often treated with androgen deprivation treatment (ADT). However, SCCs do not usually benefit from ADT. A biopsy of accessible lesions is strongly recommended to identify those with SCC pathological features, as management is undoubtedly affected by this finding. Chemotherapy is the standard approach for treating patients with either localized or advanced prostatic SCC. Despite the emergence of more-aggressive treatment modalities, the prognosis of men with prostatic SCC remains dismal.

Clinical activity of enzalutamide versus docetaxel in men with castration‐resistant prostate cancer progressing after abiraterone

The optimal sequencing of the multiple active agents now available for metastatic castration‐resistant prostate cancer (mCRPC) is unclear. Prior reports have suggested diminished responses to sequential lines of androgen receptor (AR)‐targeted therapies, but it is unknown whether subsequent taxane‐based chemotherapy may be more effective than sequential AR‐targeting treatment. We sought to evaluate the clinical activity of enzalutamide versus docetaxel in men with mCRPC who progressed on abiraterone.

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

Background:Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel.Methods:We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel.Results:Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2–9.1), 4.0 (3.2–4.8), 4.1 (2.9–5.4) and 2.8 (2.5–3.2) months; median duration of enzalutamide was 9.1 (7.3–not reached), 4.7 (3.7–7.7), 5.4 (3.8–8.4) and 3.9 (3.0–4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7–16.5). 12-month OS was 78% (59–100%), 64% (45–90%), 77% (61–97%) and 51% (41–62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide.Conclusions:The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

Comparison of Prostate-Specific Membrane Antigen–Based 18F-DCFBC PET/CT to Conventional Imaging Modalities for Detection of Hormone-Naïve and Castration-Resistant Metastatic Prostate Cancer

Conventional imaging modalities (CIMs) have limited sensitivity and specificity for detection of metastatic prostate cancer. We examined the potential of a first-in-class radiofluorinated small-molecule inhibitor of prostate-specific membrane antigen (PSMA), N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC), to detect metastatic hormone-naïve (HNPC) and castration-resistant prostate cancer (CRPC). Methods: Seventeen patients were prospectively enrolled (9 HNPC and 8 CRPC); 16 had CIM evidence of new or progressive metastatic prostate cancer and 1 had high clinical suspicion of metastatic disease. 18F-DCFBC PET/CT imaging was obtained with 2 successive PET scans starting at 2 h after injection. Patients were imaged with CIM at approximately the time of PET. A lesion-by-lesion analysis of PET to CIM was performed in the context of either HNPC or CRPC. The patients were followed with available clinical imaging as a reference standard to determine the true nature of identified lesions on PET and CIM. Results: On the lesion-by-lesion analysis, 18F-DCFBC PET was able to detect a larger number of lesions (592 positive with 63 equivocal) than CIM (520 positive with 61 equivocal) overall, in both HNPC and CRPC patients. 18F-DCFBC PET detection of lymph nodes, bone lesions, and visceral lesions was superior to CIM. When intrapatient clustering effects were considered, 18F-DCFBC PET was estimated to be positive in a large proportion of lesions that would be negative or equivocal on CIM (0.45). On follow-up, the sensitivity of 18F-DCFBC PET (0.92) was superior to CIM (0.71). 18F-DCFBC tumor uptake was increased at the later PET time point (∼2.5 h after injection), with background uptake showing a decreasing trend on later PET. Conclusion: PET imaging with 18F-DCFBC, a small-molecule PSMA-targeted radiotracer, detected more lesions than CIM and promises to diagnose and stage patients with metastatic prostate cancer more accurately than current imaging methods.

Clinical activity of enzalutamide in Docetaxel-naïve and Docetaxel-pretreated patients with metastatic castration-resistant prostate cancer.

Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)‐pretreated and D‐naïve metastatic castration‐resistant prostate cancer (mCRPC) patients. Cross‐resistance between androgen receptor‐directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post‐D setting.

Comparing Sequencing of Abiraterone and Enzalutamide in Men With Metastatic Castration‐Resistant Prostate Cancer: A Retrospective Study

There are no validated clinical decision tools to aid optimal treatment selection in men with metastatic castration‐resistant prostate cancer (mCRPC). Frequently, abiraterone and enzalutamide are used prior to chemotherapy in mCRPC, given the more favorable safety profiles. However, there is no published data on clinical outcomes regarding best sequencing of these two agents.

Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study.

We have previously documented a paradoxical anti‐tumor effect when castration‐resistant prostate cancer patients were treated with intermittent, high‐dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone‐sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6‐month ADT lead‐in.

New Treatments for Bladder Cancer: When Will We Make Progress?

Opinion statementThe prognosis and long-term survival for patients with metastatic urothelial carcinoma patients is poor. Traditionally, the mainstay of treatment has been combination chemotherapy with gemcitabine and cisplatin or with the classical M-VAC. Vinflunine has become an EMA-approved second-line option in Europe. Urothelial carcinomas contain genetic alteration in multiple genes that are potentially treated by targeted therapies. Recently, a number of these new therapies have been developed in this disease. But not one has been approved for clinical use in urothelial cancers. While clinical evaluation of these agents is still in its early days, some promising findings have begun to emerge. For example, everolimus demonstrated activity in those metastatic urothelial cancer patients who harbors TSC1 mutation. With the identification of the most relevant drug targets for tumors initiation and maintenance and the best way to assess drug candidates that may only account for a small fraction of patients, it is anticipated that the therapeutic arsenal for urothelial cancers will be expanded in the future.