Peter H. J. Slootbeek 1 , Marleen L. Duizer 1 , Maarten J. van der Doelen 1 , 2 , Iris S. H. Kloots 1 , Malou C. P. Kuppen 3 , Hans M. Westgeest 4 , Carin A. Uyl‐de Groot 3 , Samhita Pamidimarri Naga 1 , 5 , Marjolijn J. L. Ligtenberg 5 , 6 , Inge M. van Oort 2 , Winald R. Gerritsen 1 , Jack A. Schalken 7 , Leonie I. Kroeze 6 , Haiko J. Bloemendal 1 , Niven Mehra , 1
03 October 2020
Platinum‐based chemotherapy is not standard of care for unselected or genetically selected metastatic castration‐resistant prostate cancer (mCRPC) patients. A retrospective assessment of 71 patients was performed on platinum use in the Netherlands. Genetically unselected patients yielded low response rates. For a predefined subanalysis of all patients with comprehensive next‐generation sequencing, 30 patients were grouped based on the presence of pathogenic aberrations in genes associated with DNA damage repair (DDR) or aggressive variant prostate cancer (AVPC). Fourteen patients (47%) were DDR deficient (DDRd), of which seven with inactivated BRCA2 (BRCA2mut). Six patients classified as AVPC. DDRd patients showed beneficial biochemical response to carboplatin, largely driven by all BRCA2mut patients having >50% prostate‐specific antigen (PSA) decline and objective radiographic response. In the wild‐type BRCA2 subgroup, 35% had a >50% PSA decline ( P = .006) and 16% radiographic response ( P < .001). Median overall survival was 21 months for BRCA2mut patients vs 7 months ( P = .041) for those with functional BRCA2. AVPC patients demonstrated comparable responses to non‐AVPC, including a similar overall survival, despite the poor prognosis for this subgroup. In the scope of the registration of poly‐(ADP)‐ribose polymerase inhibitors (PARPi) for mCRPC, we provide initial insights on cross‐resistance between PARPi and platinum compounds. By combining the literature and our study, we identified 18 patients who received both agents. In this cohort, only BRCA2mut patients treated with platinum first (n = 4), responded to both agents. We confirm that BRCA2 inactivation is associated with meaningful responses to carboplatin, suggesting a role for both PARPi and platinum‐based chemotherapy in preselected mCRPC patients.
Platinum‐based chemotherapy is not standard of care for unselected or genetically‐selected patients with metastatic castration‐resistant prostate cancer (mCRPC). However, several studies have shown that platinum‐based chemotherapy may still have a role in postponing progression in selected patient groups. This new study investigating DNA damage repair gene alterations and response to platinum‐based chemotherapy provides evidence that deep and durable responses are primarily associated with patients harbouring BRCA2 inactivation. Based on these data and the limited available literature, platinum‐based chemotherapy followed by PARP inhibition is potentially emerging as the optimal treatment sequence in pre‐selected mCRPC patients.