Timing of docetaxel chemotherapy and impact on outcomes in metastatic castrate-resistant prostate cancer (MCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 298-298
Author(s):  
Alastair Thomson ◽  
Adam Pollard ◽  
Frances May Mark
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Single Agent ◽  
Specific Antigen ◽  
Response Rates ◽  
Treated Group ◽  
Patient Choice ◽  
Gleason Grade ◽  
Psa Response ◽  
Number Of Cycles

298 Background: Docetaxel use has led to a significant prolongation in overall survival (OS) in metastatic prostate cancer after castrate resistance, with a more substantial OS gain when used in combination with initial androgen deprivation therapy (ADT). There is however limited information on outcomes in patients who initially do not receive chemotherapy, perhaps through patient choice or impaired performance status, who become suitable for docetaxel, comparing earlier with later docetaxel treatment. Methods: We retrospectively reviewed patients’ electronic clinical and prescribing records diagnosed with MCRPC and treated with docetaxel from 01/01/2006 to 24/11/2016 in a single centre in the UK. Data was reviewed for number of individual treatments received pre and post chemotherapy, including initial ADT, enzalutamide, abiraterone, docetaxel, cabazitaxel, mitoxantrone, radium 223, single agent steroids and diethylstilboestrol. Prostate specific antigen (PSA) response, number of cycles and dosing of docetaxel and OS were also reviewed. Results: 168 consecutive patients with MCRPC receiving docetaxel were reviewed. Median Gleason grade across the three groups was 8. 48 patients (29%) received docetaxel after 1 or 2 previous treatments, 105 (63%) after 3 or 4 previous treatments and 15 (9%) after 5 or 6. PSA response rates were superior in the earlier treated group (61%, p=0.003), compared with 30% and 31% respectively in the later groups. Median number of cycles was 5.5 overall, with a mean weighted dose received of 396mg/m2, 373mg/m2 and 301mg/m2 in the after 1 or 2 treatments, after 3 or 4 treatments and after 5 or 6 treatment groups. Median OS from castrate resistance for the earlier group was 29 months, not significantly less (p=0.1) than the 35 months for an intermediate number of prior treatments and 42 months for the later treated group. Conclusions: In this group of patients in routine clinical practice who do not receive docetaxel with initial ADT, PSA response rates are significantly improved and overall dose received is higher with subsequent earlier use. However, overall survival is not significantly different between the early and later docetaxel treated patients.

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castrate-sensitive prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 117-117
Author(s):  
Mary Mahler ◽  
Esmail Mutahar Al-Ezzi ◽  
Noa Shani Shrem ◽  
Eric Winquist ◽  
Christina M. Canil ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
Median Time ◽  
Median Number ◽  
Time To Progression ◽  
Chemohormonal Therapy ◽  
Radium 223 ◽  
Psa Response ◽  
Number Of Cycles

117 Background: Since docetaxel has been advanced to the metastatic castrate-sensitive prostate cancer (mCSPC) setting, there is a lack of evidence guiding its re-introduction upon castrate-resistant (CR) progression. We sought to identify clinical characteristics and outcomes of patients subjected to docetaxel rechallenge (DR) following prior docetaxel exposure in the mCSPC realm. Methods: Patients rechallenged with docetaxel following treatment in the mCSPC setting were identified from three academic centres in Ontario, Canada. Retrospective chart reviews were performed to identify clinical, treatment and outcome variables. Results: Of the 45 patients with DR initiated between 06/2015 and 07/2020, the median age was 65, 60% had a Gleason score of ≥8, and 64% had an ECOG of ≤1. 56% had bone only metastasis, 4% lymph node only metastasis, 29% bone and lymph node metastasis, and 11% had visceral metastasis. In the mCSPC setting, 98% of patients received 6 cycles of docetaxel with 13% requiring dose delays. Of 43 informative patients, all had a PSA response to chemohormonal therapy. 91% achieved at least a 50% PSA response (PSA50), of which 40% had a 50-89% PSA reduction and 51% had a ≥90% PSA reduction. 29% of patients obtained a PSA nadir of < 0.2 ng/mL. 16% had CR progression in < 6 months, 56% in 6-12 months, and 28% in > 12 months. DR was initiated after a median of 20.8 months (range 6.0-40.4) following the last dose of docetaxel for mCSPC, and was given as first line treatment for CR disease to 7%, second line to 51%, third line to 40%, and fourth line or beyond to 2% of patients. 69% of patients had received an androgen-receptor axis targeted therapy prior to DR, 18% radium 223, and 7% had received a trial drug. Notably, no patients had received cabazitaxel prior to DR. The median number of cycles of docetaxel received at rechallenge was 5 (range 1-11) with 18% of patients requiring treatment delays. 64% of patients stopped treatment due to progression, 16% due to side effects, 7% at the patient’s request, 7% due to completion of the planned number of cycles, and 6% due to death or other causes. Among 44 informative patients, 23% achieved at least a PSA50, with 18% having a 50-90% PSA reduction, and 5% having a ≥90% PSA reduction. The median time to progression (biochemical, radiographic, or death) was 2.3 months (95%CI 1.7-4.4) and the median overall survival was 11.0 months (95%CI 8.5-14.3). Conclusions: DR following exposure to docetaxel in the mCSPC setting resulted in a PSA50 in only around one quarter of patients. Both the median time to progression and overall survival were found to be short. With future investigations, we hope to identify clinical variables that will help predict which patients might benefit most from DR.

scholarly journals CDK12-Mutated Prostate Cancer: Clinical Outcomes With Standard Therapies and Immune Checkpoint Blockade

2020 ◽  
pp. 382-392 ◽  
Author(s):  
Michael T. Schweizer ◽  
Gavin Ha ◽  
Roman Gulati ◽  
Landon C. Brown ◽  
Rana R. McKay ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
High Rate ◽  
Gleason Grade ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Grade Group ◽  
Distinct Subgroup

PURPOSE Translational studies have shown that CDK12 mutations may delineate an immunoresponsive subgroup of prostate cancer, characterized by high neo-antigen burden. Given that these mutations may define a clinically distinct subgroup, we sought to describe outcomes to standard drugs and checkpoint inhibitors (CPI). PATIENTS AND METHODS Clinical data from consecutive patients with CDK12 mutations were retrospectively collected from 7 centers. Several clinical-grade sequencing assays were used to assess CDK12 status. Descriptive statistics included PSA50 response rate (≥ 50% decline in prostate-specific antigen from baseline) and clinical/radiographic progression-free survival (PFS). RESULTS Of 52 patients with CDK12-mutated prostate cancer, 27 (52%) had detected biallelic CDK12 alterations. At diagnosis, 44 (88%) had Gleason grade group 4-5, 52% had T3-T4, and 14 (27%) had M1 disease. Median follow-up was 8.2 years (95% CI, 5.6 to 11.1 years), and 49 (94%) developed metastatic disease. Median overall survival from metastasis was 3.9 years (95% CI, 3.2 to 8.1 years). Unconfirmed PSA50 response rates to abiraterone and enzalutamide in the first-line castration-resistant prostate cancer setting were 11 of 17 (65%) and 9 of 12 (75%), respectively. Median PFS on first-line abiraterone and enzalutamide was short, at 8.2 months (95% CI, 6.6 to 12.6 months) and 10.6 months (95% CI, 10.2 months to not reached), respectively. Nineteen patients received CPI therapy. PSA50 responses to CPI were noted in 11%, and PFS was short; however, the estimated 9-month PFS was 23%. PFS was higher in chemotherapy-naïve versus chemotherapy-pretreated patients (median PFS: not reached v 2.1 months, P = .004). CONCLUSION CDK12 mutations define an aggressive prostate cancer subgroup, with a high rate of metastases and short overall survival. CPI may be effective in a minority of these patients, and exploratory analysis supports using anti–programmed cell death protein 1 drugs early. Prospective studies testing CPI in this subset of patients with prostate cancer are warranted.

Docetaxel in older patients for metastatic prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 187-187 ◽  
Author(s):  
Frances May Mark ◽  
Adam Pollard ◽  
Alastair H Thomson
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Clinical Practice ◽  
Metastatic Prostate Cancer ◽  
Age Groups ◽  
Response Rates ◽  
Routine Clinical Practice ◽  
Age Group ◽  
Psa Response ◽  
Castrate Resistant

187 Background: Docetaxel use has led to a significant prolongation in overall survival in metastatic prostate cancer (MPC). There is however limited information on treatment tolerance and outcomes in patients 80 years old and over in routine clinical practice. With the ever aging population it is becoming more important to assess outcomes in this age group. Methods: Patients diagnosed with MPC and treated with docetaxel from 2006 to 2016 were identified and their records retrospectively reviewed via electronic clinical and prescribing systems in a single centre in the UK. Data was assessed for prostate specific antigen (PSA) response, number of cycles and dosing of docetaxel and castrate resistant overall survival (OS). Results: 209 consecutive patients with MPC receiving docetaxel were reviewed. Three patient groups were identified; younger than 75 years old (n = 150, 37 early (as part of initial therapy) docetaxel), 75-79 years (n = 40, 2 early docetaxel) and 80 years or over (n = 19, no early docetaxel). When comparing mean OS excluding early docetaxel treatment, respective mean survival times for each of the three age groups, younger to older were 1001, 1045 and 1294 days, with between class difference being insignificant. The PSA response rates to docetaxel excluding first line use were compared between the age groups and did not show a significant difference at 39% in the youngest group, 38% in the intermediate age group and 42% for the oldest patients. There was a trend that the older the patient, the more likely docetaxel was the final systemic treatment given at 42% (80 years or over), 32% (75-79 years) and 23% (younger than 75 years). The 80 years or over group received fewer docetaxel cycles (3.8, p = 0.006) and less dose per course (226mg/m2, p = 0.004) than the group less than 75 years (5.8 cycles, 409mg/m2) and 75-79 years (5.1 cycles, 341mg/m2). Conclusions: In this group of patients, in routine clinical practice, the 80 years and over age group received fewer cycles of docetaxel in MPC and less dose per course, but nevertheless achieved similar PSA response rates and castrate resistant OS. Given these results, docetaxel should be considered as a treatment option in suitable patients of 80 years and over.

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).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 80-80
Author(s):  
Wassim Abida ◽  
Akash Patnaik ◽  
David Campbell ◽  
Jeremy David Shapiro ◽  
Alan Haruo Bryce ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Response Rate ◽  
Objective Response ◽  
Specific Antigen ◽  
Response Rates ◽  
Clinical Activity ◽  
Plasma Samples ◽  
Tp53 Mutations ◽  
Measurable Disease ◽  
Psa Response

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]

Effectiveness of abiraterone as salvage therapy in patients with docetaxel- and castration-resistant prostate cancer (mDCPC) that progressed during second-line chemotherapy with carboplatin plus weekly docetaxel (DC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 162-162
Author(s):  
Christoph W. Reuter ◽  
Michael A. Morgan ◽  
Martin Fenner ◽  
Viktor Grünwald ◽  
Arnold Ganser
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Disease Progression ◽  
Salvage Therapy ◽  
Specific Antigen ◽  
Free Testosterone ◽  
Serum Levels ◽  
Castration Resistant Prostate Cancer ◽  
Psa Response ◽  
The Impact

162 Background: Our recent data have shown that carboplatin AUC5 on d1 plus docetaxel at a dose of 35 mg/m2 iv on d1, 8, 15 every 4 weeks (q4w) is an effective salvage therapy in mDRPC. Patients (pts) who have progressive disease during DC treatment survive only ~7 months and many are symptomatic. We have demonstrated that high free testosterone (FT) serum levels during DC treatment have a negative prognostic value for PSA response and overall survival in these pts. In this study the impact of abiraterone treatment and other subsequent salvage regimens after DC failure was analyzed. Methods: DC failure was defined as disease progression during DC treatment according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 74 consecutive DRPC pts were treated with at least 2 cycles DC until disease progression. At the time of the current analysis 67 pts have progressed and 41 pts received one or more subsequent therapies (1-3). Results: Overall survival (OS) of all 67 pts who have progressed during DC treatment was 7.1 months (CI 95% 1.8, 12.3). 41 pts received subsequent salvage therapies including mitoxantrone-prednisone-etoposide (MPE) (n=10), cabazitaxel (n=10), docetaxel-oxaliplatin (n=8), abiraterone (n=15) and doxorubicin-ketokonazol (n=5). OS of these 41 pts was 14.6 months (CI 95% 11.0, 18.3).In pts receiving abiraterone as salvage treatment, OS after DC was 21.8 months (CI 95% 7.2, 36.5) versus 11.9 months (CI 95% 9.0, 14.8) in pts receiving other regimens (HR 0.302, CI 95% 0.11, 0.8; p=0.016). Responses of prostate-specific antigen (PSAR; ≥30% and ≥50%) were only observed in pts receiving abiraterone (8/15, 53.3% and 4/15, 26.7%, respectively). Conclusions: Our data demonstrate for the first time that testosterone is an important prognostic factor for PSA response and OS in mDRPC patients receiving DC chemotherapy and that targeting testosterone after DC failure prolongs post-DC survival.

Circulating microRNAs associated with docetaxel-resistant castration resistant prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 44-44
Author(s):  
Lisa Horvath ◽  
Hui-Ming Lin ◽  
Lesley Castillo ◽  
Kate Lynette Mahon ◽  
Karen Chiam ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Specific Antigen ◽  
Family Members ◽  
Response To Therapy ◽  
Circulating Microrna ◽  
Castration Resistant Prostate Cancer ◽  
Circulating Micrornas ◽  
Castration Resistant ◽  
Psa Response

44 Background: Despite a range of new treatments, docetaxel (DTX) remains the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, only 50% of patients respond to docetaxel at the cost of potentially significant toxicity. Therefore, there is a need for new biomarkers to identify early response to therapy. This study aims to determine if circulating microRNAs are associated with DTX chemotherapy outcome in CRPC. Methods: Global microRNA profiling was performed on DTX-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards measured the levels of 46 candidate microRNAs in plasma/serum from 97 CRPC patients, collected pre- and three weeks post-cycle one of DTX. Responses were defined by the PCWG1 serum prostate-specific antigen (PSA) response criteria; partial response (PR), stable disease (SD), progressive disease (PD). Multiple T-test, Mann-Whitney U, Kaplan-Meier, Receiver Operating Characteristic (ROC), and Cox regression analyses were used to assess the associations between microRNA levels and clinical outcomes. Results: Eighteen microRNAs were associated with PSA response or overall survival (p<0.05). DTX non-responders (PD+SD) and patients with shorter survival had high pre-DTX levels of miR-200 family members (miR-200a, miR-200b, miR-200c, miR-429; p<0.05), or decreased/unchanged post-DTX levels of miR-17 family members (miR-19b, miR-20a, miR-20b; p<0.05). The combined levels of miR-20a, miR-146a, miR-200b, miR-200c, miR-222, and miR-301b predicted PSA response (ROC AUC 0.74, 95% CI 0.64-0.84). Pre-DTX miR-200a levels (HR 3.0, 95%CI 1.6-5.8; p=0.001) and post-DTX change in miR-20a (HR 3.4, 95%CI 1.8-6.3; p=0.0002) were independent predictors of overall survival when modeled with hemoglobin levels (HR 2.6, 95%CI 1.4-5.1; p=0.02), PSA response (HR 2.1, 95%CI 1.1-3.9; p=0.03), and visceral metastases (HR 2.0, 95%CI 1.1-3.5; p=0.03). Conclusions: Circulating microRNAs are potential early predictors of DTX chemotherapy outcome and may be useful in stratifying patients in future clinical trials. These microRNAs may also be involved in DTX resistance and represent potential therapeutic targets.

Abiraterone acetate plus prednisone (AAP) in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) and prior diethylstilbestrol (DES) therapy: Preliminary results.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 235-235
Author(s):  
Diogo Assed Bastos ◽  
Marcos Tobias Machado ◽  
Renato Panhoca ◽  
Giovani Thomaz Pioner ◽  
Gustavo Werutsky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Group Performance ◽  
Performance Status ◽  
Prospective Trial ◽  
Eastern Cooperative Oncology Group ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Psa Response

235 Background: AAP is approved for patients with chemotherapy-naïve mCRPC, but the population with previous use of DES was not studied before. DES is a commonly used hormone therapy for mCRPC in second and plus lines, especially in developing countries, due to lack of access to novel and efficacious therapies. The objective of this trial is to describe the efficacy and safety of AAP after DES treatment in patients who are chemotherapy-naïve, potentially affecting chemotherapy onset. This is the first and only prospective trial to show this data. Methods: This phase 2 multicenter, open-label single-arm study evaluated 46 patients receiving AA (1000 mg daily) + low-dose prednisone (P; 10 mg daily) and androgen deprivation therapy in patients with DES–refractory mCRPC enrolled from Oct 2014 to Oct 2015. The primary efficacy endpoint was time to prostate-specific antigen progression (PSAP) by Prostate Cancer Working Group (PCWG2) criteria. Secondary endpoints included PSA response (≥50% reduction), overall survival, and safety. Results: At baseline, median age was 69 years, median PSA was 40 ng/mL, there were no visceral metastases, 98% of patients had Eastern Cooperative Oncology Group Performance Status 0-1, and 44% had Gleason scores ≥7. Thirty two subjects (71.1%) had PSAP. PSA response was achieved by 47% of patients at week 12 and 56% at any time. Three patients remain on study drug and 4 are in follow-up. AA treatment continued until PSAP, clinical progression, consent withdrawal, or unacceptable toxicity. The median duration of study treatment was 8.6 months. The median time to PSAP was 7.4 months (95% CI = 5.6-9.4) and the median overall survival was 25.6 months (95% CI = 15.7-NE). Treatment-related adverse events included hypertension (19.6%), hyperglycemia (19.6%), fatigue (17.4%), and hypokalemia (4.5%); most grade 1-2. Conclusions: The present study confirmed that AAP provides PSA responses even in heavily treated patients, showing clinical benefit post-DES in chemotherapy-naive mCRPC patients. It also confirmed tolerability of AAP, with an easily manageable toxicity profile. Clinical trial information: NCT02217566.

scholarly journals CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors

2020 ◽  
pp. 370-381 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Pedro Isaacsson Velho ◽  
Wei Fu ◽  
Hao Wang ◽  
Neeraj Agarwal ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Features ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Gleason Grade ◽  
Castration Resistant Prostate Cancer ◽  
Loss Of Function ◽  
Therapeutic Outcomes ◽  
Psa Response ◽  
Systemic Therapies

PURPOSE In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12-aberrant prostate cancers. METHODS We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors. RESULTS Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.

Weekly High-Dose Calcitriol and Docetaxel in Metastatic Androgen-Independent Prostate Cancer

2003 ◽  
Vol 21 (1) ◽  
pp. 123-128 ◽  
Author(s):  
Tomasz M. Beer ◽  
Kristine M. Eilers ◽  
Mark Garzotto ◽  
Merrill J. Egorin ◽  
Bruce A. Lowe ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Single Agent ◽  
Specific Antigen ◽  
High Dose ◽  
Time To Progression ◽  
Oral Hydration ◽  
Phase Ii Studies ◽  
Measurable Disease ◽  
Psa Response ◽  
Androgen Independent

Purpose: To determine the safety and efficacy of weekly high-dose oral calcitriol (Rocaltrol, Roche Pharmaceuticals, Basel, Switzerland) and docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) in patients with metastatic androgen-independent prostate cancer (AIPC).Patients and Methods: Thirty-seven patients were treated with oral calcitriol (0.5 μg/kg) on day 1 followed by docetaxel (36 mg/m2) on day 2, repeated weekly for 6 weeks of an 8-week cycle. Patients maintained a reduced calcium diet and increased oral hydration. Prostate-specific antigen (PSA) response was the primary end point, which was defined as a 50% reduction in PSA level confirmed 4 weeks later.Results: Thirty of 37 patients (81%; 95% confidence interval [CI], 68% to 94%) achieved a PSA response. Twenty-two patients (59%; 95% CI, 43% to 75%) had a confirmed > 75% reduction in PSA. Eight of the 15 patients with measurable disease (53%; 95% CI, 27% to 79%) had a confirmed partial response. Median time to progression was 11.4 months (95% CI, 8.7 to 14 months), and median survival was 19.5 months (95% CI, 15.3 months to incalculable). Overall survival at 1 year was 89% (95% CI, 74% to 95%). Treatment-related toxicity was generally similar to that expected with single-agent docetaxel. Pharmacokinetics of either calcitriol or docetaxel were not affected by the presence of its companion drug in an exploratory substudy.Conclusion: The combination of weekly oral high-dose calcitriol and weekly docetaxel is a well-tolerated regimen for AIPC. PSA and measurable disease response rates as well as time to progression and survival are promising when compared with contemporary phase II studies of single-agent docetaxel in AIPC. Further study of this regimen is warranted.

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