Metastatic prostate cancer

 

Prostate cancer

With onset of mets, 5 yr OS is 30%. Therefore delaying metastatic disease is a good surrogate goal.

Metastatic castration sensitive disease

• Corner stone of rx is ADT ( surgical or pharmacological)
• AE of ADT: sexual dysfunction, cardiovascular disease, diabetes, cognitive dysfunction, and decreased mineral bone density.

CHAARTED and STAMPEDE trials: use of docetaxel with ADT as front line Rx

The use of upfront docetaxel was shown to improve overall survival (OS) in patients with mCSPC, especially for men with high-volume disease (presence of visceral metastases and/or ≥ 4 bone metastases with ≥ 1 metastasis not involving the axial skeleton or pelvis). In an updated analysis of the CHAARTED trial, the median OS, the primary end point, was significantly improved in the 513 patients with high-volume disease (hazard ratio [HR], 0.63; 95% CI, 0.50 to 0.79) but not in the 277 patients with low-volume disease.

Metaanalysis of the above 2 trials and GETUG-15-->  addition of docetaxel to ADT reduced all-cause death as compared to ADT alone in the overall population (HR, 0.77) So the docetaxel group has a 77% risk of all cause death compared to ADT alone group.

Main AE: docetaxel group--> higher rate of neuropathy and neutropenia

LALITUDE: Abiraterone

Addition of abiraterone to ADT in patients with newly diagnosed high-risk mCSPC (defined as the presence of ≥ 2 of the following: Gleason score ≥ 8, ≥ 3 bone lesions, or presence of measurable visceral metastasis) was shown to improve OS (HR, 0.66; 95% CI, 0.56 to 0.78) as well as quality of life (QoL) in the LATITUDE trial.

A post hoc analysis of the STAMPEDE trial provided the rationale for using abiraterone in men with mCSPC regardless of risk stratification (OS: HR, 0.54; 95% CI, 0.41 to 0.70; 3-year failure-free survival: HR, 0.31; 95% CI, 0.25 to 0.39).

TITAN: Apalutamide

TITAN enrolled patients with confirmed adenocarcinoma of the prostate and documented distant metastatic disease (i.e. ≥ 1 lesion on bone scanning, with or without visceral or lymph node involvement) who were castration sensitive (i.e. were not receiving ADT at the time of disease progression)

The 2-year OS was 82.4% in the apalutamide group compared with 73.5% in the ADT only group.

48% reduction in the risk of death with apalutamide (HR, 0.52).

ENZAMET and ARCHES: Enzalutamide

 In ENZAMET, 5-year overall survival of 57% (0·53–0·61) in the control group and 67% (0·63–0·70) in the enzalutamide group.

43% received triplet therapy but only 30% completed all 6 cycles of docetaxel in addition to enza. The benefit did not reach statistical significance but the trial was underpowered to detect a benefit. So for now, not recommended. AE was signficantly higher.

ARCHES: Overall survival at 24, 36, and 48 months was 86% vs 82%, 78% vs 69%, and 71% vs 57%

enzalutamide plus ADT significantly reduced the risk of death in patients with metastatic hormone-sensitive prostate cancer by 34% vs placebo plus ADT.

TRIPLET Therapy

ADT+ Docetaxel with abiraterone or darolutamide: PEACE 1 ( Abi), ARASENS( daro). Use in high vol disease per NCCN in those fit for chemo.

PEACE 1- 10% more SE with triplet. Better OS and rPFS in Abiraterone arm. oS HR 0.82

ARANSENS- 12% 4 yr OS benefit ( 62% versus 50% favoring daro at 4 yr) HR 0.68 ( risk of death lower by 32%)

Metastatic castration resistant prostate cancer

1. Abiraterone: docetaxel pretreated patients median OS- 14.8, docetaxel naive median OS 34 m, COU-AA-1 and COU-AA-2 trials
2. Enzalutamide: AFFIRM and PREVAIL for pretreated and naive respectively, median OS 18 months and 32 with enza
3. Cabazitaxel : approx 25 months OS with C20 and C25mg/m2 q 3 weeks FIRSTANA trial, but not superior to docetaxel
4. Docetaxel : TAX 372 median OS 19 months ( versus mitoxantrone)
5. Radium 223: ALSYMPCA mCRPC with symptomatic bone metastases, without evidence of visceral disease and the maximum lymph node diameter of ≤ 3 cm. HR for median OS 0.70.
6. Sip-T: dendritic cell vaccine. Sipuleucel-T is a dendritic cell vaccine prepared from patients' peripheral blood mononuclear cells obtained through leukapheresis. It is approved for the treatment of asymptomatic or minimally symptomatic patients with mCRPC without evidence of visceral disease.
7. Pembrolizumab: high TMB or MSI high ( less than 3% of men with mCRPC) in the third line setting only ( ie similar to Lu-PSMA space but not category 1)
8. 177Lu-PSMA-617 : VISION tria. Approved for progression after taxane and novel AR therapy. Improves median OS. 15 months.patients with more than1 PSMA-positive lesion and/ or metastatic disease that is predominately PSMA-positive and with no dominant PSMA-negative metastatic lesions. 22% of patients in this trial had visceral mets, so this can be used for patients in the third line setting with visceral mets and PSMA positive lesions.
9. Single agent PARP inhibitors: Olaparib: olaparib was approved in May 2020 for patients with mCRPC who previously progressed on enzalutamide or abiraterone and who carry alterations (germline and/or somatic) in any of the following genes: BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D, and RAD54L. 
10. PARP inhibitors with Abiraterone: Olaparib with abiraterone: not yet approved frontline although ProPEL trial showed a rPFS benefit irrespective of HRR status. Niraparib showed a benefit only in HRR patients when given with Abiraterone front line in CRPC.