De novo metastatic castration-sensitive prostate cancer (mCSPC) is small subgroup of prostate cancer associated with poor prognosis. The aim of our study was to assess the expression of programmed ...death-ligand 1 (PD-L1) in tumor cells of de novo mCSPC patients. Patients referred to our institution from January 2007 to October 2017 with de novo mCSPC and available diagnostic tissue were included. We tested the PD-L1 pharmaDx qualitative immunohistochemical assay, a monoclonal rabbit anti-PD-L1, clone 28-8 intended for use in the detection of PD-L1 protein in formalin-fixed paraffin-embedded. Kaplan-Meier method was used to estimate survivals according to the expression of PD-L1. The study population included 32 de novo mCSPC patients, analyzed for PD-L1 expression using 2 cut-off values (1% and 5%) to define the positivity. Total of 46.9% of cases had tumor PD-L1 expression ≥1%, and 31.3% had expression ≥5%. No differences were found between the PD-L1 expression ≥1% and the involvement of liver, lung, and number of bone metastases, and the disease volume based on CHAARTED classification. PD-L1 tumors had higher incidence of Gleason score ≥8 compared with PD-L1 tumors (P=0.037), while the incidence of lymph node metastases was higher in PD-L1 tumors (P=0.044). No difference in the median overall survival (mOS) was observed between the PD-L1 population and the PD-L1 patients (43.8 vs. 29.6 mo; P=0.88). The tumor PD-L1 expression cannot be considered a prognostic factor for de novo mCSPC, even if its prognostic and predictive significance have to be thoroughly investigated to better define the selected group of prostate cancer patients that might benefit from checkpoint blockade immunotherapy.
Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors ...are crucial to improve patients’ counseling and management. The present study aimed to externally validate the prognostic value of a previously developed
red cell-based score
, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the
red cell-based score
and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the
score
and the objective response rate (ORR). The prognostic impact of the
red cell-based score
on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used median PFS (mPFS): 17.4
vs
8.2 months, HR 0.66, 95% CI 0.47–0.94; median OS (mOS): 42.0
vs
17.3 months, HR 0.60, 95% CI 0.39–0.92;
p
< 0.001 for both. We validated the prognostic significance of the
red cell-based score
in patients with mRCC treated with first-line immunotherapy combinations. The
score
is easy to use in daily clinical practice and it might improve patient counselling.
Abstract only
326
Background: Antiangiogenic therapy has been a milestone in the treatment of metastatic renal cell carcinoma (mRCC) for years. The positive results with immune-checkpoint inhibitors ...(ICI) are changing the frontline standard of care of mRCC patients (pts). To date, prospective data are lacking to determine the efficacy of antiangiogenic therapy in pts progressed to ICI. The multikinase inhibitor Cabozantinib (cabo) has shown prolonged survival in pre-treated mRCC pts. Moreover, by targeting multiple pathways and crucial kinases involved in microenvironment-driven immune-escape, it may represent an ideal agent to be used sequentially after ICI. Methods: This is the first prospective open label, single arm, multicenter, phase II study to evaluate efficacy and safety of Cabo in pts with mRCC pre-treated with adjuvant or first line PD-1/PD-L1-based therapy (as monotherapy or in combination with an TKI or anti CTLA-4). Cabo 60 mg once daily was administered until progressive disease (PD) or unacceptable toxicity. The primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Results: Among 23 patients enrolled, 22 were included in the analysis (one was excluded for screening failure). Median age was 59.5 years (range: 29-74), 69.5% were male. At baseline, Karnofsky performance status was 100 in 59% of pts, 80-90 in 31.8% and 70-80 in 9%. 22.7% of pts had a good Heng score, 50% intermediate and 27.2% poor. Median duration of the previous therapy with anti PD-1 or anti-PD-L1 compounds was 4.3 months. Pts received an average of 4.7 months of Cabo. Among evaluable cases, 6 pts (27.2%) achieved a partial response and 5 pts (22.7%) stable disease. The median follow-up was 7.2 months and the median PFS was 7.2 months. 2 pts discontinued treatment for toxicity, 8 pts for PD, 1 patient discontinued treatment for different reason than PD, 11 pts are still on treatment. Grade (G) 3 adverse events (AEs) occurred in 22.7% of pts; the most common AEs were hand and foot syndrome (HFS) (G1 in 36.3% of pts, G2 18.1%, G3 4.5%), diarrhea (G1 31.8%, G2 18.1%), hypothyroidism (G1 9.09 %, G2 22.7 %), mucositis (G1 36.3%, G2 4,5%), and fatigue (G1 18.1%, G2 18.1%). Transitory withholding of cabo was observed in 63.6% of pts (14/22) and it was due to AEs in the 90% of the cases. For 5/22 pts (22.7 %), dose reduction was needed to manage AEs. The most common AEs leading to temporary drug interruption were HFS G1-3 (13.9%), liver disfunction G1-G2 (13.9%), diarrhea G1-G2 (11.6%), nausea and vomiting G2 (11.6 %) and fatigue G2 (9.3%). Conclusions: So far, the treatment with cabo after a I line anti-PD-1 based immunotherapy resulted active and well tolerated. Clinical trial information: NCT03463681 .
The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety ...profile of talazoparib.
Men received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs.
In the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% 62/127), nausea (33.1% 42/127), decreased appetite (28.3% 36/127), and asthenia (23.6% 30/127). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% 15/127) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% 2/127; leukopenia 0.8% 1/127).
Common TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC.
NCT03148795.
In the past few years, the immune checkpoint inhibitor (ICI) nivolumab has become standard of care in the treatment of metastatic renal cell carcinoma (mRCC) progressing after antiangiogenic agents. ...To date, neither expression of programmed death ligand-1 (PD-L1) nor any other biomarker can be used to predict responses to ICIs, although intermediate–poor International Metastatic Database of Renal Carcinoma (IMDC) risk patients and those with sarcomatoid tumors appear to achieve superior benefit from immunotherapy. Paradoxically, ICIs may sometimes increase the speed of tumor growth. This rare phenomenon, called hyperprogression, has first been described in patients with melanoma and lung cancer treated with ICIs and is associated with poor survival. Here, we present the case of a patient affected by an intermediate IMDC risk mRCC with diffuse sarcomatoid features who achieved long disease control with first-line sunitinib and then started a second-line treatment with nivolumab. Unexpectedly, he experienced a dramatic acceleration of tumor growth and died soon after the third infusion of nivolumab. Then, we review the frequency of hyperprogression in mRCC and discuss the biological peculiarity of sarcomatoid RCC in terms of different responses to ICIs and antiangiogenic agents.
12044
Background: Novel anti-androgen hormonal therapies (NAHTs) for advanced prostate cancer (PC) are mainly oral with an overall good toxicity profile and offer the convenience of home ...administration and reduced hospital footfalls. This imposes the burden of self-administration, often unsupervised, on a population of elderly patients overwhelmed by the assumption of many other concomitant medications. Therefore, lack of treatment adherence is becoming an increasingly social and health issue. Methods: In a prospective observational cohort study, metastatic castration-resistant PC (mCRPC) patients aged ≥70 years receiving abiraterone (ABI) or enzalutamide (ENZ) were enrolled in six Italian centres of the Meet-Uro network and monitored for their treatment adherence. Monitoring included pill counting, self-assessment questionnaire and clinical diaries at each clinical visit. Non-adherence rates were based on proportions of missed/prescribed pills ratios by pill counting as an overall estimate or the median of individual values. Results: Overall, 234 pts were recruited (median age: 78 years 73-82, 86 were treated with ABI and 148 with ENZ; 69% of the pts received NAHT in the pre-chemotherapy setting, while 24% in the post-chemo and 6% had the two treatments consecutively. Pts were monitored for adherence for a median time of seven cycles IQR:4-12. The two arms were well balanced for all baseline characteristics, besides steroids use (100% vs 9%, p < 0.001), as ABI requires steroids, and Charlson score, whose range was higher for ENZ pts than ABI pts (range 10-12 vs 8-11, p = 0.028). Overall, the percentage of non-adherence was higher for ABI than ENZ (5.2 vs 4.2 missed/prescribed pills, p < 0.001). After Bonferroni correction, geriatric G8 score correlated with non-adherence (p = 0.004, r = 0.18). Pts on ENZ tended to report missing pills more frequently than ABI pts, and the reason for non-adherence was forgetfulness (42% vs 17%, p < 0.001). A third of pts never completed the clinical diary given at each cycle. Overall survival (OS) within the study was 48.8 months. However, patients on ABI had a longer progression-free survival (PFS) compared to pts treated with ENZ (median PFS 28.4 24.2-32.5 vs 23.1 18.2-28.1 months, p = 0.041). Conclusions: Physicians tend to treat elderly and frailer people with ENZ. mCRPC patients on ENZ are more adherent to treatment, with forgetfulness being a potential barrier. Nevertheless, OS and PFS were consistent with those from ABI and ENZ pre-chemo registration studies, with ABI conferring a longer PFS in our study population.
Purpose
To assess caregivers’ characteristics and influence of the presence or absence of the caregiver on clinical outcomes of older (≥70 years) metastatic castration-resistant prostate cancer ...(mCRPC) patients treated with abiraterone (ABI) or enzalutamide (ENZ).
Methods
Patients from the Meet-URO 5 ADHERE study were assessed with a 5-item caregiver evaluation questionnaire focusing on the presence, age, degree of kinship, working status and qualification of the caregiver. We investigated the association between the presence of a caregiver and the clinical characteristics and outcomes of enrolled patients.
Results
No differences were found in the main clinical characteristics between patients with or without a caregiver, except for a lower median G8 score (
p
= 0.0453) in the caregiver group. A longer radiographic PFS (rPFS) was observed in the group without a caregiver, with a trend towards more prolonged overall survival (OS) in the same group.
Conclusion
Our work suggests a detrimental effect of caregivers in managing older mCRPC patients treated with ABI or ENZ, especially those identified as frail by the geriatric G8 screening score. Further work is needed to identify and address patients’ vulnerability areas, which could have a detrimental effect on prognosis.
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442
Background: Niraparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) enzymes. Based on the association of mutations in homologous recombination repair (HRR) genes with ...platinum sensitivity, aim of this phase II trial was to compare maintenance treatment with niraparib plus BSC vs. BSC alone in pts with advanced UC who obtain objective response (OR) or stable disease (SD) with first-line PBCT. Methods: Meet-URO12 is a randomized phase II multicentre trial enrolling pts with advanced transitional cell UC, without evidence of progression after 4-6 cycles of first-line PBCT (cisplatin or carboplatin). Pts were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone). Primary endpoint was progression-free survival (PFS). 77 pts were planned and 65 PFS events were needed to detect Hazard Ratio 0.57, with 80% power and one-tailed alpha 0.1. Accrual was prematurely stopped due to availability of avelumab in the same setting, and protocol was amended to perform analysis with ≥ 40 PFS events. Molecular characteristics, including alteration of HRR genes, were assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay. Results: Between Aug 2019 and Mar 2021, 58 pts were randomized in 14 Italian centers (39 assigned to arm A and 19 to arm B); 1 pt assigned to arm A did never start niraparib. Median age was 69y (44-84); ECOG PS0 65.5%/ PS1 34.5%; best response with PBCT OR 55.2%/ SD 44.8%. As of Aug 2021, after a median follow-up of 8.5 mos, 47 PFS events were recorded. Median PFS was 2.1 mos in arm A and 2.4 mos in arm B (HR 0.92; 95%CI 0.49 – 1.75, p=0.81). 6-months progression-free rate was 28.2% and 26.3%, respectively. Time to treatment failure for pts who started niraparib was 2.4 mos. Out of 47 pts with molecular info, 21 (44.7%) had HRR alterations: 6 (12.8%) known pathogenic mutations and 15 (31.9%) variants of unknown significance. In pts with pathogenic mutations, median PFS was 2.0 mos in arm A and 1.9 mos in arm B. In pts with any HRR mutation, median PFS was 2.0 mos in arm A and 2.0 mos in arm B. Any grade≥3 treatment-emergent adverse event (AE) was reported in 25/38 pts (65.8%) in arm A and in 3/19 pts (15.8%) in arm B. 18/38 pts (47.4%) needed dose reduction of niraparib. Most common AEs with niraparib were anemia (50.0%, G3 10.5%), thrombocytopenia (36.8%, G3-4 15.8%), neutropenia (21.1%, G3 5.3%), fatigue (31.6%, G3 15.8%), constipation (31.6%, G3 2.6%), mucositis (13.2%, G3 2.6%), nausea (13.2%, G3 2.6%). Conclusions: Maintenance niraparib plus BSC did not prolong PFS, as compared with BSC alone, among pts with urothelial cancer without progression after first-line PBCT. Clinicaltrials.gov Identifier. NCT03945084. Clinical trial information: NCT03945084.
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290
Background: Second (2L) or third-line (3L) treatment options for mRCC have dramatically changed in the last years. The standard of care as per Italian Regulatory Agencies approvals ...is N or C. To date, there are no criteria for the choice between N and C, which both demonstrated OS gain in the pivotal trials. Methods: We planned a retrospective, real world analysis of the use of N and C as 2L and 3L treatment in 17 Oncology Units of Veneto Region. All consecutive patients (pts) with mRCC treated in advanced setting in 2017-2018 were included. Results: We identified 170 pts, 73% males, median age 68.4 years. All pts started a 2L treatment while only 59% received a 3L treatment. In our cohort, patients with NLR > 3 at treatment start had a shorter OS (43 vs 90 months (mos), p < 0.0001); IMDC classification maintained its prognostic role. In 2L, N was administrated in 108 pts (63%), C in 29 pts (17%); in 3L N was administrated in 42 pts (25%), C in 49 pts (29%). Reported oncologists’ reasons for 2L choice were: change of mechanism of action compared to first line (28%), response to previous TKI (21.2%), intolerance to TKI (17.6%), previous toxicity (12.9%), tumor burden (11.2%), age of the patient (4.1%). Median OS and PFS in 2L were 28.4 and 6.6 mos for N, 16.8 and 6.6 mos for 2L C. Median OS and PFS in 3L were 27 and 5.2 mos for N, 16.6 and 7.5 mos for C. 46 pts received the sequence of drugs N > C, 12 the opposite sequence C > N. Median OS for N > C vs C > N were 96.6 vs 36 mos (p > 0.0001); median PFS for both the sequences were similar at 5.7 mos (p = ns). The cost per patient of the sequence N > C is 51.606 € while for the sequence C > N is 31.480,00 €. Between the two sequences a cost effectiveness per month of survival analysis was performed: the cost per month of OS for the sequence N > C was 534,18 € while for the sequence C > N was 874,46 €, heavily higher. Conclusions: In our real-world setting cohort, most of the pts received N as 2L treatment and a minority received C. Outcome of single drug are superimposable to published literature. With the limits of the retrospective nature of the study, with a cost per month of OS lower a much longer OS, the sequence N > C appear to be a better treatment strategy.
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5047
Background: PARP inhibitors have recently been approved for the treatment of mCRPC. In this Phase 2 study, we explore the safety profile of TALA in men with mCRPC with the aim of ...understanding how patients (pts) with adverse events (AEs) were managed during the trial. Methods: TALAPRO-1 (NCT03148795) is a single-arm, open-label, phase 2 study of TALA in pts with progressive mCRPC, measurable soft tissue disease, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received ≥1 taxane-based chemotherapy and progressed on ≥1 novel hormonal therapy (enzalutamide/abiraterone). The primary objective was confirmed objective response by central independent review; the assessment of safety included AEs, incidence of dose modifications and of permanent treatment discontinuation due to AEs, and clinical laboratory tests. Results: In the TALA-treated population (1 mg/daily; n=127), 95.3% (121/127) experienced all-causality AEs. The most common (≥15%) hematologic AEs were anemia (any grade, 48.8%; G3, 30.7% no G4 events), thrombocytopenia (all grade, 18.9%; G3/4, 8.7%), and neutropenia (all grade, 16.5%, G3, 7.9% no G4). Median time from first dose of TALA to onset of first episode of G≥3 anemia, neutropenia, and thrombocytopenia was 56, 48, and 17 days, respectively. G3 anemia lasted a median of 7 days, G3 neutropenia lasted a median of 12 days, G3 and G4 thrombocytopenia lasted a median of 8 and 11 days, respectively. Hematologic AEs typically occurred during the first 4–5 months of TALA treatment and were managed by dose modifications and supportive care. 34.6% of pts received a blood transfusion product, and most transfusions occurred when hemoglobin was between 7.0–10.0 g/dL. Overlapping G3/4 hematologic AEs were infrequent on TALA (anemia + neutropenia 4.7%; anemia + thrombocytopenia 5.5%; neutropenia + thrombocytopenia 1.6%). In pts who had anemia, 12.6% also had fatigue; in those with thrombocytopenia, 4.7% had a subsequent bleeding event; in those with neutropenia, 1.6% had an overlapping infection. The most common non-hematologic AEs (≥15%) were nausea (any grade, 33.1%; G3/4, 2.4%), decreased appetite (any grade, 28.3%; G3/4, 3.1%), and asthenia/fatigue (any grade, 23.6%/19.7%; G3/4, 3.9%/1.6%). In the treated population, dose reduction of TALA due to all-causality AE occurred in 33 pts (26.0%). Treatment discontinuation due to all-causality AEs was low and occurred in 15 pts (11.8%); the most frequent (≥2 pts) AEs leading to discontinuation of TALA were back pain and platelet count decrease (each, 1.6% 2/127 pts). There were no treatment-related deaths. Conclusions: A manageable safety profile and durable antitumor effects were observed with TALA in men with heavily pretreated mCRPC in this phase 2 study. Clinical trial information: NCT03148795.
