Androgen Receptor-directed Therapy Research Articles

Clinical Management of Advanced Prostate Cancer: Where Does Radiopharmaceutical Therapy Fit in the Treatment Algorithm?

Most men with newly appreciated metastatic prostate cancer are optimally treated with a backbone consisting of androgen receptor-directed therapy with or without taxane chemotherapy. Despite improvements in disease outcomes, prostate cancer remains an extremely heterogeneous disease with variable mechanisms of therapeutic resistance. As a result, it remains a leading cause of cancer-related death in men. Radiopharmaceutical therapy has emerged as an alternative, non-androgen receptor-directed treatment modality for metastatic castration-resistant prostate cancer that impacts patient survival and represents a potentially more personalized approach. In this review, we aim to outline the current treatment landscape for metastatic prostate cancer with a focus on radiopharmaceutical therapy, specifically 177Lu-PSMA-617. In addition, we illustrate various clinical challenges with 177Lu-PSMA-617 treatment to date and explore investigative efforts to leverage radiopharmaceutical therapies as part of combination regimens or earlier in the treatment algorithm to further improve patient outcomes. Finally, we introduce ongoing studies of alternative radiopharmaceutical therapies in metastatic prostate cancer that may be incorporated into the treatment algorithm pending further study.

Safety and Efficacy of [177Lu]-PSMA-I&T Radioligand Therapy in Octogenarians with Metastatic Castration-Resistant Prostate Cancer: Report on 80 Patients over the Age of 80 Years.

177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new treatment option for metastatic castration-resistant prostate cancer (mCRPC). Its low toxicity profile favors use in elderly patients or in patients with critical comorbidities. The purpose of this analysis was to evaluate the efficacy and safety of [177Lu]-PSMA RLT in mCRPC patients at least 80 y old. Methods: Eighty mCRPC patients at least 80 y old underwent [177Lu]-PSMA-I&T RLT and were retrospectively selected. The patients were previously treated by androgen receptor-directed therapy, received taxane-based chemotherapy, or were chemotherapy-ineligible. The best prostate-specific antigen (PSA) response was calculated, as well as clinical progression-free survival (cPFS) and overall survival (OS). Toxicity data were acquired until 6 mo after the last treatment cycle. Results: Of 80 patients, 49 (61.3%) were chemotherapy-naïve and 16 (20%) had visceral metastases. The median number of previous mCRPC treatment regimens was 2. In total, 324 cycles (median, 4 cycles; range, 1-12) with a median cumulative activity of 23.8 GBq (interquartile range, 14.8-42.2) were applied. A PSA decline of 50% was achieved in 37 (46.3%) patients. Chemotherapy-naïve patients showed higher 50% PSA response rates than chemotherapy-pretreated patients (51.0% vs. 38.7%, respectively). Overall, median cPFS and OS were 8.7 and 16.1 mo, respectively. The median cPFS and OS of chemotherapy-naïve patients were significantly longer than those of chemotherapy-pretreated patients (10.5 vs. 6.5 mo and 20.7 vs. 11.8 mo, respectively, P < 0.05). A lower hemoglobin level and higher lactate dehydrogenase level at baseline were independent predictors of shorter cPFS and OS. Treatment-emergent grade 3 toxicities were anemia in 4 patients (5%), thrombocytopenia in 3 patients (3.8%), and renal impairment in 4 patients (5%). No nonhematologic grade 3 and no grade 4 toxicities were observed. The most frequent clinical side effects were grade 1-2 xerostomia, fatigue, and inappetence. Conclusion: [177Lu]-PSMA-I&T RLT in mCRPC patients at least 80 y old is safe and effective, comparable to previously published data on non-age-selected cohorts with a low rate of high-grade toxicities. Chemotherapy-naïve patients showed a better and longer response to therapy than taxane-pretreated patients. [177Lu]-PSMA RLT seems to be a meaningful treatment option for older patients.

Abstract 5053: Artificial intelligence (AI)-based multimodal framework predicts androgen-deprivation therapy (ADT) outcomes in non-metastatic castration resistant prostate cancer (nmCRPC) from SPARTAN

Abstract Objective: AI has demonstrated great promise in learning sophisticated features and relations in data that would otherwise remain hidden to the human eye. Here, we developed a proprietary AI-based multimodal approach to integrate clinical, digitized hematoxylin-eosin (H&amp;E), and radiology bone scan (rBS) data for outcome prediction in ADT-treated nmCRPC patients. Identifying prostate cancer patients who may not benefit from ADT could improve the medical management of this disease beyond current definitive therapy. Methods: Patients in the ADT+placebo arm from SPARTAN clinical trial on nmCRPC with available clinical, H&amp;E, and rBS were used (n=154). These patients were randomly divided into 70% (n=107) discovery and 30% (n=47) hold-out test datasets. Using the discovery set, we developed and trained a multimodal approach that combines survival convolutional neural networks (SCNNs1) and Cox proportional-hazards model (CPH) to learn ADT outcomes for overall survival (OS) and time to PSA progression (TTP) from the integration of imaging data and 11 traditional clinical features (e.g., tumor stage, Gleason score, PSA). The ability of the trained framework in predicting outcomes and risk stratification was evaluated on the hold-out set. Bootstrap analysis with Wilcoxon signed rank test was used to determine the significance of the multimodal framework’s performance improvement compared to clinical CPH. Results: The multimodal framework was predictive of ADT outcomes for OS and TTP in nmCRPC patients. In SPARTAN’s hold-out set, the multimodal framework significantly improved the predictive power of clinical CPH by 14%—16% across both outcomes (Wilcoxon signed rank P&amp;lt;0.0001). In particular, the multimodal framework’s concordance index (c-index) was 0.72 for OS and 0.73 for TTP, while clinical CPH’s c-index was 0.62 for OS, and 0.64 for TTP. Further, multimodal framework significantly stratified high- from low-risk nmCRPC patients for OS and TTP (log-rank P= 0.0049-0.0072), while clinical CPH failed to stratify risk for OS (log-rank P= 0.2891). Conclusion: AI-based framework that learns from the integration of different data types improves outcome prediction in ADT-treated nmCRPC. The multimodal approach demonstrates promise in treatment decision support for the early use of androgen receptor-directed therapy and patient selection for clinical trials with novel treatment combinations. Reference: 1. Mobadersany, Pooya, et al. "Predicting cancer outcomes from histology and genomics using convolutional networks." Proceedings of the National Academy of Sciences 115.13 (2018): E2970-E2979. Conflict of interest statement P.M., J.L., D.G., C.A., S.M., S.B., M.K.Y., K.T., N.H., J.Z., J.G., N.K., and S.S.F.Y., are employees of Janssen Pharmaceutical, LLC. Citation Format: Pooya Mobadersany, Justin Lucas, Darshana Govind, Clemente Aguilar-Bonavides, Sharon McCarthy, Sabine Brookman-May, Margaret K. Yu, Ken Tian, Natalie Hutnick, Jose Zamalloa, Joel Greshock, Najat Khan, Stephen S.F. Yip. Artificial intelligence (AI)-based multimodal framework predicts androgen-deprivation therapy (ADT) outcomes in non-metastatic castration resistant prostate cancer (nmCRPC) from SPARTAN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5053.

Effect of androgen receptor directed therapy in prostate cancer patients with COVID-19.

161 Background: TMPRSS2 is one of the two key enzymes that SARS-CoV-2 requires for its entry to the cell. TMPRSS2 is regulated by androgen receptor. It is well described Androgen Receptor Directed Therapy (ARDT) downregulates the expression of TMPRSS2. We hypothesized that the ARDT has a protective role in patients with prostate cancer (PCa) from poor outcome of COVID-19. Methods: A retrospective chart review of PCa patients with COVID-19 between March to October 2020 in the Yale-New Haven Health System was performed. Demographics, comorbidities, home medications, laboratory data, treatment, and clinical outcomes of COVID-19 were collected. ARDT was defined as the use of GnRH agonist, GnRH antagonist, or androgen receptor antagonist. This study was reviewed and approved by the Institutional Review Boards of Yale University. Results: A total of 146 (1.1%) prostate cancer cases were identified from the 13,642 cases of COVID-19. The clinical characteristics are summarized in the table. Twenty-five (17%) were on active ARDT and 121 (83%) not on ARDT (non-ARDT). The rates of hospitalization were the same: 52%, between the ARDT and non-ARDT group. Of those admitted, mean duration of hospitalization were 9.2 days (Range 1-25) and 14.9 days (Range: 2-47) in ARDT and non-ARDT groups, respectively (p=0.14). Rates of hospital stay &gt;30 days were 0% versus 14.3% (9/63) in ARDT and non-ARDT groups, respectively (p=0.15). Intubation rates were 0% versus 11% (7/63) for ARDT and non-ARDT groups, respectively (p=0.21). Mortality rates were 8% and 13.2%, in ARDT and non-ARDT groups, respectively (p=0.47). Conclusions: The prevalence of PCa was infrequent. Despite advanced stage of the cancer in ARDT group, there was a trend toward decreased severity of COVID-19 and mortality rates compared to non-ARDT group. Our data support further investigation on a protective role of hormone therapy in PCa patients with COVID-19.[Table: see text]

PARP Inhibition in Advanced Prostate Cancer.

In May 2020, the poly(ADP-ribose) polymerase (PARP) inhibitors rucaparib and olaparib were Food and Drug Administration approved for the management of metastatic castration-resistant prostate cancers. Rucaparib was approved for tumors that harbor alterations in BRCA1 and BRCA2 following progression on chemotherapy and androgen receptor-directed therapy, whereas olaparib was approved for tumors that harbor alterations in a broader range of DNA damage repair genes following progression on androgen receptor-directed therapy. Loss-of-function mutations in genes such as BRCA1 and BRCA2 increase reliance on PARP-mediated mechanisms of DNA repair, and inhibition of this pathway results in the accumulation of lethal levels of DNA damage. This dependence is advantageous in the management of prostate cancer, as mutations in DNA damage repair genes are frequent. This review summarizes the role of PARP in cell homeostasis, methods of targeting PARP in cancer cells, and current clinical trials in the management of advanced prostate cancer with PARP inhibitors.

Increasing prevalence of metastatic castration-resistant prostate cancer in a managed care population in the United States.

Numerous treatment breakthroughs for patients with metastatic castration-resistant prostate cancer (mCRPC) have been demonstrated in clinical trials in the past 15years. However, real-world evidence on the changing epidemiology and longevity of this population has not been demonstrated. This study assessed prevalence trends for mCRPC over eightyears in a large managed care population. In a claims database, adult male patients were included with ≥ 1 claim for prostate cancer, pharmacologic/surgical castration, and metastatic disease during the identification period. The index mCRPC date was the first metastatic claim; sixmonths of continuous enrollment before and after was required. Patients with metastatic disease at baseline were excluded. Patients were followed until death, end of study, or disenrollment, whichever was earliest. Total, mCRPC per-prostate cancer, and age-specific prevalence rates were calculated cross-sectionally for each year under study (2010-2017). Of 343,089 patients identified with a claim for prostate cancer, 3690 mCRPC cases (1.1%) were identified. Incidence (new cases per year) remained relatively constant over the study period while prevalence of mCRPC (total cases per year) increased. mCRPC prevalence increased with increasing age. Total and mCRPC per-prostate cancer prevalence rates increased in monotonic, year-over-year trends from 2010 to 2017, while incidence (new cases per year) of mCRPC remained relatively stable. This study found increasing prevalence of mCRPC in an insured patient population during the 8-year period, coupled with stable incidence, validating that patients with the disease are living longer. With the addition of androgen receptor-directed therapies and poly(ADP-ribose) polymerase inhibitors in recent years, this trend will likely continue.

ICEPAC: A phase II multicenter study of avelumab combined with stereotactic ablative body radiotherapy (SABR) in metastatic castration-resistant prostate cancer (mCRPC).

86 Background: Studies investigating immune checkpoint inhibitors (ICI) in mCRPC have produced modest results. Radiation therapy may be synergistic with ICIs. We hypothesised that SABR would enhance anti-tumour activity of PD-L1 inhibitor avelumab in patients (pts) with progressive mCRPC. Methods: This phase II, single arm, multicentre study enrolled mCRPC pts following progression on ≥1 novel androgen receptor-directed therapy. Up to two lines of prior taxane chemotherapy were permitted. Pts received avelumab 10mg/kg IV q2weeks for a total of 24 weeks (12 cycles). A single fraction of 20Gy SABR was administered to 1-2 disease sites within five days prior to first and second doses of avelumab. Primary endpoint was disease control rate (DCR); secondary endpoints were PSA response (PSA50), overall response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS) and safety. Radiographic disease assessment (CT and bone scintigraphy) was performed after cycles 6 and 12 of avelumab treatment. Following enrolment of 14 pts, a protocol amendment allowed avelumab beyond 12 cycles in pts with disease control at 24 weeks. Results: Thirty-one pts were enrolled, with 30 evaluable for the primary endpoint. Median follow-up was 18 months (mo). Pt characteristics: median age 71 years (IQR 64-75), bone-only disease 42%, visceral disease 16%, prior taxane chemotherapy 84%, treatment with both abiraterone and enzalutamide 13%. Seventy metastatic sites received SABR, most frequently to bone (90%) and soft tissue (29%) disease. Avelumab was given as second-line, third-line and fourth- or greater line systemic therapy in 29%, 42% and 29% of pts, respectively. Median cycles of avelumab administered was 9 (IQR 5-13). DCR (95% CI) was 50% (31-69) and 60% (32-84) in all-comers and soft tissue disease subgroup, respectively. Following protocol amendment, 7/17 pts (41%) received avelumab beyond 12 cycles. Incidence of grade 3-4 treatment-related AEs was 16% (no grade 5 events), with three pts requiring oral/IV corticosteroid therapy. Conclusions: Avelumab with SABR demonstrated durable disease control in treatment-refractory mCRPC with an acceptable toxicity profile. This combination warrants further investigation. Clinical trial information: ACTRN12618000954224. [Table: see text]

Association of co-occurring gene alterations and clinical activity of rucaparib in patients with BRCA1 or BRCA2 mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC).

80 Background: The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib was granted accelerated approval by the US Food and Drug Administration for patients with BRCA+ mCRPC based on results from the phase 2 TRITON2 study (NCT02952534). The TP53 tumor suppressor gene is among the most frequently mutated genes in human cancers, including mCRPC, and alterations in TP53, PTEN, and RB1 are associated with poor prognosis in patients with prostate cancer and other tumor types. We present data on co-occurring alterations in patients with BRCA+ mCRPC treated with rucaparib in TRITON2. Methods: Patients had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy and were treated with rucaparib 600 mg BID. Tissue and/or cell-free DNA extracted from plasma samples were profiled comprehensively for genomic alterations using Foundation Medicine, Inc., next-generation sequencing assays. Objective response rate (ORR) was assessed per modified Response Evaluation Criteria in Solid Tumors and Prostate Cancer Working Group 3 criteria by independent radiologic review of patients with measurable disease. Prostate-specific antigen (PSA) response rate (≥50% decrease from baseline) was assessed in all patients. Results: Tissue and/or plasma samples were available for 114/115 patients with BRCA+ mCRPC (visit cutoff date: Dec. 23, 2019). Among patients with BRCA+ mCRPC who had samples available for comprehensive genomic profiling, 36.8% (42/114) had a co-occurring alteration in TP53. Deleterious alterations in PTEN were observed in 34.2% (39/114) of patients, 44% (17/39) of which were homozygous deletions of PTEN. RB1 loss was observed in 12.3% (14/114) of patients and was seen more frequently in patients with measurable disease (18.0%, 11/61) than in patients with non-measurable disease (5.7%, 3/53). Although patients with and without TP53 mutations had generally similar baseline demographics and disease characteristics, visceral disease was more prevalent in patients with TP53 mutations (54.8%; 23/42) than in those without them (29.2%; 21/72). Similar ORR and PSA response rates were seen in patients with BRCA+ mCRPC with or without TP53 mutation, with a non-significant trend towards lower response rates in patients with co-occurring TP53 alterations. Conclusions: Results from TRITON2 showed antitumor activity for rucaparib in patients with BRCA+ mCRPC associated with or without co-occurring alterations in TP53. Demographics and additional efficacy analyses in genomic subgroups with co-occurring alterations in TP53, PTEN, and RB1 will be reported. Clinical trial information: NCT02952534. [Table: see text]

177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial

Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

Abstract A075: Lifestyle-associated metabolites drive neuroendocrine differentiation in prostate cancer

Abstract Prostate cancer affects African American (AA) men disproportionately in the US, but even more so in the state of South Carolina, with 3 times higher mortality rates for AA men when compared to European American (EA) men. Neuroendocrine prostate cancer (NEPC) is a subtype of castrate resistant prostate cancer with aggressive clinical features and poor overall survival. NEPC is associated with androgen independence and a lack of therapeutic options. Although de novo NEPC is rare, recent studies support the idea that transformation of prostate adenocarcinoma cells through a process of neuroendocrine differentiation (NED) into NEPC as a mechanism of resistance to androgen receptor-directed therapies (ADT). The investigators have identified a lifestyle factor known as advanced glycation end-products (AGEs) that promote a more aggressive prostate cancer phenotype through the induction of a specific microRNA (miR-204) and MYC (a known driver of NEPC). The role of miR-204 in prostate cancer was considered controversial with some groups reporting a tumor suppressor and others an oncogenic role. More recent studies now show that miR-204 plays an oncogenic role in AR negative cells representing NEPC and as a tumor suppressor in AR positive cells representing prostate adenocarcinoma. We show that AGEs upregulate miR-204, MYC and drive NED in vitro and drive aggressive tumor growth in vivo. Relevant as both AGEs and miR-204 are elevated in AA men, when compared to EA men, with prostate cancer. We also show that inhibition of miR-204 can inhibit the neuroendocrine phenotype, including the downregulation of MYC. This innovative study is the first to link a lifestyle factor (AGE) and a plasma biomarker (miR-204) together as drivers of racial disparities in prostate cancer aggression, and as drivers that can be clinically targeted and may be informative for novel therapeutic interventions to delay or prevent the emergence of NEPC during ADT. Work supported by NIH/NCI Project #1U54CA210963 Citation Format: Ashley E. Knowell, Lourdes M Nogueira, Taiwo Biotidara, Brandon Sutton, Arabia Satterwhite, Michael Lilly, Shanora Brown, Dave Turner, Victoria Findlay. Lifestyle-associated metabolites drive neuroendocrine differentiation in prostate cancer [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A075.

Genomic characteristics associated with clinical activity of rucaparib in patients (pts) with BRCA1 or BRCA2 (BRCA)-mutated metastatic castration-resistant prostate cancer (mCRPC).

178 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in pts with mCRPC and a deleterious germline or somatic alteration in BRCA ( BRCA pts) or 1 of 13 other DNA damage repair (DDR) genes. Methods: Eligible pts had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy. Deleterious DDR gene alterations were identified from central testing of plasma and/or tissue samples by Foundation Medicine or from local testing. Results: As of Jul 2, 2019 (visit cutoff), 98 BRCA pts had received rucaparib; median (range) duration of follow-up was 13.0 (4.1–25.8) mo. Confirmed objective response rate (ORR) in BRCA pts (with investigator-assessed measurable disease) and PSA response rates (in pts with and without measurable disease) are shown in the Table. A biallelic alteration was observed in 81.4% (35/43) of BRCA pts for whom zygosity could be determined, and pts with homozygous BRCA loss (20.4%; 20/98) demonstrated high ORR (66.7% [95% CI, 38.4-88.2]; 10/15) and PSA response rates (75.0% [95% CI, 50.9-91.3]; 15/20). The safety profile in BRCA pts was consistent with the overall TRITON2 pt population. Conclusions: Results from TRITON2 showed antitumor activity with rucaparib in pts with mCRPC and a deleterious BRCA alteration. Responses were observed in patients with germline or somatic alterations in BRCA1 or BRCA2. The activity of rucaparib in these and additional genomic subgroups (e.g., based on zygosity, plasma genomic testing, or co-occurring alterations) will be reported. Clinical trial information: NCT02952534. [Table: see text]

Abstract 727: Comprehensive genomic profiling of &amp;gt;1000 plasma and tumor tissue samples from metastatic castration-resistant prostate cancer (mCRPC) patients gives insight into targeted treatment strategies

Abstract Background: The phase 2 TRITON2 (NCT02952534) study is evaluating the poly(ADP-ribose) polymerase inhibitor rucaparib in mCRPC patients with a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or 1 of 12 other DNA damage repair (DDR) genes who have progressed on prior androgen receptor-directed therapy and 1 taxane-based therapy. Here we present results from central genomic screening of plasma and tissue samples for TRITON2. Methods: Plasma samples were profiled for genomic alterations (GAs) in 70 genes and tumor tissue FFPE samples for GAs in 395 genes by Foundation Medicine, Inc., using next-generation sequencing (NGS) assays. Deleterious alterations included frameshift, nonsense, and deleterious missense mutations, protein-truncating rearrangements, and (for tissue samples) homozygous loss. Tissue samples included both archival and more recent specimens, whereas plasma samples were collected at the time of disease progression on prior therapy. Results: As of July 2, 2018, 359 plasma samples from patients with mCRPC were screened for deleterious GAs in a DDR gene. Of the plasma samples, 96% (343/359) were successfully sequenced for a comprehensive genomic profile. The most commonly altered genes were AR (49%) and TP53 (48%). Deleterious GAs were detected in BRCA1 (2%), BRCA2 (10%), ATM (15%), CDK12 (6%), or other DDR genes (6%). GAs in the MAPK pathway were observed in 5% of plasma samples. Additionally, 738 tissue samples from primary prostate cancer tumors (78%) or metastases (22%) were profiled. Only 66% of tissue samples (487/738) were sequenced successfully, highlighting the challenges associated with NGS of predominantly archival prostate tissues (median sample age, 2.5 years [range, 4 days to 21 years]). The most commonly altered genes were TP53 (38%), PTEN (33%), ERG-TEMPRSS2 fusions (28%), AR (15%), and MYC (9%). Deleterious GAs were observed in BRCA1(2%), BRCA2 (9%), ATM (7%), CDK12 (7%), or other DDR genes (5%), as well as in the PI3K/AKT (41%), Wnt (11%), MAPK (5%), and mismatch repair (3%) pathways. Further, GAs in the DDR, PI3K/AKT, and Wnt pathways were observed at a higher rate in metastatic (42%, 40%, and 15%, respectively) than in primary prostate tissues (32%, 34%, and 12%, respectively). Updated and expanded genomic analyses and plasma-tissue concordance analyses will be presented. Conclusions: Genomic NGS profiling of plasma and FFPE tumor tissue samples successfully identified patients with GAs in a DDR gene for the evaluation of rucaparib in mCRPC. The plasma assay is convenient for patients and has a low NGS failure rate, whereas the tumor tissue assay has a higher failure rate but can detect more alteration types. Taken together, these data highlight the strengths and limitations of tissue and plasma testing to identify GAs for targeted therapies in mCRPC. Citation Format: Foad Green, Jeremy D. Shapiro, Ray McDermott, Josep Maria Piulats, Alison Reid, Peter Ostler, Jingsong Zhang, David Campbell, Dominique Spaeth, Ivor Percent, Arif Hussain, Andrew D. Simmons, Tony Golsorkhi, Simon P. Watkins, Andrea Loehr, Simon Chowdhury, Wassim Abida. Comprehensive genomic profiling of &amp;gt;1000 plasma and tumor tissue samples from metastatic castration-resistant prostate cancer (mCRPC) patients gives insight into targeted treatment strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 727.

Emerging Therapies in Metastatic Prostate Cancer.

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

Prognostic and predictive biomarkers in prostate cancer: latest evidence and clinical implications.

Advances in our understanding of the mechanisms driving castration-resistant prostate cancer have promoted the development of several new drugs including androgen receptor-directed therapy and chemotherapy. Concomitant docetaxel treatment at the beginning of hormonal therapy for metastatic prostate cancer has resulted in longer overall survival than with hormonal therapy alone. Elucidating an appropriate treatment sequence using these therapies is important for maximizing clinical benefit in castration-sensitive and castration-resistant prostate cancer patients. The development of advanced high-throughput ‘omics’ technology has enabled the use of novel markers to guide prognosis and treatment of this disease. In this review, we outline the genomic landscape of prostate cancer and the molecular mechanisms of castration-resistant progression, and how these affect the development of new drugs, and their clinical implications for selecting treatment sequence. We also discuss many of the potential tissue-based or liquid biomarkers that may soon enter clinical use, with the hope that several of these prognostic or predictive markers will guide precision medicine for prostate cancer patients in the near future.

Prognostic factors for clinical outcomes in patients with metastatic castration resistant prostate cancer treated with sequential novel androgen receptor-directed therapies.

Prognostic factors associated with clinical outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with a novel androgen receptor-directed therapies (ARDT) in the second line setting has not been formally evaluated. We retrospectively reviewed and analyzed medical records of all patients with mCRPC who received sequential treatment with ARDT. We analyzed potential clinical factors associated with post treatment endpoints including 50% decline in prostatic-specific antigen (PSA), PSA-progression-free survival (PFS), clinical or radiographic PFS and overall survival (OS). Prognostic univariate and multivariate Cox proportional hazard models were developed and assessed. One hundred twenty-six patients with mCRPC treated with a second-line novel ARDT were included. Overall, 50% decline in PSA was observed in 22% of patients and a median PSA-PFS of 2.9 months and a PFS of 3.6 months. After adjusting for potential confounders including prior exposure to docetaxel and number of prior antiandrogen agents, time to development of CRPC was an independent factor associated with PSA-PFS (hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.99-1; P = 0.02) and PFS (HR: 0.99; CI: 0.98-1; P= 0.01). PSA response (50% decline) to first-line novel ARDT correlated negatively with PSA-PFS with second-line novel ARDT (HR: 1.7; 95% CI: 1.14-2.53; P = 0.009) and lower pre-treatment levels of albumin were associated with shorter PFS (HR: 0.56; 95% CI: 0.32-0.97; P = 0.03). Performance status, pre-treatment levels of albumin, extent of disease and time to development CRPC were associated with OS. Second-line ARDT is associated with modest outcomes in patients with mCRPC. Time to development of CRPC is the strongest predictor of PSA response, PSA-PFS and OS which suggest that intrinsic resistance to AR directed treatment is the major treatment outcome factor in these patients. Future studies in patients receiving long term ARTD should include the identification of predictive biomarkers to facilitate treatment selection.

Quo vadis: advanced prostate cancer-clinical care and clinical research in the era of multiple androgen receptor-directed therapies.

The novel androgen receptor-directed therapies abiraterone acetate and enzalutamide, having demonstrated improved survival in randomized phase 3 studies of men with metastatic castration-resistant prostate cancer, have ushered in a new era in the treatment of this disease. Additional novel androgen receptor-directed therapies, such as ARN-509 and orteronel, are in various phases of clinical trials and development. However, the emergence of therapeutic resistance and clinical disease progression is inevitable. Although advances in genomic technologies have led to unprecedented understanding of the biology of castration-resistant prostate cancer, efforts only now are underway to elucidate the mechanisms of resistance associated with abiraterone and enzalutamide. A tremendous challenge in the near future will be to determine the optimal sequence or combination of therapies to overcome resistance mechanisms. In this review, the current landscape of androgen receptor-directed therapies and future directions necessary to enhance their clinical efficacy for the maximal benefit of patients are discussed.

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. We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (≥ 50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models. One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P = 0.089). Median TTPP was 7.2 months (95% CI = 4.5 - 17.2) in the D-naïve group versus 2.6 mo (95% CI = 1.9 - 3.5) in the D-pretreated group (P < 0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI = 2.5 - 4.8) for D-pretreated men (P < 0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR = 2.32; 95% CI = 1.19 - 4.50; P = 0.013) and marginally significant for PFS (HR = 1.90; 95% CI = 0.94 - 3.84; P = 0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n = 34), results suggested a trend towards shorter duration of response in D-pretreated patients. The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents.

The link between androgen receptor splice variants and castration-resistant prostate cancer.

Resistance to the latest advanced prostate cancer therapies, including abiraterone and enzalutamide, is associated with increased expression of constitutively active androgen receptor splice variants (AR-Vs). The exact mechanism by which these therapies result in AR-Vs is unknown, but may include genomic rearrangement of the androgen receptor gene as well as alternative splicing of the AR pre-messenger RNA (mRNA). An additional complication that hinders further development of effective AR strategies is that the mechanisms by which the directed therapies are bypassed may vary. Finally, the question must be addressed as to whether the androgen receptor remains to be the driver of most castration resistant disease or whether truly AR-independent tumors arise after successful androgen ablation therapy. In this review, we will examine androgen receptor splice variants as an alternative mechanism by which prostate cancer becomes resistant to androgen receptor-directed therapy.

The unfolding treatment landscape for men with castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) is a fatal disease in virtually all patients. Docetaxel chemotherapy became the standard front-line agent based on the results of the TAX327 trial in 2004, with a survival advantage of 3 months achieved over mitoxantrone. Over the past few years, an improved understanding of the molecular biology of castration-resistance has resulted in expansion of the treatment armamentarium for advanced prostate cancer with the emergence of novel androgen receptor-directed therapies, cytotoxic chemotherapies, as well as immunotherapies. Four different agents have very recently gained approval by the U.S. Food and Drug Administration for the treatment of CRPC and this review will summarize the development, mechanism of action, and safety and efficacy of these agents as demonstrated in preclinical as well as clinical studies.