Clinical trial NCT05649943: Multimodal Approach in Patients With mHSPC. Randomized Trial of APA+ADT vs APA-ADT and Local Treatment
Official title: APPROACH : Multimodal Approach in Patients With mHSPC. A Pragmatic Randomized Trial of Apalutamide Plus Androgen Deprivation Therapy (APA-ADT) Versus APA-ADT Plus Local Treatment. A Meet-URO 29 Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
Collaborators: name: ASST Santi Paolo e Carlo
name: European Institute of Oncology
First posted: 2022-12-14
Enrollment: 566
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized
Primary purpose: TREATMENT

Brief summary: Italian multicenter study, will enroll \~566 pts with oligometastatic hormone sensitive prostate cancer who are candidates to receive treatment with apalutamide.

After 6 months from the start of treatment, patients will be randomized to receive local treatment based on the investigator's choice ( either one between primary radiotherapy or cytoreductive prostatectomy), in addition to apalutamide, or to continue just with medical therapy.

Detailed description: Primary end point: To determine whether treatment with apalutamide in combination with androgen-deprivative therapy for 6 months followed by locoregional treatment with radiotherapy or radical prostatectomy has better efficacy than medical treatment with apalutamide + ADT alone in terms of radiographic progression-free survival (rPFS), specifically time to radiographic progression in soft tissue per RECIST 1.1 or in bone per PCWG3 criteria by investigator, or death. Secondary end points: To evaluate tumor shrinkage after locoregional approach and to evaluate short and long term side effects after locoregional surgery or RT, time to PSA progression, time to castration resistance, cancer specific survival, overall survival and quality of life according to EPIC-26 and EQ-5D-5L questionnaires.

Eligibility criteria: Inclusion Criteria:

* Age \> 18
* Histologically confirmed diagnosis of prostate adenocarcinoma
* Metastatic disease documented by ≥1 bone lesion with Technetium 99m (99mTc) bone scan. Individuals with only one bone lesion should have confirmation of that lesion on CT or MRI.
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) Grade ≤ 2
* No previous treatment with antiandrogens or GnRH analogues, or a treatment ≤ 3 months.
* No previous systemic or local treatment for prostate adenocarcinoma, including pelvic radiotherapy.
* Laboratory values at the time of screening:

  a. Neutrophils ≥ 1500/μL b. Hemoglobin ≥ 9.0 mg/μL (no transfusions in the past 28 days) c. Platelets ≥ 100,000/μL d. Creatinine ≤ 2 x upper limit of normal and serum albumin ≥ 3.0 g/dL f. Total bilirubin ≤ 1.5 x upper limit of normal \[NOTE: In subjects with Gilbert syndrome, if total bilirubin is \>1.5 x ULN, measure direct and indirect bilirubin, and if direct bilirubin is ≤ 1.5 x ULN subjects may be eligible\]; g. AST and ALT ≤ 2.5 x upper limit of normal
* Able to swallow Apalutamide tablets whole.
* All subjects must sign an Informed Consent Form indicating that they understand the purpose of the study and its procedures and intend to participate. The subject must be willing and must be able to comply with the restrictions specified in this protocol.

Inclusion criteria for cytoreductive surgery:

* Age \>18 years
* Clinical stage cT3
* Robot-assisted radical prostatectomy with iliac obturator lymphadenectomy
* Surgical piece management criteria similar to Proteus criteria.

Exclusion Criteria:

* Pathologic findings consistent with small cell, ductal, or neuroendocrine prostate cancer.
* Known brain metastases.
* Lymph node metastases only.
* Visceral metastases.
* Patients not eligible for surgery or radiotherapy.
* Unacceptable increase in cardiovascular risk, defined as the occurrence of at least one of the following episodes in the 6 months prior to randomization: unstable angina, myocardial infarction, symptomatic congestive heart failure, clinically significant thromboembolic events (e.g., pulmonary embolism), or clinically significant ventricular arrhythmias .
* Uncontrolled high blood pressure (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg).
* Previous treatment with antiandrogens, GnRH analogues, or other systemic treatments for adenocarcinoma of the prostate.
* Previous local treatment with surgery and/or radiotherapy.
* Any prior malignancy (except adequately treated basal cell carcinoma or a squamous cell skin carcinoma, superficial bladder carcinoma, or any other in situ carcinoma currently in complete remission) within 5 years of randomization.
* Known allergies, hypersensitivity or intolerance to the excipients of Apalutamide.
* Patients who, within 28 days prior to randomisation, have received:

  1. transfusions (red blood cells and/or platelets);
  2. hematopoietic growth factors;
  3. major surgery.
* Symptomatic and/or chronic viral hepatitis; chronic liver disease; moderate or severe liver failure (class B and C according to the Child-Pugh scale); encephalopathy, ascites or thrombo-haemorrhagic disorders secondary to liver failure.
* Gastrointestinal disorders affecting drug absorption
* Active infections requiring systemic therapy such as human immunodeficiency virus (HIV);
* Any condition or situation which, in the judgment of the investigator, precludes participation in this trial.

Exclusion criteria for cytoreductive surgery:

* Contraindication for surgery

Primary outcomes:
measure: Radiographic Progression-Free Survival (rPFS)
timeFrame: Up to 48 months
Secondary outcomes:
measure: Local event - free survival
timeFrame: Up to 48 months
measure: Local treatment - free survival
timeFrame: Up to 48 months
Other outcomes:
Locations:
city: Milano
country: Italy
facility: European Institute of Oncology
state: Lombardia
city: Milano
country: Italy
facility: ASST Santi Paolo e Carlo
state: Lombardia
city: Milan
country: Italy
facility: Istituto Tumori Milano
state: Mi
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: Valentina Guadalupi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juarez Soto A, Merseburger AS, Ozguroglu M, Uemura H, Ye D, Deprince K, Naini V, Li J, Cheng S, Yu MK, Zhang K, Larsen JS, McCarthy S, Chowdhury S; TITAN Investigators. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019 Jul 4;381(1):13-24. doi: 10.1056/NEJMoa1903307. Epub 2019 May 31.
citation: Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, De Porre P, Smith AA, Brookman-May SD, Li S, Zhang K, Rooney B, Lopez-Gitlitz A, Small EJ. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021 Jan;79(1):150-158. doi: 10.1016/j.eururo.2020.08.011. Epub 2020 Sep 6.
citation: Metcalfe MJ, Smaldone MC, Lin DW, Aparicio AM, Chapin BF. Role of radical prostatectomy in metastatic prostate cancer: A review. Urol Oncol. 2017 Apr;35(4):125-134. doi: 10.1016/j.urolonc.2017.01.001. Epub 2017 Feb 9.
citation: Mathieu R, Korn SM, Bensalah K, Kramer G, Shariat SF. Cytoreductive radical prostatectomy in metastatic prostate cancer: Does it really make sense? World J Urol. 2017 Apr;35(4):567-577. doi: 10.1007/s00345-016-1906-3. Epub 2016 Aug 8.
citation: Gravis G, Boher JM, Joly F, Soulie M, Albiges L, Priou F, Latorzeff I, Delva R, Krakowski I, Laguerre B, Rolland F, Theodore C, Deplanque G, Ferrero JM, Culine S, Mourey L, Beuzeboc P, Habibian M, Oudard S, Fizazi K; GETUG. Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol. 2016 Aug;70(2):256-62. doi: 10.1016/j.eururo.2015.11.005. Epub 2015 Nov 21.
citation: Inaba K, Tsuchida K, Kashihara T, Umezawa R, Takahashi K, Okuma K, Murakami N, Ito Y, Igaki H, Sumi M, Nakayama Y, Shinoda Y, Hara T, Matsui Y, Komiyama M, Fujimoto H, Itami J. Treatment results of radiotherapy to both the prostate and metastatic sites in patients with bone metastatic prostate cancer. J Radiat Res. 2021 May 12;62(3):511-516. doi: 10.1093/jrr/rraa056.
citation: Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. J Urol. 2015 Mar;193(3):832-8. doi: 10.1016/j.juro.2014.09.089. Epub 2014 Sep 22.
citation: Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol. 2014 Jun;65(6):1058-66. doi: 10.1016/j.eururo.2013.11.012. Epub 2013 Nov 20.
citation: Sooriakumaran P, Karnes J, Stief C, Copsey B, Montorsi F, Hammerer P, Beyer B, Moschini M, Gratzke C, Steuber T, Suardi N, Briganti A, Manka L, Nyberg T, Dutton SJ, Wiklund P, Graefen M. A Multi-institutional Analysis of Perioperative Outcomes in 106 Men Who Underwent Radical Prostatectomy for Distant Metastatic Prostate Cancer at Presentation. Eur Urol. 2016 May;69(5):788-94. doi: 10.1016/j.eururo.2015.05.023. Epub 2015 May 30.
citation: Gratzke C, Engel J, Stief CG. Role of radical prostatectomy in metastatic prostate cancer: data from the Munich Cancer Registry. Eur Urol. 2014 Sep;66(3):602-3. doi: 10.1016/j.eururo.2014.04.009. Epub 2014 May 10. No abstract available.
citation: Leyh-Bannurah SR, Gazdovich S, Budaus L, Zaffuto E, Briganti A, Abdollah F, Montorsi F, Schiffmann J, Menon M, Shariat SF, Fisch M, Chun F, Steuber T, Huland H, Graefen M, Karakiewicz PI. Local Therapy Improves Survival in Metastatic Prostate Cancer. Eur Urol. 2017 Jul;72(1):118-124. doi: 10.1016/j.eururo.2017.03.020. Epub 2017 Apr 3.
citation: Heidenreich A, Fossati N, Pfister D, Suardi N, Montorsi F, Shariat S, Grubmuller B, Gandaglia G, Briganti A, Karnes RJ. Cytoreductive Radical Prostatectomy in Men with Prostate Cancer and Skeletal Metastases. Eur Urol Oncol. 2018 May;1(1):46-53. doi: 10.1016/j.euo.2018.03.002. Epub 2018 May 15.
citation: Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, Ritchie AWS, Attard G, Chowdhury S, Cross W, Dearnaley DP, Gillessen S, Gilson C, Jones RJ, Langley RE, Malik ZI, Mason MD, Matheson D, Millman R, Russell JM, Thalmann GN, Amos CL, Alonzi R, Bahl A, Birtle A, Din O, Douis H, Eswar C, Gale J, Gannon MR, Jonnada S, Khaksar S, Lester JF, O'Sullivan JM, Parikh OA, Pedley ID, Pudney DM, Sheehan DJ, Srihari NN, Tran ATH, Parmar MKB, Sydes MR; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018 Dec 1;392(10162):2353-2366. doi: 10.1016/S0140-6736(18)32486-3. Epub 2018 Oct 21.
citation: Van den Broeck T, Oprea-Lager D, Moris L, Kailavasan M, Briers E, Cornford P, De Santis M, Gandaglia G, Gillessen Sommer S, Grummet JP, Grivas N, Lam TBL, Lardas M, Liew M, Mason M, O'Hanlon S, Pecanka J, Ploussard G, Rouviere O, Schoots IG, Tilki D, van den Bergh RCN, van der Poel H, Wiegel T, Willemse PP, Yuan CY, Mottet N. A Systematic Review of the Impact of Surgeon and Hospital Caseload Volume on Oncological and Nononcological Outcomes After Radical Prostatectomy for Nonmetastatic Prostate Cancer. Eur Urol. 2021 Nov;80(5):531-545. doi: 10.1016/j.eururo.2021.04.028. Epub 2021 May 5.