THERAPEUTIC EFFICACY OF ABIRATERONE ACETATE VERSUS CONCOMITANT 177LU-DKFZ-PSMA-617 AND ABIRATERONE ACETATE THERAPY IN PATIENTS WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER: OPEN LABEL, TWO-ARM, PHASE II TRIAL

In the USA andEurope, prostate cancer (PCa) is the second most common malignancy and secondleading cause of cancer mortality among male patients [1]. The proportion ofpatients with metastatic disease in the US is approximately 3% [2], with higherrates globally [3]. Past 70 years androgen deprivation therapy has been themainstay options for the treatment of prostate cancer. Initial approach for themanagement of prostate cancer by androgen deprivation therapy results in adecrease in the concentration of prostate-specific antigen as well as tumorregression and relief of symptoms indicating reactivated androgen receptorsymptoms in most patients, but the response to treatment is not durable inpatients with advanced cancer, and with time, PSA concentrations increase,indicating reactivated androgen-receptor signaling [4]. Most of the patientswith metastatic prostate cancer who initially respond to androgen deprivationtherapy or surgical castration eventually progress to castration resistantdisease (CRPC).

Metastatic castrationresistant prostate cancer (mCRPC) is defined as disease progression despiteandrogen suppression therapy. 10-20% of prostate cancer cases progress to mCRPC[5]. 90% of mCRPC patients present with bone metastases causing pain, stressfractures and morbidity [6].

Docetaxelchemotherapy has historically been utilized in the CRPC setting following tworandomized clinical trials (RCTs) demonstrating improved overall survival (OS)when compared with mitoxantrone plus prednisone [7,8]. Similarly, abirateroneacetate, an inhibitor of cyto-chrome P-450c17, which is critical for androgenbiosynthe-sis [9,10], demonstrated improved OS in the CRPC setting, bothpredocetaxel [11,12] and postdocetaxel treatment [13,14].  Recently, a number of RCTs have demonstratedthat the addition of either docetaxel [15-17] or abiraterone [18] to ADTimproves OS in men with hormone-naïve metastatic PCa, compared with ADT alone.

Radionuclidetherapies play an important role in patients who do not respond to docetaxelchemotherapy and progress with persistently elevated serum prostate specificantigen levels.

The combination ofradium-223 dichloride and abiraterone acetate was associated with significantreductions in bone pain, as well as improvements in Quality of life (QOL) inmCRPC patients [19-23]. Recently, a urea based motif of 2-[3-(1-Carboxy-5-{3-naphthalen-2-yl-2-[(4-{[2-(4,7,10-tris-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl)-acetylamino]-methyl}-cyclohexanecarbonyl)-amino]-propionylamino}-pentyl)-ureido]-pentanedioicacid also known as PSMA-617 has been synthesized. Preclinical studies haveshown 177Lu-DKFZ-PSMA-617 to have faster blood clearance, loweruptake in liver, high binding affinity and tumour to background ratios,efficient internalization into the prostate cancer cells, early uptake andclearance from the kidney within 24-hours post injection, leading to excellentimage quality and effective targeted therapy [24]. PSMA-617 binds to theextracellular domain rather than intracellular of domain of PSMA, thus177Lu-DKFZ-PSMA-617can bind to the viable cells and provide an effective target for prostatecancer therapy. Moreover, 177Lu (Eβmax: 0.5 MeV, t½: 6.7 days) ismore suitable for the treatment of smaller lesions and metastases, accompaniedby a minimization of kidney dose in comparison to the application of90Ylabelled peptides [25]. Secondly, due to beta and gamma emission of 177Lu,dosimetry and imaging is possible (26). Two studies by Kabasakal et al. [27]and Delker et al. [28] reported 177Lu-DKFZ-PSMA-617 to be safe inthe treatment of mCRPC patients from dosimetric point of view. Clinical studiesof have proved 177Lu-DKFZ-PSMA-617 to be an effective therapeutictarget in the treatment of mCRPC [29]. A recent report from our centre provedpromising results of 177Lu-DKFZ-PSMA-617 in the improvement of theoverall and progression-free survival [30,31]. Recently, studies have shown thecombination of radium-223 dichloride and abiraterone acetate to be associatedwith significant reduction in the bone pain as well as improvements in thequality of life in patients with metastatic castration resistant prostatecancer [19-23]. However, unlike radium-223 dichloride which is adsorbed only inbone, 177Lu-DKFZ-PSMA-617 is PSA receptor specific and shows aviduptake in primary, lymph node metastasis and skeletal metastasis as well.Moreover, there are no studies reported till date to demonstrate the efficacyof combined 177Lu-DKFZ-PSMA-617 and abiraterone acetate therapy inmCRPC patients. As there are no published studies which directly examine thisquestion, we employed a phase II trial to perform a direct comparison of OS formen treated with Abiraterone- ADT to concomitant 177Lu-DKFZ-PSMA-617and abiraterone acetate therapy.

Lacunae in literature and rationale of the current study

Only one RCT has beenreported regarding the efficacy of concomitant radium-223 dichloride andabiraterone acetate in mCRPC patients. Although, there is only one studyregarding the combined radionuclide and abiraterone acetate therapy, certaindrawbacks persist:

1.     Studies using177Lu –DKFZ-PSMA-617 and abirateroneacetate have not been reported in literature in CRPC are scarce in theliterature.

2.     Radium-223 dichloride for bone pain treatment is an alphaemitter and is not available in India.

3.     Radium-223 dichloride is absorbed only in bone and can onlybe used to treat bone pain in skeletal metastases.

4.     There is no data of two-armed study comparing onlyabiraterone acetate versus combined abiraterone acetate + radionuclidetherapies.

177Lucl3 is produced inthe nuclear reactor, readily available and procured from BRIT, BARC,Mumbai. Moreover, unlike radium-223 dichloride, 177Lu-DKFZ-PSMA-617 is a highly specificradiopharmaceutical showing avidity in primary tumor site, lymph node, softtissue lesions and skeletal metastasis as well. Thus, the present study is directed to compare the efficacy of abirateroneacetate therapy and concomitant therapy in mCRPC patients