Antoine Angelergues

Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer

BACKGROUND A prostate-specific antigen (PSA) flare occurs in about 15% of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. This flare has no standard definition. Its impact on treatment efficacy is unclear. We sought to evaluate the incidence and characteristics of PSA flare on cabazitaxel, and its impact on survival. METHODS Multicentre retrospective review of consecutive patients treated with cabazitaxel second-line chemotherapy for mCRPC. Collection of baseline characteristics, disease history and PSA levels before and during cabazitaxel therapy. Overall survival (OS) and radiological/clinical progression-free survival (PFS) for patient groups corresponding to different definitions of PSA flare estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS Overall, 125 patients were included. Median PFS and OS were 6.5 and 13.3 months, respectively. Depending upon the definition used, flare incidence ranged from 8.3% to 30.6%. The flare lasted <2.6 months. A PSA flare followed by a ⩾ 50% decrease was associated with a median PFS and OS of 11.2 and 25.2 months, respectively. Median PFS and OS for a ⩾ 30% rather than ⩾ 5 0% decrease were 10.4 and 16.5 months. These outcomes were not significantly different from those in patients with immediate PSA decreases of ⩾ 50% or ⩾ 30% from baseline, but were significantly better than in patients experiencing no PSA decrease (p = 0.006 and 0.015, respectively, for OS). CONCLUSION The PSA response to cabazitaxel, with or without initial flare, was associated with a strong survival benefit. The taxane-induced flare during the first 12 weeks of therapy can be ignored when evaluating PSA response.

Efficacy of cabazitaxel and its relationship with predictors of poor response to second hormonal therapies (2d HT) in metastatic castration-resistant prostate cancer (mCRPC).

137 Background: Potential predictors of low response to 2d HT including new agents have been recently identified: high Gleason score, rapid progression with first androgen deprivation therapy (ADT), chemotherapy lines >1 and low baseline testosterone (T) levels. We evaluated the influence of these factors on the efficacy of cabazitaxel (C), a new taxane developed to overcome docetaxel (D) resistance. METHODS Records of 84 consecutive mCRPC pts (median 67 yrs) treated with C for disease progression on D or after D were retrospectively collected in 8 French centers. Baseline characteristics, disease history, PSA response, overall survival (OS) and radiological or clinical progression-free survival (PFS) were collected. RESULTS At C initiation, 84% of pts were ECOG 0-1, 59% had pain and 24% received ≥2 prior chemotherapy lines. Metastases were located in bone (93%), lymph nodes (49%) and visceral/soft tissues (9%). Gleason score was 8-10 in 47%, median time to progression with first ADT was 20 months and median T was 0.1 ng/ml. Median number of C cycles received was 6 (range 2-14). Efficacy of C was not influenced by Gleason score, response duration to first ADT, prior number of chemo lines, or baseline T (table). Main grade ≥ 3 toxicities were neutropenia (32%), anaemia (17%), thrombocytopenia (8%), diarrhoea (6%), and febrile neutropenia (5%). There was no grade ≥3 peripheral neuropathy and no toxic death. CONCLUSIONS This retrospective study suggests that C is effective and shows an acceptable safety profile. Efficacy was not influenced by predictors of poor response to 2d HT (high Gleason, short response to first ADT, Number of chemo lines, low T levels). If these results are confirmed in further investigations, cabazitaxel could be proposed whatever the baseline characteristics of mCRPC pts. [Table: see text].

Retrospective registry evaluating the PSA flare phenomenon with cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC).

122 Background: PSA initial flare followed by a decrease is documented in up to 18% of mCRPC patients (pts) treated with docetaxel (D). There is no standard definition of this phenomenon, and its significance in terms of treatment efficacy and prognosis remains unclear. We evaluated the PSA flare incidence and characteristics with cabazitaxel (C), a new taxane developed to overcome D resistance, and its impact on outcome. METHODS A retrospective review of 84 consecutive pts (median 67 yrs) treated with C for mCRPC progressing during or after D was conducted in 8 French centers. Baseline characteristics, disease history, PSA values before and during C, overall survival (OS) and radiological or clinical progression-free survival (PFS) were collected. RESULTS At C initiation, most pts (84%) were ECOG 0-1, 59.5% had pain and 23.8% received ≥2 chemotherapy lines. Metastases were located in bone (92.9%), lymph nodes (48.8%) and visceral/soft tissues (9.5%). Median number of C cycles was 6 (range 2-14). Median OS and PFS from first C cycle were 16.4 and 6.7 months, respectively. Flare incidence, PFS and OS varied with the definition used (table). Definition [3] seems to us the most clinically relevant, and showed a close estimate of PFS compared to pts with immediate PSA decrease from baseline. We recommend to use this definition in clinical practice. CONCLUSIONS PSA flare occurred in 16% pts treated with C and was associated with as good outcome as immediate responders. C should not be withdrawn prematurely in case of isolated initial PSA rise. This finding supports the PCWG 2 recommendation that early rise (prior to 12 weeks) with cytotoxics should be ignored in determining PSA response. [Table: see text].

Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer

To evaluate the safety and efficacy of a 2‐weekly cabazitaxel schedule in patients with metastatic castration‐resistant prostate cancer (mCRPC).

Prostate cancer: Cabazitaxel—the taxane of choice in the new mCRPC landscape?

Cabazitaxel, a next-generation taxane, retains its efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress on new androgen receptor (AR)-targeted agents such as abiraterone acetate or enzalutamide. These findings are reinforced by in vitro preclinical data confirming cross-resistance between abiraterone and enzalutamide, but not between cabazitaxel and AR-targeted agents.

Human and murine prostate basal/stem cells are not direct targets of prolactin

Local overexpression of prolactin (PRL) in the prostate of Pb-PRL transgenic mice induces benign prostate tumors exhibiting marked amplification of the epithelial basal/stem cell compartment. However, PRL-activated intracellular signaling seems to be restricted to luminal cells, suggesting that basal/stem cells may not be direct targets of PRL. Given their described role as prostate cancer-initiating cells, it is important to understand the mechanisms that regulate basal/stem cells. In this study, we evaluated whether PRL can act directly on these cells, by growing them as prostaspheres. For this, primary 3D prostasphere cultures were prepared from unfractionated cells isolated from freshly harvested human and mouse benign prostate tissues and subjected to PRL stimulation in vitro. None of the various concentrations of PRL tested showed any effects on the sizes or numbers of the prostaspheres generated. In addition, neither activation of canonical PRL-induced signaling pathways (Stat5, Stat3 or Erk1/2) nor increased expression of the proliferation marker Ki-67 were detected by immunostaining in PRL-stimulated prostaspheres. Consistent with the absence of response, PRL receptor mRNA levels were generally undetectable in mouse sphere cells. We conclude that human and mouse prostate basal/stem cells are not direct targets of PRL action. The observed amplification of basal/stem cells in Pb-PRL prostates might be due to paracrine mechanisms originating from PRL action on other cell compartments. Our current efforts are aimed at unraveling these mechanisms.

Immunothérapie dans les cancers de la prostate

IMMUNOTHERAPY IN URO-ONCOLOGY Immunotherapy is moving forward in prostate cancer. The autologous vaccine, Sipuleucel-T has been the first vaccine to be approved by FDA. First results with GVAX, tasquinimob or anti-PD-1 have been disappointing. Ipilimumab seen to be more active at an earlier stage of prostate disease. Identifying predictive factor or surrogate markers of activity of immunotherapy and which agents are clinically effective alone or in combination with others therapies such as hormonal or bone targeted therapies are warranted.

Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel, Cabazitaxel, and Androgen Receptor-Targeted Agents

Micro‐Abstract Several agents have demonstrated an overall survival (OS) benefit in metastatic castration‐resistant prostate cancer (mCRPC); however, optimal sequencing is unknown. Retrospective analysis of data from 574 mCRPC patients showed increasing OS with the number of therapies provided; a sequence including docetaxel, cabazitaxel (CABA), and an androgen receptor–targeted agent (ART) provided the greatest benefit. Prior administration of ART did not appear to influence CABA activity. These findings will help guide treatment decisions in daily practice. Background: Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration‐resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor–targeted agents (ART) after androgen‐deprivation therapy (ADT) and docetaxel (DOC). Patients and Methods: Records of 574 consecutive patients treated (2012−2016) at 44 centers in 6 countries were retrospectively examined. Results: A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate‐specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA. Conclusion: OS appeared to increase with the number of life‐extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.

789PPROGNOSTIC FACTORS FOR SURVIVAL AND SEQUENCING OF LIFE-EXTENDING THERAPIES IN METASTATIC CASTRATION RESISTANT PROSTATE CANCER (MCRPC) PATIENTS (PTS) IN POST-DOCETAXEL (D) SETTING

ABSTRACT Aim: Background: Abiraterone (A), Cabazitaxel (C), enzalutamide (E) are able to prolong overall survival (OS) in mCRPC post-D. Optimal sequencing of these agents is not known. In this large retrospective cohort of mCRPC pts treated with C, we evaluated the impact of prognostic factors and sequencing on OS calculated from the first therapy post-D. Methods: Methods: Records of 246 consecutive mCRPC pts (median age 68 y, Gleason ≥8 at diagnosis 49.6%) who were treated with C (after D) were retrospectively collected in 25 centers (France, Spain, Turkey). Disease history, treatment with A/E before or after C, clinical characteristics at initiation of first therapy post-D (A/E or C) were collected. The influence of selected variables and sequencing with A/E on OS was analyzed by multivariate logistic regression. Results: Results: At initiation of first therapy post-D, 86.0% of pts were ECOG 0-1, 61.4% had pain, 63.1% had radiological progression and 47.5% had clinical progression. 17.0% of pts had visceral mets. Median duration of response to first androgen deprivation therapy was 20.3 months (mo). All pts received C (median 6 cycles, range 2-28), mainly after 1 line D (75.4%). A/E were given before C in 24.8% or after C in 17.5%. With C, a PSA decrease of ≥50% and ≥30% was reached in 40.8% and 52.9% of pts. Median clinical and/or radiological PFS was 8 mo. Median OS was 13.5 mo when C was used without A/E,28.9 mo if patients subsequently received A/E and 22.4 mo if A/E were administered before C. In multivariate analysis, OS was significantly reduced in pts with visceral mets (HR [95% CI]: 1.92 [1.19-3.11]) and in those with pain at initiation of first therapy post-D (1.51 [1.05-2.18]). Conversely, OS was significantly prolonged in pts having received 2 active therapies (C and A/E) post-D, with a greater OS benefit when A/E was given after C (0.34 [0.21-0.56]) instead of before C (0.57 [0.39-0.85]). Conclusions: Conclusions: With the limitation of retrospective design,pts receiving D, C and A/E had a significantly prolonged OS versus those receiving only D and C,which stresses the needs for maximize OS with all available treatment options. Greatest OS benefit was observed in pts receiving D → C → A/E. Disclosure: S. Oudard: Consultant or AdvisoryRole; Entity: Sanofi, Novartis, Roche, Bayer, Keocyt, Amgen, Relationship: Myself, compensation: Compensated, Honoraria, Entity: Sanofi, Novartis, Roche, Bayer, Keocyt, Amgen, Pfizer, Relationship: Myself; A. Angelergues: Honoraria: Entity: Sanofi-Aventis, Relationship: Myself; A. Flechon: Honoraria: Entity: Sanofi-Aventis, Astellas, Janssen, Ferring, Relationship: Myself; M. Ozguroglu: Consultant or AdvisoryRole, Entity: Sanofi-Aventis, Janssen, Astellas, Relationship: Myself, Compensation: Compensated; J. Bellmunt: Consultant or AdvisoryRole - Sanofi Honoraria - Sanofi ResearchFunding - Sanofi; All other authors have declared no conflicts of interest.