In the USA and Europe, prostate cancer (PCa) is the second most common malignancy and second leading cause of cancer mortality among male patients [1]. The proportion of patients with metastatic disease in the US is approximately 3% [2], with higher rates globally [3]. Past 70 years androgen deprivation therapy has been the mainstay options for the treatment of prostate cancer. Initial approach for the management of prostate cancer by androgen deprivation therapy results in a decrease in the concentration of prostate-specific antigen as well as tumor regression and relief of symptoms indicating reactivated androgen receptor symptoms in most patients, but the response to treatment is not durable in patients with advanced cancer, and with time, PSA concentrations increase, indicating reactivated androgen-receptor signaling [4]. Most of the patients with metastatic prostate cancer who initially respond to androgen deprivation therapy or surgical castration eventually progress to castration resistant disease (CRPC).

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

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

Radionuclide therapies play an important role in patients who do not respond to docetaxel chemotherapy and progress with persistently elevated serum prostate specific antigen levels.

The combination of radium-223 dichloride and abiraterone acetate was associated with significant reductions in bone pain, as well as improvements in Quality of life (QOL) in mCRPC 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]-pentanedioic acid also known as PSMA-617 has been synthesized. Preclinical studies have shown ¹⁷⁷Lu-DKFZ-PSMA-617 to have faster blood clearance, lower uptake in liver, high binding affinity and tumour to background ratios, efficient internalization into the prostate cancer cells, early uptake and clearance from the kidney within 24-hours post injection, leading to excellent image quality and effective targeted therapy [24]. PSMA-617 binds to the extracellular domain rather than intracellular of domain of PSMA, thus¹⁷⁷Lu-DKFZ-PSMA-617 can bind to the viable cells and provide an effective target for prostate cancer therapy. Moreover, ¹⁷⁷Lu (Eβmax: 0.5 MeV, t½: 6.7 days) is more suitable for the treatment of smaller lesions and metastases, accompanied by a minimization of kidney dose in comparison to the application of⁹⁰Y labelled 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 in the treatment of mCRPC patients from dosimetric point of view. Clinical studies of have proved ¹⁷⁷Lu-DKFZ-PSMA-617 to be an effective therapeutic target in the treatment of mCRPC [29]. A recent report from our centre proved promising results of ¹⁷⁷Lu-DKFZ-PSMA-617 in the improvement of the overall and progression-free survival [30,31]. Recently, studies have shown the combination of radium-223 dichloride and abiraterone acetate to be associated with significant reduction in the bone pain as well as improvements in the quality of life in patients with metastatic castration resistant prostate cancer [19-23]. However, unlike radium-223 dichloride which is adsorbed only in bone, ¹⁷⁷Lu-DKFZ-PSMA-617 is PSA receptor specific and shows avid uptake in primary, lymph node metastasis and skeletal metastasis as well. Moreover, there are no studies reported till date to demonstrate the efficacy of combined ¹⁷⁷Lu-DKFZ-PSMA-617 and abiraterone acetate therapy in mCRPC patients. As there are no published studies which directly examine this question, we employed a phase II trial to perform a direct comparison of OS for men treated with Abiraterone- ADT to concomitant ¹⁷⁷Lu-DKFZ-PSMA-617 and abiraterone acetate therapy.

 Lacunae in literature and rationale of the current study

Only one RCT has been reported regarding the efficacy of concomitant radium-223 dichloride and abiraterone acetate in mCRPC patients. Although, there is only one study regarding the combined radionuclide and abiraterone acetate therapy, certain drawbacks persist:

1.      Studies using¹⁷⁷Lu –DKFZ-PSMA-617 and abiraterone acetate have not been reported in literature in CRPC are scarce in the literature.

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

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

4.      There is no data of two-armed study comparing only abiraterone acetate versus combined abiraterone acetate + radionuclide therapies.

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